Atlas of Genetics and Cytogenetics in Oncology and Haematology

Transcription

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and
educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
Staff
Mohammad Ahmad, Mélanie Arsaban, Houa Delabrousse, Marie-Christine Jacquemot-Perbal, Maureen Labarussias,
Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain
Zasadzinski.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year
by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French
National Center for Scientific Research (INIST-CNRS) since 2008.
The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Editor
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee
Alessandro Beghini
Anne von Bergh
Judith Bovée
Vasantha Brito-Babapulle
Charles Buys
Anne Marie Capodano
Fei Chen
Antonio Cuneo
Paola Dal Cin
Louis Dallaire
Brigitte Debuire
François Desangles
Enric Domingo-Villanueva
Ayse Erson
Richard Gatti
Ad Geurts van Kessel
Oskar Haas
Anne Hagemeijer
Nyla Heerema
Jim Heighway
Sakari Knuutila
Lidia Larizza
Lisa Lee-Jones
Edmond Ma
Roderick McLeod
Cristina Mecucci
Yasmin Mehraein
Fredrik Mertens
Konstantin Miller
Felix Mitelman
Hossain Mossafa
Stefan Nagel
Florence Pedeutour
Elizabeth Petty
Susana Raimondi
Mariano Rocchi
Alain Sarasin
Albert Schinzel
Clelia Storlazzi
Sabine Strehl
Nancy Uhrhammer
Dan Van Dyke
Roberta Vanni
Franck Viguié
José Luis Vizmanos
Thomas Wan
(Ankara, Turkey)
(Milan, Italy)
(Rotterdam, The Netherlands)
(Leiden, The Netherlands)
(London, UK)
(Groningen, The Netherlands)
(Marseille, France)
(Morgantown, West Virginia)
(Ferrara, Italy)
(Boston, Massachussetts)
(Montreal, Canada)
(Villejuif, France)
(Paris, France)
(London, UK)
(Ankara, Turkey)
(Los Angeles, California)
(Nijmegen, The Netherlands)
(Vienna, Austria)
(Leuven, Belgium)
(Colombus, Ohio)
(Liverpool, UK)
(Helsinki, Finland)
(Milano, Italy)
(Newcastle, UK)
(Hong Kong, China)
(Braunschweig, Germany)
(Perugia, Italy)
(Homburg, Germany)
(Lund, Sweden)
(Hannover, Germany)
(Lund, Sweden)
(Cergy Pontoise, France)
(Braunschweig, Germany)
(Nice, France)
(Ann Harbor, Michigan)
(Memphis, Tennesse)
(Bari, Italy)
(Villejuif, France)
(Schwerzenbach, Switzerland)
(Bari, Italy)
(Vienna, Austria)
(Clermont Ferrand, France)
(Rochester, Minnesota)
(Montserrato, Italy)
(Paris, France)
(Pamplona, Spain)
(Hong Kong, China)
Solid Tumours Section
Genes Section
Genes / Leukaemia Sections
Leukaemia Section
Deep Insights Section
Genes / Deep Insights Sections
Leukaemia Section
Genes / Solid Tumours Section
Education Section
Leukaemia / Solid Tumours Sections
Cancer-Prone Diseases / Deep Insights Sections
Cancer-Prone Diseases Section
Leukaemia Section
Genes / Deep Insights Sections
Leukaemia Section
Deep Insights / Education Sections
Education Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Solid Tumours Sections
Genes / Leukaemia Section
Genes Section
Education Section
Genes Section
Genes / Cancer-Prone Diseases Sections
Education Section
Leukaemia Section
Leukaemia Section
Volume 14, Number 12, December 2010
Table of contents
Gene Section
CKS2 (CDC28 protein kinase regulatory subunit 2)
Yongyou Zhang
1100
CRTC2 (CREB regulated transcription coactivator 2)
Kristy A Brown, Nirukshi Samarageewa
1104
IL22RA1 (interleukin 22 receptor, alpha 1)
Pascal Gelebart, Raymond Lai
1106
MAPK7 (mitogen-activated protein kinase 7)
Francisco de Asís Iñesta-Vaquera, Ana Cuenda
1111
SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1))
Céline Pinheiro, Fátima Baltazar
1115
STOML2 (stomatin (EPB72)-like 2)
Wenfeng Cao, Liyong Zhang, Fang Ding, Zhumei Cui, Zhihua Liu
1118
AMOT (angiomotin)
Roshan Mandrawalia, Ranjan Tamuli
1121
BRCA2 (breast cancer 2, early onset)
Frédéric Guénard, Francine Durocher
1124
FST (follistatin)
Michael Grusch
1132
GATA6 (GATA binding protein 6)
Rosalyn M Adam, Joshua R Mauney
1136
HIPK2 (homeodomain interacting protein kinase 2)
Dirk Sombroek, Thomas G Hofmann
1141
RAD9A (RAD9 homolog A (S. pombe))
Vivian Chan
1145
SCAF1 (SR-related CTD-associated factor 1)
Christos Kontos, Andreas Scorilas
1149
SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae))
Ruo-Chia Tseng, Yi-Ching Wang
1152
1157
SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding))
Asli Sade, Sreeparna Banerjee
1160
TMPRSS2 (transmembrane protease, serine 2)
Youngwoo Park
1163
TMSB10 (thymosin beta 10)
Xueshan Qiu
1166
t(11;14)(q13;q32)
in multiple myeloma
Atlas
of Genetics
and Cytogenetics
Huret JL, Laï JL
TYMP (thymidine phosphorylase)
Irene V Bijnsdorp, Godefridus J Peters
1170
Leukaemia Section
der(6)t(1;6)(q21-23;p21)
Adriana Zamecnikova
1175
ins(9;4)(q33;q12q25)
Jean-Loup Huret
1177
Solid Tumour Section
t(19;22)(q13;q12) in myoepithelial carcinoma
Jean-Loup Huret
1179
Deep Insight Section
Glutathione S-Transferase pi (GSTP1)
Isabelle Meiers
1181
The roles of SRA1 gene in breast cancer
Yi Yan, Charlton Cooper, Etienne Leygue
1186
Gene Section
Review
Yongyou Zhang
Case Western Reserve University, WRB-3101, 2103 Cornell Rd, Cleveland, OH 44106, USA (YZ)
Published in Atlas Database: February 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/CKS2ID40093ch9q22.html
DOI: 10.4267/2042/44906
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Description
Identity
The open reading frame encodes a 79 amino acid
protein, with an estimated molecular weight of
approximately 9860 Da.
Other names: CKSHS2
HGNC (Hugo): CKS2
Location: 9q22.2
Note: There is no evidence that CKS2 gene has
different transcript variant.
Expression
Basic level expression in all mammalian cells and
aberrant expression in cancer cells.
Localisation
DNA/RNA
Cytoplasm and nucleus.
Function
Transcription
CKS2 protein binds to the catalytic subunit of the
cyclin-dependent kinases and is essential for their
biological function of cell cycle control. Especially,
CKS2 is required for the first metaphase/anaphase
transition of mammalian meiosis. The mice ablated of
Cks2 are viable but sterile in both sexes. Sterility is due
to failure of both male and female germ cells to
progress from the first meiotic metaphase to anaphase.
In cancer cells, CKS2 may protect the cells from
apoptosis.
mRNA is 627 bp.
Homology
Pseudogene
The CKS2 protein is evolutionary conserved.
Mammalian cells express two well-conserved CKS
members, like the human CKS2 and CKS1B proteins.
CKS2 and CKS1B may have redundant function in
some context and have different functions in other
context. The CKS2 protein is highly conserved cross
species.
Genomic organization of the CKS2 gene.
Description
Three exons, spans approximately 5.5 kb of genomic
DNA in the centromere-to-telomere orientation. The
translation initiation codon ATG is located in exon 1,
and the stop codon in exon 3.
1 processed, non-expressed, pseudogene in human
genome.
Protein
Note
The Cks2 protein can form a special homohexamer
structure. Six kinase subunits can bind the assembled
hexamer, and therefore this Cks2 hexamer may
participate in cell cycle control by acting as the hub for
Cdk multimerization in vivo.
Mutations
Note
Mutation of glutamine for glutamate 63 (E63Q),
1100
Zhang Y
disrupted the essential biological function of the protein
and significantly reduced its ability to bind to cyclindependent kinases, but preserves protein structure and
assembly.
(Wiese et al., 2007). CKS2 was also showed to be
higher in liver metastasis compared with primary colon
cancer (Lin et al., 2007).
Oncogenesis
Amplification and overexpression of CKS2 were
associated with liver metastasis and poor prognosis in
colon cancer. CKS2 is required for germ cell to go past
the first meiotic metaphase and enter anaphase. In
cancer cell, overexpression of CKS2 can accelerate the
cell cycles and promote the cell proliferation. Recently
research showed that CKS2 may also be involved in
apoptosis and metabolism since it can protect
mitochondrial genome integrity via interaction with
mitochondrial single-stranded DNA-binding protein.
Study also showed CKS2 as a transcriptional target
downregulated by the tumor suppressor p53. CKS2
expression was found to be repressed by p53 both at the
mRNA and the protein levels, which may provide a
mechanism that explain why CKS2 is upregulated in
many types of cancer. All of these suggest that CKS2
alterations may have a significant biological role in the
tumorigenesis in different tissue. The novel therapeutic
strategy for cancer though may be developed via
inhibiting the CKS2 activity. Therefore, disruption of
CKS2-Cyclin Complex assembly or down-regulation of
CKS2 expression may be used for cancer therapy.
Implicated in
Various cancers
Note
Emerging evidence showed that the expression of
CKS2 is elevated in multiple cancers, including
prostate cancer, breast cancer, gastric cancer, colorectal
cancer, uterine cervical cancer, bladder cancer,
nasopharyngeal carcinoma, melanoma, lymphoma,
lung cancer, esophageal squamous cell carcinoma et al.
The expression of CKS2 is correlated with poor
survival rate of the patients of some cancers.
Prognosis
Overexpression of CKS2 has been reported to be
associated with high aggressiveness and a poor
prognosis in multiple cancers, including breast cancer,
prostate cancer, colon cancer, hepatocellular carcinoma
and meningiomas et al.
Hepatocellular carcinoma (HCC)
Note
Expressions of CKS2 were significantly higher in HCC
compared with the adjacent noncancerous tissues
(including chronic hepatitis and cirrhosis) and normal
liver tissues. Overexpression of CKS2 in HCC were
closely associated with poor differentiation features
(Shen et al., 2010).
Esophageal squamous cell carcinoma
Note
Gene expression profiling of lymph node metastasis by
oligomicroarray analysis and Real-time RT-PCR
confirmed that CKS2 is unregulated in laser
microdissection of esophageal squamous cell
carcinoma compared with adjacent normal tissue
(Uchikado et al., 2006).
Gastric cancer
Note
CKS2 was showed to be significantly unregulated in
gastric cancers. The high level of CKS2 was highly
correlated with tumor differentiation and pathological
grade of the tumor size, lymph node, and metastasis
stage (Kang et al., 2009).
Uterine cervical cancer
Note
CKS2 was showed significantly higher in node positive
tumor compared with negative one. The CKS2
expression is correlated with metastatic phenotypes and
progression free survival. (Lyng et al., 2006).
Prostate cancer
Note
CKS2 were significantly unregulated in prostate tumors
of human and animal models, as well as prostatic
cancer cell lines. Forced expression of CKS2 in benign
prostate tumor epithelial cells promoted cell population
growth. Inhibition of CKS2 expression can induce
programmed cell death and inhibit the tumorigenesis.
(Lan et al., 2008). Over expression of CKS2 may
linked with androgen-independent prostate cancer
progression (Stanbrough et al., 2006).
Bladder cancer
Note
Large-scale gene expression profiling and Real-Time
RT-PCR confirmed that a the CKS2 expression is
elevated in invasive bladder cancer compared with
superficial cancer (Kawakami et al., 2006).
Glioblastoma
Note
CKS2 was significantly up-regulated in primary
glioblastomas compared with the non-neoplastic brain
tissues (Scrideli et al., 2008).
Colon cancer
Note
CKS2 was reported significantly overexpressed in
microdissected invasive colon tumor cells compared
with adjacent normal epithelial cells
Meningioma
Note
This microarray-based expression profiling study
1101
Zhang Y
bladder cancer through genome-wide gene
profiling. Oncol Rep. 2006 Sep;16(3):521-31
showed CKS2 is unregulated in atypical and anaplastic
meningiomas compared with benign meningiomas
(Fevre-Montange et al., 2009).
Lyng H, Brøvig RS, Svendsrud DH, Holm R, Kaalhus O,
Knutstad K, Oksefjell H, Sundfør K, Kristensen GB, Stokke T.
Gene expressions and copy numbers associated with
metastatic phenotypes of uterine cervical cancer. BMC
Genomics. 2006 Oct 20;7:268
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Thomassen M, Kerndrup GB, Rasmussen T. Myeloma cell
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Identification of differentially expressed genes in human
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Honnorat J, Guyotat J, Jouvet A. Microarray gene expression
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This article should be referenced as such:
Zhang Y. CKS2 (CDC28 protein kinase regulatory subunit 2).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11001103.
Miller WR. Clinical, pathological, proliferative and molecular
responses associated with neoadjuvant aromatase inhibitor
1103
Gene Section
Mini Review
Kristy A Brown, Nirukshi Samarageewa
Prince Henry's Institute, Clayton, Victoria, 3168, Australia (KAB, NS)
Online updated version : http://AtlasGeneticsOncology.org/Genes/CRTC2ID50581ch1q21.html
DOI: 10.4267/2042/44907
localisation sequence (NLS) at amino acids 56-144 as
well as two nuclear export sequences (NES1 and
NES2) within the region of amino acids 145-320.
Identity
Other names: TORC2, RP11-422P24.6
HGNC (Hugo): CRTC2
Location: 1q21.3
Function
Transcriptional coactivator for CREB (cAMPresponsive element binding protein).The highly
conserved N-terminal coiled-coil domain of the CRTC2
interacts with the bZip domain of CREB which
activates both consensus and variant cAMP response
element (CRE) sites, leading to activation of CREB
target gene expression. CRTC2 responds to stimulation
by cAMP, calcium, fasting hormones, G proteincoupled receptors, and AMPK/SIKs.
DNA/RNA
Description
10,893 bases; on minus strand.
Includes 14 exons.
Transcription
Transcript measures 2598 bp with a 2082 bp coding
sequence.
Implicated in
Protein
Peutz-Jeghers syndrome
Description
Note
Peutz-Jeghers syndrome (PJS) is an autosomaldominant genetic disorder that is characterised by an
increased risk of developing malignant tumours. Most
of the identified mutations in the LKB1 gene are
localised to the catalytic kinase domain so that it is
thought that PJS results from loss of LKB1 kinase
activity. The silencing of LKB1, leads to the decreased
activity of AMPK and SIK and leads to the increased
nuclear translocation and activity of CRTC2.
Disease
Gastrointestinal polyps and cancers including
esophagus, stomach, small intestine, colon, pancreas,
lung, testes, breast, uterus, ovary and cervix.
693 amino acids; 73,302 Da.
Expression
Particularly abundant in B and T lymphocytes. Higher
levels were also seen in muscle, lung, spleen, ovary and
breast. Lower expressions found in brain, colon, heart,
kidney, prostate, small intestine and stomach, with
significantly lowest expression in liver and pancreas.
Localisation
Phosphorylation
of
CRTC2
triggers
the
phosphorylation-dependent binding to 14-3-3 proteins,
and hence sequestration of CRTC2 in the cytosol
thereby preventing its nuclear translocation and the
activation of CREB. Proteins known to phosphorylate
CRTC2 at Ser171 include AMP-
Oestrogen-receptor (ER) positive breast
cancer
Note
The increased prevalence of oestrogen-dependent,
postmenopausal breast cancers is correlated with
activated protein kinase (AMPK) and the salt-inducible
kinases (SIKs). Dephosphorylated CRTC2 readily
translocates to the nucleus. CRTC2 contains a nuclear
1104
Brown KA, Samarageewa N
Okamoto M, Montminy M. The CREB coactivator TORC2
functions as a calcium- and cAMP-sensitive coincidence
detector. Cell. 2004 Oct 1;119(1):61-74
elevated local levels of oestrogens as a result of an
increase in cytochrome P450 aromatase expression
within the adipose stromal (hAS) cells surrounding the
breast tumour - aromatase is the enzyme responsible for
the conversion of androgens to oestrogens. This is
governed by promoter switching from the distal
promoter I.4 to the proximal promoter PII on the
CYP19A1 gene, that encodes aromatase, in response to
factors derived from the tumour such as prostaglandin
E2 (PGE2). Interestingly, the LKB1/ AMPK pathway
has been shown to inhibit aromatase expression via the
cytoplasmic sequestration of CRTC2. However, PGE2
inhibits LKB1/AMPK signaling, leading to the nuclear
translocation of CRTC2 and its enhanced binding and
activation of aromatase promoter PII in hAS cells.
Furthermore, the adipokine leptin, produced at higher
levels in obesity, has been shown to cause an increase
in CRTC2 nuclear translocation and consequently, in
aromatase expression.
Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent
signaling pathways. Annu Rev Biochem. 2006;75:137-63
Katoh Y, Takemori H, Lin XZ, Tamura M, Muraoka M, Satoh T,
Tsuchiya Y, Min L, Doi J, Miyauchi A, Witters LA, Nakamura H,
Okamoto M. Silencing the constitutive active transcription
factor CREB by the LKB1-SIK signaling cascade. FEBS J.
2006 Jun;273(12):2730-48
Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol.
2006 Dec;18(6):598-608
Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS,
Bare O, Labow M, Spiegelman B, Stevenson SC. Transducer
of regulated CREB-binding proteins (TORCs) induce PGC1alpha transcription and mitochondrial biogenesis in muscle
cells. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):1437984
Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR,
Simpson ER. Subcellular localization of cyclic AMP-responsive
element binding protein-regulated transcription coactivator 2
provides a link between obesity and breast cancer in
postmenopausal women. Cancer Res. 2009 Jul 1;69(13):53929
References
Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia
L, Hogenesch JB, Montminy M. TORCs: transducers of
regulated CREB activity. Mol Cell. 2003 Aug;12(2):413-23
Brown KA, Simpson ER. Obesity and breast cancer: progress
to understanding the relationship. Cancer Res. 2010 Jan
1;70(1):4-7
Sofi M, Young MJ, Papamakarios T, Simpson ER, Clyne CD.
Role of CRE-binding protein (CREB) in aromatase expression
in breast adipose. Breast Cancer Res Treat. 2003
Jun;79(3):399-407
Brown KA, Samarageewa N. CRTC2 (CREB regulated
transcription coactivator 2). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(12):1104-1105.
Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G,
Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H,
1105
Gene Section
Mini Review
Pascal Gelebart, Raymond Lai
Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta,
Edmonton, Alberta, Canada (PG, RL)
Online updated version : http://AtlasGeneticsOncology.org/Genes/IL22RA1ID44568ch1p36.html
DOI: 10.4267/2042/44908
Identity
nucleotides, encoding a protein of 594 amino acid
residues.
Other names: CRF2-9, IL22R, IL22R1
HGNC (Hugo): IL22RA1
Location: 1p36.11
Pseudogene
None.
Protein
DNA/RNA
Description
Description
IL22RA1 is composed of 574 amino acid residues, and
the predicted molecular weight of the immature protein
is 63 kDa. IL22RA1 protein is composed of six
putative domains, including the signal peptide (residue
1 to 15), the extracellular domain (residue 16 to 228),
the transmembrane domain (residue 229 to 249), the
cytoplasmic domain (residue 250 to 574), and two
fibronectin type-III domains (residue 18-115 and 141221).
The gene spans a region of 23.3 kb including seven
exons.
Transcription
One only transcript form containing 7 exons has been
described.
The last exon is partially untranslated. The transcript
length is 1725
Representation of the IL22RA1 gene organization. IL22RA1 gene and RNA.
1106
Gelebart P, Lai R
IL22RA1 protein organization and localization. IL22RA1 protein domains.
Localization of IL22RA1 by immunufluorescence confocal microscopy in ALK+ALCL cells.
Expression
IL22RA1 expression is relatively restricted, being
found at the highest level in the pancreas, small
intestine, colon, kidney, and liver. Importantly,
IL22RA1 is not detectable in normal immune cells,
including monocytes, B-cells, T-cells, natural killer
cells, macrophages and dendritic cells, cell types that
are normally found in the bone marrow, peripheral
blood, thymus and spleen.
Localisation
IL22RA1 is localized at the plasma membrane.
Crystal structure of IL22RA1 with IL22 at 1.9 A resolution.
Adapted from PDB (access number: 3DLQ).
1107
Gelebart P, Lai R
FACS analysis of IL22RA1 expression in peripheral mononuclear cells from healthy donor.
IL22RA1 signaling.
and translocate to the nucleus to modulate the
transcription of various target genes.
Function
IL22RA1 is one of the subunits of the IL20, IL22 and
IL24 receptor complex. Cytokine binding to IL22RA1
results in its aggregation, which activates the associated
JAK via its autophosphorylation. This in turn leads to
the phosphorylation and activation of STAT proteins.
Subsequently, phosphorylated STAT proteins dimerize
Mutations
Site-directed mutagenesis experiments have revealed
critical amino acid residues involved in its binding to
IL22. Specifically, mutation of residue 58 from K to A
1108
Gelebart P, Lai R
reduces the binding of IL22. Mutation of the residue 60
from Y to A or R results in a complete loss of response
to IL22.
Natural IL22RA1 variants have been reported,
including those carrying mutations at the residue 130 (S
to P), 205 (V to I), 209 (A to S), 222 (L to P), 407 (M
to V) and 518 (R to G).
the chromosomal translocation is that of the
t(2;5)(p23;q35), which leads to the juxtaposition of the
nucleophosmin (NPM) gene at 5q35 with the ALK
gene at 2p23. Mounting evidence suggests that the
resulted oncogenic fusion protein, NPM-ALK, plays
crucial roles in the pathogenesis of these tumors.
Prognosis
Patients with ALK+ALCL are typically treated with
combination chemotherapy containing doxorubicin.
ALK+ALCL represents one of the most common
pediatric lymphoid malignancies. The prognosis of
pediatric ALK+ALCL patients is significant better than
that of adult patients.
Cytogenetics
t(2;5)(p23;q35) in most ALK+ALCL patients; other
translocation variants have been described.
Hybrid/Mutated gene
NPM-ALK
Implicated in
ALK-positive anaplastic large cell
lymphoma (ALK+ALCL)
Disease
Anaplastic lymphoma kinase (ALK)-positive anaplastic
large-cell lymphoma (ALCL), or ALK+ALCL, is a
specific type of non-Hodgkin lymphoma characterized
by the T/null-cell immunophenotype, consistent
expression of CD30 and reciprocal chromosomal
translocations involving the ALK gene. In most cases,
Representation of the NPM-ALK oncoprotein organization and sequence.
Abnormal protein
NPM-ALK
References
Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E,
Dickensheets H, Donnelly RP, Pestka S. Identification of the
functional interleukin-22 (IL-22) receptor complex: the IL-10R2
chain (IL-10Rbeta ) is a common chain of both the IL-10 and
IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF)
receptor complexes. J Biol Chem. 2001 Jan 26;276(4):2725-32
Structure of the oncogenic fusion protein NPM-ALK.
Lécart S, Morel F, Noraz N, Pène J, Garcia M, Boniface K,
Lecron JC, Yssel H. IL-22, in contrast to IL-10, does not induce
Ig production, due to absence of a functional IL-22 receptor on
activated human B cells. Int Immunol. 2002 Nov;14(11):1351-6
Oncogenesis
Aberrant expression of IL22RA1 in ALK+ALCL
lymphoma cells allows these cells to be responsive to
IL-22 stimulation, which further stimulate STAT3
signaling and the growth of these cells. Blocking the
IL-22 signaling pathway using a neutralizing antibody
has been shown to significantly decrease the growth of
ALK+ALCL cells in-vitro. The aberrant expression of
IL22RA1 in ALK+ALCL is dependent on the
expression of NPM-ALK, since siRNA to
downregulate NPM-ALK dramatically shut down
IL22RA1 expression.
Wang M, Tan Z, Zhang R, Kotenko SV, Liang P. Interleukin 24
(MDA-7/MOB-5) signals through two heterodimeric receptors,
IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem. 2002 Mar
1;277(9):7341-7
Dumoutier L, Lejeune D, Hor S, Fickenscher H, Renauld JC.
Cloning of a new type II cytokine receptor activating signal
transducer and activator of transcription (STAT)1, STAT2 and
STAT3. Biochem J. 2003 Mar 1;370(Pt 2):391-6
Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell
lymphoma. Blood. 2007 Oct 1;110(7):2259-67
1109
Gelebart P, Lai R
Bard JD, Gelebart P, Anand M, Amin HM, Lai R. Aberrant
expression of IL-22 receptor 1 and autocrine IL-22 stimulation
contribute to tumorigenicity in ALK+ anaplastic large cell
lymphoma. Leukemia. 2008 Aug;22(8):1595-603
interleukin-22 receptor recruits STAT3 by interacting with its
coiled-coil domain. J Biol Chem. 2009 Sep 25;284(39):2637784
Endam LM, Bossé Y, Filali-Mouhim A, Cormier C, Boisvert P,
Boulet LP, Hudson TJ, Desrosiers M. Polymorphisms in the
interleukin-22 receptor alpha-1 gene are associated with
severe chronic rhinosinusitis. Otolaryngol Head Neck Surg.
2009 May;140(5):741-7
Bleicher L, de Moura PR, Watanabe L, Colau D, Dumoutier L,
Renauld JC, Polikarpov I. Crystal structure of the IL-22/IL22R1 complex and its implications for the IL-22 signaling
mechanism. FEBS Lett. 2008 Sep 3;582(20):2985-92
de Oliveira Neto M, Ferreira JR Jr, Colau D, Fischer H,
Nascimento AS, Craievich AF, Dumoutier L, Renauld JC,
Polikarpov I. Interleukin-22 forms dimers that are recognized
by two interleukin-22R1 receptor chains. Biophys J. 2008 Mar
1;94(5):1754-65
Gelebart P, Lai R. IL22RA1 (interleukin 22 receptor, alpha 1).
Dumoutier L, de Meester C, Tavernier J, Renauld JC. New
activation modus of STAT3: a tyrosine-less region of the
1110
Gene Section
Review
Francisco de Asís Iñesta-Vaquera, Ana Cuenda
Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (FdAIV,
AC)
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK7ID41294ch17p11.html
DOI: 10.4267/2042/44909
(MAPK7a, b and c) have been reported. Mouse splice
variants are generated by alternative splicing across
introns 1 and/or 2 (Yan et al., 2001).
Identity
Other names: BMK1, ERK4, ERK5, PRKM7
HGNC (Hugo): MAPK7
Location: 17p11.2
Pseudogene
DNA/RNA
Protein
Description
Note
ERK5, also known as MAPK7 or "Big MAP-Kinase 1"
(BMK1) belongs to the Mitogen Activated Protein
Kinase (MAPK) family, and therefore to the CGMC
kinases in the human kinome (Manning et al., 2002).
ERK5, at 98 kDa, is twice the size of other MAPKs and
hence the largest kinase within its group.
No human or mouse pseudogene known.
The MAPK7 entire gene spans 5,82 kb on the short arm
of chromosome 17. It contains 6 exons.
Transcription
The human MAPK7 gene encodes an 816 amino-acids
protein of about 98 kDa. MAPK7 mRNA is 2445 bp.
There are 11 transcripts, seven of which are protein
coding. In mice, three splice variants
MAPK7 genomic context (Chromosome 17; location 17p11.2).
Genomic organization of MAPK7 gene on chromosome 17p11.2.
The boxes indicate coding regions (exons 1-6) of the gene.
1111
Iñesta-Vaquera FdA, Cuenda A
Schematic representation of the human ERK5 (MAPK7) protein domains. NES1 and NES2, bipartite nuclear exportation signal; PB1-BD,
PB1 (Phox and Bem domain 1) binding domain; Kinase Domain, catalytic kinase domain; TEY, sequence motif containing ERK5
regulatory phosphorylation residues; PR-1 and PR-2, proline rich domains; Transcriptional trans-activation, transcriptional activity
domain.
It possesses a catalytic N-terminal domain, which share
50% homology with ERK1 (MAPK3) and ERK2
(MAPK1) and a unique C-terminal tail of about 400
amino-acids long. In vivo, ERK5 is activated to the
same extent by environmental stresses, such as
oxidative and osmotic shock, and by growth factors. In
addition, ERK5 may be activated by the cytokine
Interleukin-6 in B cells.
Function
Genetic studies have shown that ERK5 (MAPK7) is
essential for cardiovascular development and neuronal
differentiation. ERK5 knock-out mice die at
midgestation due to developmental failures in
structures as placenta, heart and vascular system
(Regan et al., 2002; Sohn et al., 2002; Yan et al., 2003;
Hayashi et al., 2004; Wang et al., 2005). ERK5 also
regulates cell survival in a variety of tissues. At
nervous system, ERK5 acts as a neuroprotector from
neurotrophic factor withdrawal and toxic insults
(Cavanaugh, 2004). Also, ERK5 is required to mediate
the survival response of neurons to nerve growth factor
(Finegan et al., 2009). In the immune system, the
ERK5 pathway regulates apoptosis of developing
thymocytes (Sohn et al., 2008) and protects B cells
from proapoptotic stimuli (Carvajal-Vergara et al.,
2005). ERK5 is also required for cell cycle progression.
It regulates cyclin D1 expression (Mulloy et al., 2003)
and is necessary for EGF-induced cell proliferation and
progression through the cell cycle (Kato et al., 1998).
Moreover, it has been suggested that the ERK5NFKappaB pathway may be required for a timely
mitotic entry (Cude et al., 2007). Additionally, ERK5,
along with other MAPK pathways can play an indirect
role in cytoskeleton rearrangement (Barros and
Marshall, 2005), in promoting SRC-induced podosome
formation (Schramp et al., 2008), and in cell
attachment to the extracellular matrix and in
endothelial cell migration (Spiering et al., 2009;
Sawhney
et
al.,
2009).
ERK5 (MAPK7) is a protein with kinase activity (in its
N-terminal region) and also transcriptional activation
activity (in the C-terminal half). Downstream targets of
ERK5 include the transcription factors MEF2A,
Description
Human ERK5 (MAPK7) is a Ser/Thr protein kinase of
816 amino-acids with a predicted mass of 98 kDa. The
ERK5 N-terminus domain resembles the typical MAPK
catalytic domain and includes the MAPK-conserved
TXY activation sequence (T218EY220) in the activation
loop. The activation of ERK5 occurs via interaction
with and dual phosphorylation in its TEY motif by
MKK5 (Mody et al., 2003). MKK5 mediated ERK5
activation leads to ERK5 autophosphorylation in its
unique C-terminal domain (Morimoto et al., 2007).
Expression
ERK5 (MAPK7) mRNA
throughout all tissues.
is
widely
expressed
Localisation
Both in tissues and in cultured cells, ERK5 (MAPK7)
localizes to the cytoplasm of cells and/or to the nucleus.
As shown in the above diagram, ERK5 molecule
contains a bipartite nuclear exportation signal. In
resting cells, the N- and C-terminal halves of ERK5
interact producing a nuclear export signal (NES) that
retains ERK5 in the cytoplasm of the cells. Upon
stimulation, the interaction between the N- and the Cterminal halves is disrupted, and therefore ERK5 enters
the nucleus (Kondoh et al., 2006).
1112
MEF2C and MEF2D, SAP1a, c-Myc and CREB. For
example, ERK5 phosphorylates SAP1, which enhances
its transcriptional activity promoting c-FOS expression
(Terasawa et al., 2003), and activates the serum- and
glucocorticoid-inducible
kinase1
(SGK1)
by
phosphorylating Ser78 in response to growth factors
(Hayashi et al., 2001). In cardiac tissue, ERK5 may
couple cells electrically and metabolically by
phosphorylating the gap-junction protein Cx43 at a key
residue for gap junction communication (Cameron et
al., 2003). Also, phosphorylated ERK5 regulates gene
expression through its C-terminal transcriptional
activation domain (Morimoto et al., 2007).
References
Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee
JD. Bmk1/Erk5 is required for cell proliferation induced by
epidermal growth factor. Nature. 1998 Oct 15;395(6703):713-6
Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y,
Lee JD. BMK1 mediates growth factor-induced cell proliferation
through direct cellular activation of serum and glucocorticoidinducible kinase. J Biol Chem. 2001 Mar 23;276(12):8631-4
Yan C, Luo H, Lee JD, Abe J, Berk BC. Molecular cloning of
mouse ERK5/BMK1 splice variants and characterization of
ERK5 functional domains. J Biol Chem. 2001 Apr
6;276(14):10870-8
Esparís-Ogando A, Díaz-Rodríguez E, Montero JC, Yuste L,
Crespo P, Pandiella A. Erk5 participates in neuregulin signal
transduction and is constitutively active in breast cancer cells
overexpressing ErbB2. Mol Cell Biol. 2002 Jan;22(1):270-85
Homology
ERK5 (MAPK7) N-terminal half shares a 50%
sequence identity with ERK1/2. The homology of the
C-terminal part of ERK5 with other protein has not
been reported. ERK5 possesses ortholog in the majority
of mammals (sharing 80-98% homology). In C.
elegans, the SMA-5 protein is a 60% similar to human
ERK5 (Watanabe et al., 2005). In Saccharomyces
cerevisiae, Slt2p (Mpk1p) is an ERK5 ortholog
(Truman et al., 2006).
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S.
The protein kinase complement of the human genome.
Science. 2002 Dec 6;298(5600):1912-34
Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K. Erk5
null mice display multiple extraembryonic vascular and
embryonic cardiovascular defects. Proc Natl Acad Sci U S A.
2002 Jul 9;99(14):9248-53
Sohn SJ, Sarvis BK, Cado D, Winoto A. ERK5 MAPK regulates
embryonic angiogenesis and acts as a hypoxia-sensitive
repressor of vascular endothelial growth factor expression. J
Biol Chem. 2002 Nov 8;277(45):43344-51
Mutations
Note
Not identified.
Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C,
Lee JD, Abe J, Yang J. Regulation of epidermal growth factorinduced connexin 43 gap junction communication by big
mitogen-activated protein kinase1/ERK5 but not ERK1/2
kinase activation. J Biol Chem. 2003 May 16;278(20):18682-8
Implicated in
Breast cancer
Mody N, Campbell DG, Morrice N, Peggie M, Cohen P. An
analysis of the phosphorylation and activation of extracellularsignal-regulated protein kinase 5 (ERK5) by mitogen-activated
protein kinase kinase 5 (MKK5) in vitro. Biochem J. 2003 Jun
1;372(Pt 2):567-75
Note
ERK5 (MAPK7) expression and activity is increased in
breast cancer tumours. ERK5 overexpression has been
established as an independent predictor of disease-free
survival in breast cancer (Montero et al., 2009). In cell
models, ERK5 has been linked to the regulation of
breast cancer cells proliferation (Esparís-Ogando et al.,
2002).
Mulloy R, Salinas S, Philips A, Hipskind RA. Activation of cyclin
D1 expression by the ERK5 cascade. Oncogene. 2003 Aug
21;22(35):5387-98
Terasawa K, Okazaki K, Nishida E. Regulation of c-Fos and
Fra-1 by the MEK5-ERK5 pathway. Genes Cells. 2003
Mar;8(3):263-73
Prostatic cancer
Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur
JS. Knockout of ERK5 causes multiple defects in placental and
embryonic development. BMC Dev Biol. 2003 Dec 16;3:11
Note
ERK5 (MAPK7) immunoreactivity is significantly upregulated in high-grade prostate cancer. Increased
ERK5 cytoplasmic signals correlated with metastases
and locally advanced disease at diagnosis. Strong
nuclear ERK5 localization in prostatic tumours
correlates with poor disease-specific survival
(McCracken et al., 2008).
Cavanaugh JE. Role of extracellular signal regulated kinase 5
in neuronal survival. Eur J Biochem. 2004 Jun;271(11):2056-9
Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED,
Eliceiri B, Yang Y, Ulevitch RJ, Lee JD. Targeted deletion of
BMK1/ERK5 in adult mice perturbs vascular integrity and leads
to endothelial failure. J Clin Invest. 2004 Apr;113(8):1138-48
Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5
MAP kinase pathways can lead to disruption of the actin
cytoskeleton. J Cell Sci. 2005 Apr 15;118(Pt 8):1663-71
Hepatic carcinoma
Note
An increase in ERK5 (MAPK7) copy number was
detected in primary HCC tumours. It has been
suggested that MAPK7 is likely the target of 17p11
amplification and that the ERK5 protein promotes the
growth of hepatic carcinoma cells by regulating mitotic
entry (Zen et al., 2009).
Carvajal-Vergara X, Tabera S, Montero JC, Esparís-Ogando A,
López-Pérez R, Mateo G, Gutiérrez N, Parmo-Cabañas M,
Teixidó J, San Miguel JF, Pandiella A. Multifunctional role of
Erk5 in multiple myeloma. Blood. 2005 Jun 1;105(11):4492-9
Wang X, Merritt AJ, Seyfried J, Guo C, Papadakis ES, Finegan
KG, Kayahara M, Dixon J, Boot-Handford RP, Cartwright EJ,
1113
Mayer U, Tournier C. Targeted deletion of mek5 causes early
embryonic death and defects in the extracellular signalregulated kinase 5/myocyte enhancer factor 2 cell survival
pathway. Mol Cell Biol. 2005 Jan;25(1):336-45
Sohn SJ, Lewis GM, Winoto A. Non-redundant function of
Watanabe N, Nagamatsu Y, Gengyo-Ando K, Mitani S,
Ohshima Y. Control of body size by SMA-5, a homolog of MAP
kinase BMK1/ERK5, in C. elegans. Development. 2005
Jul;132(14):3175-84
Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C.
Regulation of neuronal survival by the extracellular signalregulated protein kinase 5. Cell Death Differ. 2009
May;16(5):674-83
Kondoh K, Terasawa K, Morimoto H, Nishida E. Regulation of
nuclear translocation of extracellular signal-regulated kinase 5
by active nuclear import and export mechanisms. Mol Cell Biol.
2006 Mar;26(5):1679-90
Montero JC, Ocaña A, Abad M, Ortiz-Ruiz MJ, Pandiella A,
Esparís-Ogando A. Expression of Erk5 in early stage breast
cancer and association with disease free survival identifies this
kinase as a potential therapeutic target. PLoS One.
2009;4(5):e5565
the MEK5-ERK5 pathway in thymocyte apoptosis. EMBO J.
2008 Jul 9;27(13):1896-906
Truman AW, Millson SH, Nuttall JM, King V, Mollapour M,
Prodromou C, Pearl LH, Piper PW. Expressed in the yeast
Saccharomyces cerevisiae, human ERK5 is a client of the
Hsp90 chaperone that complements loss of the Slt2p (Mpk1p)
cell integrity stress-activated protein kinase. Eukaryot Cell.
2006 Nov;5(11):1914-24
Sawhney RS, Liu W, Brattain MG. A novel role of ERK5 in
integrin-mediated cell adhesion and motility in cancer cells via
Fak signaling. J Cell Physiol. 2009 Apr;219(1):152-61
Spiering D, Schmolke M, Ohnesorge N, Schmidt M, Goebeler
M, Wegener J, Wixler V, Ludwig S. MEK5/ERK5 signaling
modulates endothelial cell migration and focal contact turnover.
J Biol Chem. 2009 Sep 11;284(37):24972-80
Cude K, Wang Y, Choi HJ, Hsuan SL, Zhang H, Wang CY, Xia
Z. Regulation of the G2-M cell cycle progression by the ERK5NFkappaB signaling pathway. J Cell Biol. 2007 Apr
23;177(2):253-64
Zen K, Yasui K, Nakajima T, Zen Y, Zen K, Gen Y, Mitsuyoshi
H, Minami M, Mitsufuji S, Tanaka S, Itoh Y, Nakanuma Y,
Taniwaki M, Arii S, Okanoue T, Yoshikawa T. ERK5 is a target
for gene amplification at 17p11 and promotes cell growth in
hepatocellular carcinoma by regulating mitotic entry. Genes
Chromosomes Cancer. 2009 Feb;48(2):109-20
Morimoto H, Kondoh K, Nishimoto S, Terasawa K, Nishida E.
Activation of a C-terminal transcriptional activation domain of
ERK5 by autophosphorylation. J Biol Chem. 2007 Dec
7;282(49):35449-56
McCracken SR, Ramsay A, Heer R, Mathers ME, Jenkins BL,
Edwards J, Robson CN, Marquez R, Cohen P, Leung HY.
Aberrant expression of extracellular signal-regulated kinase 5
in human prostate cancer. Oncogene. 2008 May
8;27(21):2978-88
Iñesta-Vaquera FdA, Cuenda A. MAPK7 (mitogen-activated
protein kinase 7). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(12):1111-1114.
Schramp M, Ying O, Kim TY, Martin GS. ERK5 promotes Srcinduced podosome formation by limiting Rho activation. J Cell
Biol. 2008 Jun 30;181(7):1195-210
1114
Gene Section
Mini Review
SLC16A1 (solute carrier family 16, member 1
(monocarboxylic acid transporter 1))
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus of
Gualtar, 4710-057 Braga, Portugal (CP, FB)
Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC16A1ID44046ch1p13.html
DOI: 10.4267/2042/44910
Pseudogene
Identity
1 related pseudogene identified - AKR7 family
pseudogene (AFARP1), non-coding RNA.
Other names: FLJ36745, HHF7, MCT, MCT1,
MGC44475
HGNC (Hugo): SLC16A1
Location: 1p13.2
Protein
Description
DNA/RNA
500 amino acids; 53958 Da; 12 transmembrane
domains, intracellular N- and C-terminal and a large
intracellular loop between transmembrane domains 6
and 7.
Note
Human SLC16A1 was firstly cloned in 1994, by Garcia
and colleagues. Structural gene organization as well as
isolation and characterization of SLC16A1 promoter
was achieved in 2002, by Cuff and Shirazi-Beechey.
Expression
Ubiquitous.
Description
Localisation
44507 bp lenght, containing 5 exons. Various SNPs
have been described in SLC16A1 gene.
Plasma membrane; also described in rat mitochondrial
and peroxisomal membranes.
Transcription
Function
6 transcripts have been described for this gene (4 with
protein product, 2 with no protein product): SLC16A1001 (5 exons; 3910 bps transcript length; 500 residues
translation length); SLC16A1-002 (5 exons; 2101 bps
transcript length; 456 residues translation length);
SLC16A1-003 (4 exons; 865 bps transcript length; 215
residues translation length); SLC16A1-004 (2 exons;
452 bps transcript length; no translation product);
SLC16A1-005 (4 exons; 1099 bps transcript length;
296 residues translation length); SLC16A1-006 (2
exons; 430 bps transcript length; no translation
product).
Catalyses the proton-linked transport of metabolically
important monocarboxylates such as lactate, pyruvate,
branched-chain oxo acids derived from leucine, valine
and isoleucine, and ketone bodies (acetoacetate, betahydroxybutyrate and acetate).
Homology
Belongs to the major facilitator superfamily (MFS).
Monocarboxylate porter (TC 2.A.1.13) family.
SLC16A1 gene is conserved in chimpanzee, dog, cow,
mouse, rat, chicken, and zebrafish.
1115
Pinheiro C, Baltazar F
Protein diagram drawn following UniProtKB/Swiss-Prot database prediction, using TMRPres2D software.
associated with advanced gastric carcinoma,
Lauren's intestinal type, TNM staging and lymph-node
metastasis, in gastric cancer.
Implicated in
Various cancers
Colorectal carcinoma
Note
MCT1/SLC16A1 has been described to be upregulated
in a variety of tumours.
Disease
High grade glial neoplasms (Mathupala et al., 2004;
Fang et al., 2006), colorectal (Koukourakis et al., 2006;
Pinheiro et al., 2008), lung (Koukourakis et al., 2007),
cervical (Pinheiro et al., 2008), and breast carcinomas
(Pinheiro et al., in Press).
Note
MCT1/SLC16A1 has been described to be
downregulated in colorectal carcinoma (Lamber et al.,
2002).
Erythrocyte lactate transporter defect
Note
Merezhinskaya et al. (2000) identified two
heterozygous transitions in the SLC16A1 gene, in
patients with erythrocyte lactate transporter defect:
610A-G transition (resulting in a lys204-to-glu
(K204E) substitution in a highly conserved residue)
and 1414G-A transition (resulting in a gly472-to-arg
(G472R) substitution halfway along the cytoplasmic Cterminal chain). These substitutions are not conserved,
but were not identified in 90 healthy control
individuals. Erythrocyte lactate clearance in patients
with these mutations was 40 to 50% that of normal
control values.
Breast cancer
Prognosis
In breast cancer, MCT1/SLC16A1 was found to be
associated with poor prognostic variables such as basallike subtype and high grade tumours (Pinheiro et al., in
Press).
Oncogenesis
SLC16A1 is expressed in normal breast tissue, but is
silenced in breast cancer due to gene methylation
(Asada et al., 2003).
Hyperinsulinemic hypoglycemia familial
7
Gastric cancer
Note
The prognostic value of CD147 (a MCT1/SLC16A1
and MCT4/SLC16A3 chaperone required for plasma
membrane expression and activity) was associated with
MCT1/SLC16A1 co-expression in gastric cancer cells
(Pinheiro et al., 2009).
Prognosis
Co-expression of MCT1/SLC16A1 with CD147 was
Note
Otonkoski et al. (2007) identified two heterozygotic
alterations in the SLC16A1, in affected members of a
Finnish family segregating autosomal dominant
exercise-induced hyperinsulinemic hypoglycemia.
First, a 163G-A transition in exon 1 located within a
binding site for nuclear matrix protein-1 and predicted
to disrupt the binding sites of 2 potential transcriptional
1116
Mathupala SP, Parajuli P, Sloan AE. Silencing of
monocarboxylate transporters via small interfering ribonucleic
acid inhibits glycolysis and induces cell death in malignant
glioma: an in vitro study. Neurosurgery. 2004 Dec;55(6):14109; discussion 1419
repressors, and, secondly, a 25-bp insertion at
nucleotide -24 introducing additional binding sites for
the ubiquitous transcription factors SP1, USF and
MZF1. The first variation leads to a 3-fold increase in
transcription while the second variation leads to a 10fold increase in transcription. These mutations were not
found in 92 Finnish and German controls.
Fang J, Quinones QJ, Holman TL, Morowitz MJ, Wang Q,
Zhao H, Sivo F, Maris JM, Wahl ML. The H+-linked
monocarboxylate transporter (MCT1/SLC16A1): a potential
therapeutic target for high-risk neuroblastoma. Mol Pharmacol.
2006 Dec;70(6):2108-15
References
Pinheiro C, Albergaria A, Paredes J, Sousa B, Dufloth R, Vieira
D, Schmitt F, Baltazar F.. Monocarboxylate transporter 1 is
upregulated in basal-like breast carcinoma. Histopathology In
press
Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E.
Comparison of metabolic pathways between cancer cells and
stromal cells in colorectal carcinomas: a metabolic survival role
for tumor-associated stroma. Cancer Res. 2006 Jan
15;66(2):632-7
Garcia CK, Li X, Luna J, Francke U. cDNA cloning of the
human monocarboxylate transporter 1 and chromosomal
localization of the SLC16A1 locus to 1p13.2-p12. Genomics.
1994 Sep 15;23(2):500-3
Koukourakis MI, Giatromanolaki A, Bougioukas G, Sivridis E.
Lung cancer: a comparative study of metabolism related
protein expression in cancer cells and tumor associated
stroma. Cancer Biol Ther. 2007 Sep;6(9):1476-9
Brooks GA, Brown MA, Butz CE, Sicurello JP, Dubouchaud H.
Cardiac and skeletal muscle mitochondria have a
monocarboxylate transporter MCT1. J Appl Physiol. 1999
Nov;87(5):1713-8
Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah
MS, Parton LE, Schuit F, Quintens R, Sipilä I, Mayatepek E,
Meissner T, Halestrap AP, Rutter GA, Kere J. Physical
exercise-induced hypoglycemia caused by failed silencing of
monocarboxylate transporter 1 in pancreatic beta cells. Am J
Hum Genet. 2007 Sep;81(3):467-74
Merezhinskaya N, Fishbein WN, Davis JI, Foellmer JW.
Mutations in MCT1 cDNA in patients with symptomatic
deficiency in lactate transport. Muscle Nerve. 2000
Jan;23(1):90-7
Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SM, Etlinger
D, Moreira MA, Jubé LF, Queiroz GS, Schmitt F, Baltazar F.
Increasing expression of monocarboxylate transporters 1 and 4
along progression to invasive cervical carcinoma. Int J Gynecol
Pathol. 2008 Oct;27(4):568-74
Cuff MA, Shirazi-Beechey SP. The human monocarboxylate
transporter, MCT1: genomic organization and promoter
analysis. Biochem Biophys Res Commun. 2002 Apr
12;292(4):1048-56
Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L,
Martins S, Pellerin L, Rodrigues M, Alves VA, Schmitt F,
Baltazar F. Increased expression of monocarboxylate
transporters 1, 2, and 4 in colorectal carcinomas. Virchows
Arch. 2008 Feb;452(2):139-46
Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP. Molecular
changes in the expression of human colonic nutrient
transporters during the transition from normality to malignancy.
Br J Cancer. 2002 Apr 22;86(8):1262-9
Pinheiro C, Longatto-Filho A, Simões K, Jacob CE, Bresciani
CJ, Zilberstein B, Cecconello I, Alves VA, Schmitt F, Baltazar
F. The prognostic value of CD147/EMMPRIN is associated
with monocarboxylate transporter 1 co-expression in gastric
cancer. Eur J Cancer. 2009 Sep;45(13):2418-24
Asada K, Miyamoto K, Fukutomi T, Tsuda H, Yagi Y,
Wakazono K, Oishi S, Fukui H, Sugimura T, Ushijima T.
Reduced expression of GNA11 and silencing of MCT1 in
human breast cancers. Oncology. 2003;64(4):380-8
McClelland GB, Khanna S, González GF, Butz CE, Brooks GA.
Peroxisomal membrane monocarboxylate transporters:
evidence for a redox shuttle system? Biochem Biophys Res
Commun. 2003 Apr 25;304(1):130-5
Pinheiro C, Baltazar F. SLC16A1 (solute carrier family 16,
member 1 (monocarboxylic acid transporter 1)). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(12):1115-1117.
Halestrap AP, Meredith D. The SLC16 gene family-from
monocarboxylate transporters (MCTs) to aromatic amino acid
transporters and beyond. Pflugers Arch. 2004 Feb;447(5):61928
1117
Gene Section
Mini Review
Wenfeng Cao, Liyong Zhang, Fang Ding, Zhumei Cui, Zhihua Liu
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100021, China (WC, LZ, DF, ZL); Department of
Pathology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention
and Therapy, Tianjin 300060, China (WC); Department of Obstetrics and Gynecology, Affiliated Hospital of
Medical College, Qingdao University, Qingdao 266011, China (ZC)
Online updated version : http://AtlasGeneticsOncology.org/Genes/STOML2ID44346ch9p13.html
DOI: 10.4267/2042/44911
frame however, commonly forms a 356 amino acid
residue polypeptide with a predicted molecular weight
of 38.5 kDa. Similar to other family members, SLP-2
as well as the stomatin from other species shares a
characteristic NH2-terminal hydrophobic domain as
well as a consensus cognate stomatin signature
sequence that defines the stomatin gene family,
however, it lacks the NH2-terminal hydrophobic
domain (Wang et al., 2000). The SLP-2 protein
contains an alanine-rich domain and a number of
potential protein kinase C phosphorylation sites,
cAMP-and-cGMP-dependent
protein
kinase
phosphorylation sites and casein kinase II
phosphorylation sites.
Identity
Other names: HSPC108, SLP-2
HGNC (Hugo): STOML2
Location: 9p13.3
DNA/RNA
Description
The gene encoding SLP-2 was 3250 bp long and
consisted of ten exons interrupted by nine introns.
Transcription
There are 5 transcripts in this gene. However, a single
1.3 kb mRNA transcript encoding SLP-2 was
ubiquitously expressed, and the translation length is
356 residues (Owczarek et al., 2001).
Expression
SLP-2 is widely expressed in many tissues and thought
as a new component of the peripheral membrane
skeleton. Especially, in the erythrocyte membrane, it
also appears to exist at least partially as an oligomeric
protein complex. The overexpression of SLP-2 can be
found in many kinds of human tumors, such as
esophageal squamous cell carcinoma, laryngeal
squamous
cell
carcinoma,
endometrial
adenocarcinoma, and lung cancer.
Pseudogene
No known pseudogenes.
Protein
Description
NP_038470; 356 aa.
Human SLP-2 is presented on chromosome 9p13. The
sequence at the 5'-end of the mRNA is interesting for
the presence of three potential ATG initiator sites, all
sharing the same open reading
Localisation
Predominantly on plasma membrane and in the
cytoplasm.
1118
Cao W, et al.
Figure A. ALA-RICH, Alanine-rich region profile: 224-274: score = 8.657. Figure B. MYRISTYL, N-myristoylation site: 16-21:
GSllAS, 31-36: GLprNT, 209-214: GTreSA, 314-319: GVvgAL, 326-331: GTpdSL, 341-346: GtdaSL; PKC-PHOSPHO-SITE, Protein
kinase C phosphorylation site: 21-23: SgR, 78-80: SlK, 133-135: TmR, 335-337: SsR; CAMP-PHOSPHO-SITE, Camp-and-cGMPdependent protein kinase phosphorylation site: 26-29: RRaS, 200-203: KRaT; CK2-PHOSPHO-SITE, Casein kinase II
phosphorylation site: 78-81: SlkE, 156-159: SivD, 203-206: TvlE, 229-232: SeaE, 277-280: TvaE, 335-338: SsrD, 345-348: SldE; ASNGLYCOSYLATION, N-glycosylation site: 96-99: NVTL, 154-157: NASI; AMIDATION, amidation site: 219-222: eGKK.
number of different cancers, including esophageal
squamous cell carcinoma (ESCC), laryngeal squamous
cell carcinoma (LSCC), endometrial adenocarcinoma
(EAC), lung cancer (LC) and breast cancer (see below).
Function
Human SLP-2 protein with unknown function, we
hypothesize that SLP-2 may link stomatin or other
integral membrane proteins to the peripheral
cytoskeleton and thereby play a role in regulating ion
channel conductances or the organization of
sphingolipid and cholesterol-rich lipid rafts.
Some recent results indicated that SLP-2 protein can
significantly influence on multi-tumor progression,
which allowed us to identify this unwell-known gene
that maybe modulate invasion and metastasis of
different cancers.
Esophageal squamous cell carcinoma
(ESCC)
Prognosis
As shown in human ESCC, a significant correlation
exists between SLP-2 protein high expression and the
depth of ESCC invasion (P=0.033) (Wang et al., 2009).
Also, decreased cell growth and tumorigenesis in the
antisense transfectants revealed that SLP-2 may be
important in ESCC tumorigenesis (Zhang et al., 2006).
Homology
SLP-2 is one of the members of the Stomatin
superfamily, among which identified vertebrate
homologues are SLP-1, SLP-2, and SLP-3. SLP-1 is
most abundant in brain and shares many similarities
with UNC-24 (STOML1).
SLP-3 is specifically expressed in olfactory sensory
neurons (Seidel et al., 1998; Goldstein et al., 2003).
Laryngeal squamous cell carcinoma
(LSCC)
Prognosis
In addition, SLP-2 takes part in human LSCC
malignant phenotype formation and development.
High-level expression of SLP-2 protein could
contribute to the prognostic characteristics of lymph
node metastasis in human LSCC (Cao et al., 2007).
Mutations
Breast cancer
No mutations have been reported for SLP-2. Mutation
detection of SLP-2 exons was done using PCR and
automated sequencing with 30 patient-matched human
esophageal cancer tissues. No mutation was found
within the open-reading frame of SLP-2 after
sequencing results were aligned by the procedure
SeqMan of DNAStar software (Zhang et al., 2006).
Prognosis
High-level expression of SLP-2 protein shows a worse
prognosis, including increase in tumor size, progress in
clinical stage, and appearance of lymph node and/or
distant metastasis and is associated with decreased
overall survival (P=0.011). Moreover, SLP-2 can be
strongly associated with another important prognostic
factor, HER-2/neu protein expression, which shows
that they may act as dependent prognostic factors to
indicate poor prognosis (Cao et al., 2007).
Implicated in
Various cancers
Note
SLP-2 has been shown to be over-expressed in a
1119
Cao W, et al.
Owczarek CM, Treutlein HR, Portbury KJ, Gulluyan LM, Kola I,
Hertzog PJ. A novel member of the STOMATIN/EPB72/mec-2
family, stomatin-like 2 (STOML2), is ubiquitously expressed
and localizes to HSA chromosome 9p13.1. Cytogenet Cell
Genet. 2001;92(3-4):196-203
Endometrial adenocarcinoma
Prognosis
Similarly, SLP-2 is also overexpressed in human
endometrial adenocarcinoma (EAC) at both mRNA and
protein level. Sense transfection of SLP-2 in EAC cell
line accelerated cell growth whereas the antisense
transfection reduced cell growth in vitro (Cui et al.,
2007).
Goldstein BJ, Kulaga HM, Reed RR. Cloning and
characterization of SLP3: a novel member of the stomatin
family expressed by olfactory receptor neurons. J Assoc Res
Otolaryngol. 2003 Mar;4(1):74-82
Zhang L, Ding F, Cao W, Liu Z, Liu W, Yu Z, Wu Y, Li W, Li Y,
Liu Z. Stomatin-like protein 2 is overexpressed in cancer and
involved in regulating cell growth and cell adhesion in human
esophageal squamous cell carcinoma. Clin Cancer Res. 2006
Mar 1;12(5):1639-46
Lung cancer
Prognosis
At last, SLP-2 was overexpressed in human lung cancer
(Zhang et al., 2006). High-level SLP-2 expression was
significantly correlated with distant metastasis,
decreased overall survival and disease-free survival.
SLP-2 overexpression was an independent prognostic
factor in multivariate analysis using the Cox regression
model (p<0.05) (Chang et al., 2009).
Cao W, Zhang B, Liu Y, Li H, Zhang S, Fu L, Niu Y, Ning L,
Cao X, Liu Z, Sun B. High-level SLP-2 expression and HER2/neu protein expression are associated with decreased breast
cancer patient survival. Am J Clin Pathol. 2007
Sep;128(3):430-6
Cao WF, Zhang LY, Liu MB, Tang PZ, Liu ZH, Sun BC.
Prognostic
significance
of
stomatin-like
protein
2
overexpression in laryngeal squamous cell carcinoma: clinical,
histologic, and immunohistochemistry analyses with tissue
microarray. Hum Pathol. 2007 May;38(5):747-52
Mitochondrial component
Note
SLP-2 localizes in mitochondria, affects mitochondrial
membrane potential (MMP) and ATP production.
Hence, SLP-2 is a mitochondrial protein and therefore,
functions in energy process by MMP maintenance, and
subsequently affecting cell motility, proliferation and
chemosensitivity (Wang et al., 2009).
Cui Z, Zhang L, Hua Z, Cao W, Feng W, Liu Z. Stomatin-like
protein 2 is overexpressed and related to cell growth in human
endometrial adenocarcinoma. Oncol Rep. 2007 Apr;17(4):82933
References
Wang Y, Cao W, Yu Z, Liu Z. Downregulation of a
mitochondria associated protein SLP-2 inhibits tumor cell
motility, proliferation and enhances cell sensitivity to
chemotherapeutic reagents. Cancer Biol Ther. 2009
Sep;8(17):1651-8
Seidel G, Prohaska R. Molecular cloning of hSLP-1, a novel
human brain-specific member of the band 7/MEC-2 family
similar to Caenorhabditis elegans UNC-24. Gene. 1998 Dec
28;225(1-2):23-9
Chang D, Ma K, Gong M, Cui Y, Liu ZH, Zhou XG, Zhou CN,
Wang TY. SLP-2 overexpression is associated with tumour
distant metastasis and poor prognosis in pulmonary squamous
cell carcinoma. Biomarkers. 2010 Mar;15(2):104-10
Wang Y, Morrow JS. Identification and characterization of
human SLP-2, a novel homologue of stomatin (band 7.2b)
present in erythrocytes and other tissues. J Biol Chem. 2000
Mar 17;275(11):8062-71
Cao W, Zhang L, Ding F, Cui Z, Liu Z. STOML2 (stomatin
(EPB72)-like 2). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(12):1118-1120.
1120
Gene Section
Mini Review
AMOT (angiomotin)
Roshan Mandrawalia, Ranjan Tamuli
Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781 039, Assam, India
(RM, RT)
Published in Atlas Database: March 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/AMOTID632chXq23.html
DOI: 10.4267/2042/44912
(261), 721-751 (31), a PDZ-binding motif 1081-1084
(4), a SMC_prok_B region 429-549 (121), and an
angiomotin_C
terminal
599-794
(196).
Phosphorylations occur on S305, S312, S712, S714,
T717, Y719, and T1061. Phosphorylated upon DNA
damage, probably by ATM or ATR.
Isoforms:
- Isoform 1: p130 angiomotin
1084 amino acids, 118085 Da. This isoform has been
chosen as the 'canonical' sequence.
- Isoform 2: p80 angiomotin
675 amino acids, 72540 Da. The isoform differs from
the canonical sequence with N-terminal alternative
splicing region 1-409 (409) missing, which mediates
the binding of angiomotin to F-actin stress fibres. The
SMC_prok_B region is also missing in this isoform.
Identity
Other names: KIAA1071
HGNC (Hugo): AMOT
Location: Xq23
DNA/RNA
Description
DNA size 66.31 kb, mRNA size 6888 bp, 12 exons.
Protein
Description
Angiomotin protein is 1084 amino acid residues in
length. It contains two coiled coil domains 429-689
1121
AMOT (angiomotin)
Mandrawalia R, Tamuli R
acids from PDZ-binding motif results in inhibition of
chemotaxis, embryos with this mutation may lead to
death on embryonic day 9.5.
Expression
Expressed in placenta and skeletal muscle.
Predominantly expressed in endothelial cells of
capillaries, larger vessels of the placenta.
Implicated in
Localisation
Breast cancer
Cell junction, tight junction. Localized on the cell
surface. May act as a transmembrane protein.
Note
Angiomotin is linked to angiogenesis and aggressive
nature of breast tumours. Angiomotin shows high level
of expression in mammary tissues during tumour stages
as compared to normal expression level (33.1 ± 11 in
normal versus 86.5 ± 13.7 in tumour tissues,
p=0.0003). Significant high expression was found in
aggressive tumours (grade 2, grade 3 and with nodal
involvement) compared with less aggressive grade 1
tumour
(p<0.001
and
p=0.05
respectively).
Angiogenesis is the essential process in the
development and spread of breast cancer, by providing
blood supply to tumours and escape route for tumour
cells to other part of the body.
Function
Mediates inhibitory effect of angiostatin on tube
formation and the migration of endothelial cells toward
growth factors during the formation of new blood
vessels in the larger vessels of the placenta. Isoform-1
is found to control cell shape by association with Factin fibres through N-terminal part of protein. The
isoform 2 (p80) promotes angiogenesis, in part, by
conferring a hypermigratory phenotype to endothelial
cells.
Homology
The percent identity below represents identity of
AMOT over an aligned region in Unigene.
Mus musculus: 88.1 (percent identity)
Oryctolagus cuniculus: 79
Sus scrofa: 72
Danio rerio: 68.9
Fugu rubripes: 65
Xenopus laevis: 61.8
Caenorhabditis elegans: 46
Saccharomyces cerevisiae: 47
Drosophila melanogaster: 36
Hemangioendothelioma invasion
Disease
Angiomotin
expression
promotes
hemangioendothelioma invasion. Expression of human
angiomotin in mouse aortic endothelial (MAE) cells
results in stabilization of tubes in the Matrigel assay.
Cells from the established tubes invaded into the
solidified matrigel, however, cells expressing a
functional mutant lacking the PDZ protein interaction
motif did not migrate and form tubes. Angiomotin may
promote angiogenesis by both stimulating invasion as
well as stabilizing established tubes.
Mutations
Endothelial cell migration and tube
formation
Note
Several polymorphisms have been found but none of
them has shown any association with a disease.
Furthermore, endothelial cells expressing mutated
angiomotins have been reported failure in their
function, including failure to migrate and inhibition of
angiogenesis. Mutation with deletion of three amino
Note
Upon expression of angiomotin in HeLa cells,
angiomotin bound and internalized fluorescein-labeled
angiostatin, a circulating inhibitor of angiogenesis. In
endothelial cells, angiomotin protein is localized to the
1122
AMOT (angiomotin)
Mandrawalia R, Tamuli R
Ernkvist M, Aase K, Ukomadu C, Wohlschlegel J, Blackman R,
Veitonmäki N, Bratt A, Dutta A, Holmgren L. p130-angiomotin
associates to actin and controls endothelial cell shape. FEBS
J. 2006 May;273(9):2000-11
leading edge of migrating cells and results in increased
cell migration. Angiomotin-transfected MAE cells bind
and respond to angiostatin by inhibition of cell
migration and tube formation, which suggest that
angiomotin regulates endothelial cell migration and
tube formation.
Holmgren L, Ambrosino E, Birot O, Tullus C, Veitonmäki N,
References
Levchenko T, Carlson LM, Musiani P, Iezzi M, Curcio C, Forni
G, Cavallo F, Kiessling R. A DNA vaccine targeting angiomotin
inhibits angiogenesis and suppresses tumor growth. Proc Natl
Acad Sci U S A. 2006 Jun 13;103(24):9208-13
Troyanovsky B, Levchenko T, Månsson G, Matvijenko O,
Holmgren L. Angiomotin: an angiostatin binding protein that
regulates endothelial cell migration and tube formation. J Cell
Biol. 2001 Mar 19;152(6):1247-54
Jiang WG, Watkins G, Douglas-Jones A, Holmgren L, Mansel
RE. Angiomotin and angiomotin like proteins, their expression
and correlation with angiogenesis and clinical outcome in
human breast cancer. BMC Cancer. 2006 Jan 23;6:16
Zetter BR. Hold that line. Angiomotin regulates endothelial cell
motility. J Cell Biol. 2001 Mar 19;152(6):F35-6
Wells CD, Fawcett JP, Traweger A, Yamanaka Y, Goudreault
M, Elder K, Kulkarni S, Gish G, Virag C, Lim C, Colwill K,
Starostine A, Metalnikov P, Pawson T. A Rich1/Amot complex
regulates the Cdc42 GTPase and apical-polarity proteins in
epithelial cells. Cell. 2006 May 5;125(3):535-48
Bratt A, Wilson WJ, Troyanovsky B, Aase K, Kessler R, Van
Meir EG, Holmgren L. Angiomotin belongs to a novel protein
family with conserved coiled-coil and PDZ binding domains.
Gene. 2002 Sep 18;298(1):69-77
Ernkvist M, Luna Persson N, Audebert S, Lecine P, Sinha I, Liu
M, Schlueter M, Horowitz A, Aase K, Weide T, Borg JP,
Majumdar A, Holmgren L. The Amot/Patj/Syx signaling
complex spatially controls RhoA GTPase activity in migrating
endothelial cells. Blood. 2009 Jan 1;113(1):244-53
Levchenko T, Aase K, Troyanovsky B, Bratt A, Holmgren L.
Loss of responsiveness to chemotactic factors by deletion of
the C-terminal protein interaction site of angiomotin. J Cell Sci.
2003 Sep 15;116(Pt 18):3803-10
Gagné V, Moreau J, Plourde M, Lapointe M, Lord M, Gagnon
E, Fernandes MJ. Human angiomotin-like 1 associates with an
angiomotin protein complex through its coiled-coil domain and
induces the remodeling of the actin cytoskeleton. Cell Motil
Cytoskeleton. 2009 Sep;66(9):754-68
Levchenko T, Bratt A, Arbiser JL, Holmgren L. Angiomotin
expression
promotes
hemangioendothelioma
invasion.
Oncogene. 2004 Feb 19;23(7):1469-73
Bratt A, Birot O, Sinha I, Veitonmäki N, Aase K, Ernkvist M,
Holmgren L. Angiomotin regulates endothelial cell-cell
junctions and cell motility. J Biol Chem. 2005 Oct
14;280(41):34859-69
Mandrawalia R, Tamuli R. AMOT (angiomotin). Atlas Genet
1123
Gene Section
Review
Frédéric Guénard, Francine Durocher
Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CRCHUL, CHUQ
and Laval University, Quebec, G1V 4G2, Canada (FG, FD)
Online updated version : http://AtlasGeneticsOncology.org/Genes/BRCA2ID164ch13q13.html
DOI: 10.4267/2042/44913
The N-terminal part of the BRCA2 protein contains a
transcriptional activation domain (aa 18-105).
BRCA2 exon 11 encodes eight conserved motifs
termed BRC repeats. Each of these repeats is composed
of about 30 residues.
A DNA-binding domain has been located in the Cterminal region of the BRCA2 protein (aa 2478-3185).
It is composed of a conserved helical domain and three
OB folds.
Two nuclear localization signals (NLS) have been
identified in the C-terminal region of BRCA2.
Identity
Other names: BRCC2, BROVCA2, FACD, FAD,
FAD1, FANCB, FANCD, FANCD1, GLM3
HGNC (Hugo): BRCA2
Location: 13q13.1
DNA/RNA
Description
The BRCA2 gene is composed of 27 exons and spans
approximately 84.2 kb of genomic DNA.
Expression
Protein
BRCA2 expression is proportional to the rate of cell
proliferation. Non-dividing cells do not express
BRCA2 while wide expression of BRCA2 was
observed in actively dividing tissues, including the
epithelium of the breast during puberty and pregnancy.
The BRCA2 expression is regulated during the cell
cycle, with highest expression during the S phase of the
cell cycle.
Most of the BRCA2 proteins are associated to DSS1.
The presence of DSS1 was demonstrated to stabilize
the BRCA2 protein.
Description
Localisation
Human BRCA2 protein is composed of 3418 amino
acids (384 kDa).
BRCA2 is a nuclear protein.
Transcription
The BRCA2 gene encodes a 11386 bp mRNA
transcript. Transcription site is located 227 bp upstream
the first ATG of the BRCA2 ORF. The translation start
site is located in exon 2.
Pseudogene
No pseudogene reported.
Structure of BRCA2. BRCA2 is a 3418 aa protein. BRC repeats:
BRCA C-terminal repeats; NLS: Nuclear localization signals.
1124
Guénard F, Durocher F
BRCA2 mutations,
pancreatic cancer.
Function
BRCA2 has been implicated in maintenance of
genomic integrity and in the cellular response to DNA
damage. The BRCA2 protein interacts with the RAD51
recombinase to regulate homologous recombination
(HR). BRCA2 regulates the intracellular localization of
RAD51. It also targets the RAD51 to ssDNA and
inhibits dsDNA binding, thus regulating/enhancing
DNA strand exchange activity of RAD51. CHEK1 and
CHEK2 both phosphorylate the RAD51/BRCA2
complex and regulate the functional association of this
complex in response to DNA damage.
BRCA2 is also implicated in cell cycle checkpoints.
Following exposure to X-rays or UV light, cells
expressing truncated BRCA2 protein exhibit arrest in
the G1 and G2/M phases. BRCA2 protein plays a role
in mitotic spindle assembly checkpoints through
modulation of the level of spindle assembly checkpoint
proteins including Aurora A and Aurora B.
A role in regulation of transcription has been attributed
to BRCA2. BRCA2 binding to the DSS1 protein
appears to be required for proper completion of cell
division in yeast.
The BRCA2 protein demonstrated the ability to
stimulate transcription. For example, exogenous
expression of BRCA2 can stimulate transcription of
androgen receptor-regulated genes. This function of
BRCA2 is regulated by the binding of the EMSY
protein to the region of BRCA2 responsible for
transcriptional activation. An excess of EMSY results
in silencing of BRCA2-driven transcriptional
activation.
BRCA2 localizes to meiotic chromosomes during early
meiotic prophase I when homologous chromosomes
undergo synapsis. Moreover, BRCA2 interacts with the
meiosis-specific recombinase DMC1, thus implicating
BRCA2 in meiotic recombination.
for
prostate
and
Somatic
Somatic mutations in BRCA2 are infrequent in
sporadic breast cancer. Methylation of the BRCA2
promoter has not been detected in normal tissues nor in
breast and ovarian cancers. Loss of heterozygosity at
the BRCA2 locus has been frequently found in sporadic
breast and ovarian tumors.
Implicated in
Breast cancer
Note
Informations regarding breast cancer and BRCA2
mutations and polymorphisms are available in a central
repository formed by the National Human Genome
Research; National Institute of Health. This repository,
named Breast Cancer Information Core (BIC) NHGRI, is available at the following address:
http://research.nhgri.nih.gov/bic/.
Disease
Breast tumors in BRCA2 carriers are found at higher
histologic grade (2 and 3) than sporadic tumors.
Tumors from BRCA2 carriers are more commonly
found to be stage IV than sporadic control tumors and
BRCA2-associated breast cancer cases are more often
node-positive than control breast cancer cases.
Prognosis
BRCA2 mutation carriers show younger mean age at
diagnosis than sporadic breast cancer cases. Bilateral
breast cancer is found more commonly in BRCA2associated breast cancer than in sporadic breast cancer.
ER and PR expression in BRCA2 tumors are similar
than in control tumors, which contrasts with ER and PR
expression found in BRCA1 tumors.
Oncogenesis
It was suggested that genomic rearrangements account
for 7.7% of the BRCA2 mutation spectrum. Loss of the
wild-type allele is not required for breast tumorigenesis
in BRCA2 mutation carriers.
Somatic mutations of the BRCA2 gene are an
infrequent event in sporadic breast cancer tumors. Loss
of heterozygosity at the BRCA2 locus on chromosome
13q12-q13 was observed in approximately 30% of
sporadic breast cancer. Methylation of the CpG
dinucleotide within the BRCA2 promoter is not found
in normal and neoplastic breast tissues.
Homology
BRCA2 homologs have been found in a diverse range
of organisms. In addition to zebrafish and C. elegans,
homologs exist in diverse eukaryotes, from plants to
parasitic organisms.
Low general conservation is found in BRCA2. Higher
level of homology is observed for several segments,
including transactivation domain, BRC repeats and
nuclear localization signals located within C-terminal
region.
Mutations
Male breast cancer
Germinal
Note
A cumulative risk of 6% and 7% of developing breast
cancer by the age of 70 and 80, respectively, has been
estimated for male BRCA2 mutation carriers. BRCA2
mutations have been found in 14% of familial male
breast cancer and 4% of unselected male breast cancer
cases.
High risk of breast and ovarian cancer is associated
with germline BRCA2 mutations. Cumulative risk of
breast cancer in BRCA2 mutation carriers was
estimated to 45% by the age of 70 years while ovarian
cancer risk in carriers was estimated to 11%. Increased
risk of several other cancers are associated with
especially
1125
truncating mutations in these families. However, a
small study conducted on a limited number of families
found BRCA2 mutations in two families. Incomplete
segregation of the mutation with the disease was found
in these families as affected brothers did not carry these
mutations.
Prognosis
BRCA2 mutation carriers have a significantly lower
mean age at diagnosis of prostate cancer and shorter
mean survival time than non-carriers. BRCA2 mutation
carriers show more advanced tumor stage and higher
grade at diagnosis. Prostate cancer carriers of a BRCA2
mutation show poorer survival than BRCA1 carriers.
Prostate cancer patients which are carriers of the
999del5 Icelandic founder mutation appear to have
worse prognosis than non-carriers of this mutation.
Histopathological features of prostate cancer in BRCA2
mutation carriers revealed that prostate cancer
developed in mutation carriers show higher Gleason
scores in than non-carriers.
Oncogenesis
Allelic loss at the BRCA2 locus was identified in a
majority of prostate tumor samples from carriers of the
c.999del5 mutation, thus suggesting that no functional
BRCA2 protein is found in these tumors.
Disease
Male breast cancers are mostly ductal or unclassified
carcinomas. Papillary, mucinous and lobular
carcinomas each represent less than 3% of male breast
cancers. Estrogen receptor and progesterone receptor
expression is found in approximately 90% and 81% of
male breast cancers, respectively.
Prognosis
Overall survival rates for male breast cancers are lower
than for female breast cancers due to the older age and
more advances disease at the time of diagnosis. Male
breast cancers associated with BRCA2 mutation are
diagnosed at younger age than sporadic male breast
cancer cases.
Ovarian cancer
Note
Carriers of mutations in the central portion of BRCA2,
termed OCCR (ovarian cancer cluster region; aa 10122210), are at higher risk of ovarian cancer and lower
breast cancer risk than carriers of mutations outside the
OCCR.
Disease
Ovarian cancer is mostly epithelial tumors (90%) and
lifetime risk of ovarian cancer in the general population
is estimated to be 1-1.5%. Risk of ovarian cancer in
BRCA2 mutation carriers is estimated to be 10%.
Prognosis
BRCA2 ovarian tumors are similar to BRCA1 ovarian
tumors as these two types of tumors are more likely to
be serous adenocarcinomas and higher grade than
control tumors. BRCA2-associated ovarian cancers
occur later in life than BRCA1-related or control
ovarian tumors.
Oncogenesis
Complete loss of the wild-type BRCA2-allele is
observed in BRCA2-associated ovarian cancers. Loss
of heterozygosity at 13q12-q14 is also observed in
sporadic epithelial ovarian tumors. On the other hand,
CpG dinucleotide methylation of the BRCA2 promoter
is not found in sporadic ovarian cancers.
Stomach cancer
Note
Stomach cancer was reported in family members of
women with ovarian cancer carrying a BRCA2
mutation within the OCCR. On the other hand, the
presence of stomach cancer in relatives of ovarian
cancer cases is strongly predictive of the presence of a
BRCA2 mutation. Specifically, the BRCA2 999del5
mutation is associated with an increased risk of
stomach cancer in first- and second-degree relatives.
Assessment of the presence of non-breast or ovarian
cancers in BRCA2 mutation carriers estimated a
relative risk of stomach cancer of 2.59 to be associated
with BRCA2 mutations. Meta-analysis of published
studies latter confirmed increased risk of stomach
cancer in BRCA2 carriers.
Prostate cancer
Pharyngeal cancer
Note
Different studies conducted on BRCA2 mutation
carriers revealed an increased risk of prostate cancer in
BRCA2 mutation carriers. Relative risk associated with
BRCA2 mutations is estimated to be approximately 2.5
to 5.
Protein-truncating BRCA2 mutations are associated
with early-onset prostate cancer. Different studies
revealed that BRCA2 mutations are responsible for
less than 1% of early-onset prostate cancer in the US
Caucasian population while such mutations are
responsible for 2.3% of early-onset prostate cancer
diagnosed in United Kingdom.
Most studies conducted on hereditary prostate cancer
families did not revealed a contribution of BRCA2
Note
An increased risk of buccal cavity and pharynx cancer
was suggested during the assessment of cancers other
than breast and ovarian cancer in BRCA2 mutation
carriers. This was thereafter confirmed in a cohort of
BRCA2 mutation carriers leading to the estimation of a
relative risk of 7.3
(95% CI = 2.0 - 18.6). Higher relative risk of
pharyngeal cancer is found for carriers younger than 65
years old.
Gallbladder and bile duct cancer
Note
Evaluation of risks of cancers other than breast and
1126
their relatives, other studies did not confirm this
association.
ovarian cancers in BRCA2 carriers found a higher risk
of gallbladder and bile duct cancer in BRCA2 carriers
(RR = 4.97; 95% CI = 1.50-16.52). Specifically, the
6167delT Jewish Ashkenazi founder BRCA2 mutation
was observed at significantly higher rate in bile duct
cancer cases than in population controls.
Bone cancer
Note
An excess risk of bone cancer (RR = 14.4; 95% CI =
2.9 - 42.1) was observed in a cohort of BRCA2
mutation carriers from the Netherlands.
Colon cancer
Note
It was reported that risk of colorectal cancer in firstdegree relatives of BRCA2 mutation carriers affected
with ovarian cancer is increased by threefold for
BRCA2 mutations located within the OCCR.
Analysis of a BRCA2 mutation in different families led
to the suggestion that BRCA2 mutations predispose to
colon cancer. It was thereafter reported that BRCA2
mutation carriers are at increased risk of colon cancer
before the age of 65 years old. The association of
BRCA2 mutations with colon cancer was latter
confirmed in a meta-analysis.
Fanconi anemia (complementation
group D1)
Note
Biallelic mutations of the BRCA2 gene are responsible
for Fanconi anemia subgroup D1 (FA-D1).
Disease
Fanconi anemia (FA) is a rare recessive disease
characterized by various clinical features. Many
developmental defects are found in FA patients. Radial
aplasia, microcephaly, microphthalmia, small stature,
skin hyperpigmentation and malformation of the
kidneys are encountered in FA patients. Very high
frequency of bone marrow failure, leukemia and
squamous cell carcinoma of the head and neck as well
as gynecological squamous cell carcinoma are
associated with FA. Bone marrow failure generally
leads to aplastic anemia during the first decade of life.
Esophageal carcinoma and liver, brain, skin and renal
tumors are also found in FA patients.
Prognosis
The FA-D1 and FA-N subgroups are clinically
different from other FA subgroups as these subgroups
are associated with increased predisposition to solid
childhood malignancies such as medulloblastoma and
Wilms tumor.
Cytogenetics
At the cellular level, FA is a chromosomal fragility
syndrome. FA cells are hypersensitive to DNA
interstrand crosslinking agents such as mitomycin C,
diepoxybutane and cisplatin. In addition to
hypersensitivity to these agents, FA cells show an
increased number of spontaneous breaks.
Pancreas cancer
Note
Different studies suggested that BRCA2 mutations are
associated with less than 1% of sporadic pancreatic
cancer in Caucasians while such mutations could
account for 10% of sporadic pancreatic cancer in
Ashkenazi Jewish population.
Approximately 10% of patients developing pancreatic
cancer show patterns of hereditary predisposition.
Screening of BRCA2 mutations in familial pancreatic
cancer cases suggested that BRCA2 mutations account
for 6-17% of these families. Following the
identification of germline BRCA2 mutations in
pancreatic cancer, it was evaluated that BRCA2
mutations confer roughly a 3.5-folds increased risk.
Relative risk of pancreatic cancer was found to be
higher at younger age (younger than 65 years old).
Different studies evaluated the lifetime risk of
pancreatic cancer in BRCA2 mutation carriers to be
approximately 5%.
Prognosis
Among human malignancies, pancreatic cancer has one
of the worst prognoses.
Oncogenesis
Pancreatic intraepithelial neoplasia (PanIN) analysis in
BRCA2 mutation carriers revealed that loss of the wild
type BRCA2 allele is found solely in high-grade
PanIN, thus suggesting that biallelic inactivation of the
BRCA2 gene is a late event in pancreatic tumorigenesis
in patients with germline BRCA2 mutation.
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5;95(3):214-21
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Brca2 is involved in meiosis in Arabidopsis thaliana as
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Caldas C, Kouzarides T. EMSY links the BRCA2 pathway to
sporadic breast and ovarian cancer. Cell. 2003 Nov
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Heterogenic loss of the wild-type BRCA allele in human breast
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1131
Gene Section
Review
FST (follistatin)
Michael Grusch
Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a,
A-1090 Vienna, Austria (MG)
Online updated version : http://AtlasGeneticsOncology.org/Genes/FSTID44477ch5q11.html
DOI: 10.4267/2042/44914
rise to two main transcripts of 1122 bp (transcript
variant FST344) and 1386 bp (transcript variant
FST317). The first exon encodes the signal peptide, the
second exon the N-terminal domain and exons 3-5 each
code for a follistatin module. Alternative splicing leads
to usage of either exon 6A, which codes for an acidic
region in FST344 or exon 6B, which contains two
bases of the stop codon of FST317 (Shimasaki et al.,
1988).
Identity
Other names: FS
HGNC (Hugo): FST
Location: 5q11.2
Local order
RPS19P4 (ribosomal protein S19 pseudogene 4) - FST
- NDUFS4 (NADH dehydrogenase (ubiquinone) Fe-S
protein 4).
Transcription
DNA/RNA
Transcription of FST mRNA was shown to be
stimulated by TGF beta and activin A via Smad
proteins (Bartholin et al., 2002), which seems to be part
of a negative feedback loop as FST can antagonize
activin A (see below).
Description
The human FST gene is comprised of six exons
spanning 5329 bp on chromosome 5q11.2 and gives
Intron/exon structure of the FST gene and domain architecture of FST proteins. 1, 2, 3, 4, 5, 6A, 6B: exon number; SP: signal peptide;
NTD: N-terminal domain; FSD: follistatin domain; AT: acidic tail.
1132
FST (follistatin)
Grusch M
bound activin is unable to initiate signal transduction
and consequently follistatin is a potent antagonist of
physiological activin signals. Of the three follistatin
domains present in all follistatin isoforms, (Shimasaki
et al., 1988) the first two, but not the third, are
necessary for activin A binding (Keutmann et al., 2004;
Harrington et al., 2006). Aside from activins, follistatin
also binds several bone morphogenetic proteins (BMP)
including BMP2, BMP4, BMP6 and BMP7 (Iemura et
al., 1998; Glister et al., 2004). In 2004 it was shown
that follistatin binds myostatin (also known as growth
and differentiation factor 8, GDF8) with high affinity
and thereby is able to antagonize the inhibitory effect
of myostatin on muscle growth (Amthor et al., 2004).
The functional significance of the interaction between
follistatin and angiogenin, a pro-angiogenic factor
unrelated to the TGF beta family, remains to be
determined (Gao et al., 2007). The interaction of
follistatin with heparin and heparan sulfates is isoform
specific. Follistatin 288 binds to heparan sulfates,
whereas this binding is blocked by the acidic tail of
follistatin 315 (Sugino et al., 1993).
Knock-out mice for follistatin die within hours after
birth and show multiple abnormalities of muscles, skin
and skeleton (Matzuk et al., 1995). Evidence from
many organs and tissues shows that counterbalancing
of signals from TGF beta family members by follistatin
is crucial for normal tissue development, architecture
and function (de Kretser et al., 2004; McDowall et al.,
2008; Kreidl et al., 2009; Antsiferova et al., 2009).
Due to the capability for efficient antagonization of
signals from activin and myostatin, the therapeutic
application of follistatin has been discussed in several
clinical conditions involving elevated activin/myostatin
activity. Potential areas of application include blocking
increased activin expression in inflammation (Phillips
et al., 2009) and fibrotic disorders (Aoki and Kojima,
2007) and inhibition of myostatin in muscle diseases
(Rodino-Klapac et al., 2009).
Other factors and pathways that have been
demonstrated to stimulate follistatin gene transcription
are gonadotropin-releasing hormone (GnRH) acting via
cAMP and CREB (Winters et al., 2007), GLI2, a
transcription factor activated by hedgehog signaling
(Eichberger et al., 2008), dexamethasone (Hayashi et
al., 2009), androgens and activators of wnt signaling
(Willert et al., 2002; Yao et al., 2004; Singh et al.,
2009). Repression of the follistatin promoter in
response to peroxisome proliferator-activated receptor
gamma was mediated via SP1 (Necela et al., 2008).
Protein
Description
Mature secreted follistatin protein exists in three main
forms consisting of 288, 303, and 315 amino acids
(Sugino et al., 1993). The FST344 transcript gives rise
to a protein precursor of 344 amino acids, which results
in the mature 315 amino acid form after removal of the
signal peptide. A fraction of follistatin 315 is further
converted to the 303 amino acid form by proteolytic
cleavage at the C-terminus. Signal peptide removal of
FST317 leads to the mature 288 amino acid form of
follistatin. All forms of follistatin contain three
follistatin domains (FSD) characterized by a conserved
arrangement of 10 cysteine residues. The N-terminal
subdomains of the FSD have similarity with EGF-like
modules, whereas the C-terminal regions resemble the
Kazal domains found in multiple serine protease
inhibitors. The follistatin protein contains two potential
N-glycosilation sites on asparagines 124 and 288.
Localisation
Follistatin is expressed in a wide variety of tissues and
organs with the highest expression in the ovaries and
testes (Phillips and de Kretser, 1998; Tortoriello et al.,
2001). The signal peptide directs the nascent protein to
the secretory pathway and follistatin has been detected
in human serum and in cell culture supernatants of
multiple cell lines (Phillips and de Kretser, 1998).
Among the follistatin isoforms FST315 was secreted
faster than FST288 (Schneyer et al., 2003) and due to
the lack of binding to cell-surface heparin-sulfated
proteoglycans, a larger fraction of FST315 enters the
circulation (Schneyer et al., 1996).
Homology
The follistatin module with its characteristic spacing of
cysteines represents a conserved protein domain.
Follistatin modules are found in varying numbers in a
wider set of secreted proteins including FSTL1,
SPARC/osteonectin, or agrin (Ullman and Perkins,
1997). Among these, follistatin-like 3 (FSTL3, FLRG)
shares a similar overall domain architecture with
follistatin, but harbors only two instead of three
follistatin modules (Tortoriello et al., 2001). With
respect to activin binding ability, functional homology
among follistatin domain-containing proteins is only
found between follistatin and FSTL3, whereas all other
follistatin family proteins have not been demonstrated
to bind proteins of the TGF beta family (Tsuchida et
al., 2000). Follistatin is also highly conserved between
species with around 97% amino acid identity in human,
mouse and rat.
Function
Follistatin binds to several members of the TGF beta
family and blocks the interaction of these cytokines
with their cognate receptors. Follistatin was first
identified as a factor that could inhibit the release of
follicle-stimulating hormone from pituitary cells (Ueno
et al., 1987). It binds activins A, B and AB with high
affinity and was also reported to bind activin E but not
activin C (Nakamura et al., 1990; Schneyer et al., 1994;
Hashimoto et al., 2002; Wada et al., 2004). Follistatin-
1133
FST (follistatin)
Grusch M
Sugino K, Kurosawa N, Nakamura T, Takio K, Shimasaki S,
Ling N, Titani K, Sugino H. Molecular heterogeneity of
follistatin, an activin-binding protein. Higher affinity of the
carboxyl-terminal truncated forms for heparan sulfate
proteoglycans on the ovarian granulosa cell. J Biol Chem.
1993 Jul 25;268(21):15579-87
Implicated in
Malignancy
Note
Overexpression of follistatin has been found in rat and
mouse models of hepatocellular carcinoma (HCC)
(Rossmanith et al., 2002; Fujiwara et al., 2008) as well
as in tumor tissue and serum of HCC patients (Yuen et
al., 2002; Grusch et al., 2006; Beale et al., 2008).
However, follistatin had no benefit as surveillance
biomarker for HCC development in patients with
alcoholic and non-alcoholic liver disease (ALD and
NAFLD) due to the already elevated levels in the
underlying liver pathologies (Beale et al., 2008).
Follistatin overexpression was also demonstrated in
human melanoma cell lines (Stove et al., 2004) and has
been suggested as candidate biomarker for lung cancer
(Planque et al., 2009).
Schneyer AL, Rzucidlo DA, Sluss PM, Crowley WF Jr.
Characterization of unique binding kinetics of follistatin and
activin or inhibin in serum. Endocrinology. 1994
Aug;135(2):667-74
Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A.
Multiple defects and perinatal death in mice deficient in
follistatin. Nature. 1995 Mar 23;374(6520):360-3
Schneyer AL, Hall HA, Lambert-Messerlian G, Wang QF, Sluss
P, Crowley WF Jr. Follistatin-activin complexes in human
serum and follicular fluid differ immunologically and
biochemically. Endocrinology. 1996 Jan;137(1):240-7
Ullman CG, Perkins SJ. The Factor I and follistatin domain
families: the return of a prodigal son. Biochem J. 1997 Sep
15;326 ( Pt 3):939-41
Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T,
Shimasaki S, Sugino H, Ueno N. Direct binding of follistatin to
a complex of bone-morphogenetic protein and its receptor
inhibits ventral and epidermal cell fates in early Xenopus
embryo. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9337-42
Endometriosis
Note
Follistatin was increased in serum of women with
ovarian endometriosis and suggested as biomarker for
endometrioma (Florio et al., 2009).
Phillips DJ, de Kretser DM. Follistatin: a multifunctional
regulatory protein. Front Neuroendocrinol. 1998 Oct;19(4):287322
Polycystic ovary syndrome
Urbanek M, et al. Thirty-seven candidate genes for polycystic
ovary syndrome: strongest evidence for linkage is with
follistatin. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8573-8
Note
A genetic linkage analysis found evidence for linkage
of follistatin with polycystic ovary syndrome (PCOS)
(Urbanek et al., 1999). Another study reported that the
follistatin gene is not a susceptibility locus for PCOS
but a single nucleotide polymorphism of the gene may
be involved in the hyperandrogenaemia of the disease
(Jones et al., 2007).
Tsuchida K, Arai KY, Kuramoto Y, Yamakawa N, Hasegawa Y,
Sugino H. Identification and characterization of a novel
follistatin-like protein as a binding protein for the TGF-beta
family. J Biol Chem. 2000 Dec 29;275(52):40788-96
Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer
AL. Human follistatin-related protein: a structural homologue of
follistatin with nuclear localization. Endocrinology. 2001
Aug;142(8):3426-34
Liver failure
Note
Serum levels of follistatin and activin A were increased
in patients with acute liver failure and it was suggested
that a decreased follistatin/activin A ratio in the blood
may be an indicator for the severity of liver injury in
hepatitis-related acute liver disease (Hughes and Evans,
2003; Lin et al., 2006).
Bartholin L, Maguer-Satta V, Hayette S, Martel S, Gadoux M,
Corbo L, Magaud JP, Rimokh R. Transcription activation of
FLRG and follistatin by activin A, through Smad proteins,
participates in a negative feedback loop to modulate activin A
function. Oncogene. 2002 Mar 28;21(14):2227-35
Hashimoto O, Tsuchida K, Ushiro Y, Hosoi Y, Hoshi N, Sugino
H, Hasegawa Y. cDNA cloning and expression of human
activin betaE subunit. Mol Cell Endocrinol. 2002 Aug 30;194(12):117-22
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1134
FST (follistatin)
Grusch M
Schneyer A, Schoen A, Quigg A, Sidis Y. Differential binding
and neutralization of activins A and B by follistatin and
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Beale G, Chattopadhyay D, Gray J, Stewart S, Hudson M, Day
C, Trerotoli P, Giannelli G, Manas D, Reeves H. AFP, PIVKAII,
GP3, SCCA-1 and follisatin as surveillance biomarkers for
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Eichberger T, et al. GLI2-specific transcriptional activation of
the bone morphogenetic protein/activin antagonist follistatin in
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de Kretser DM, et al. The role of activin, follistatin and inhibin in
testicular physiology. Mol Cell Endocrinol. 2004 Oct 15;225(12):57-64
Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y,
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2008 Oct 9;27(46):6002-11
Glister C, Kemp CF, Knight PG. Bone morphogenetic protein
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actions of BMP-4, -6 and -7 on granulosa cells and differential
modulation of Smad-1 phosphorylation by follistatin.
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McDowall M, Edwards NM, Jahoda CA, Hynd PI. The role of
activins and follistatins in skin and hair follicle development and
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domains in follistatin biological action. Mol Endocrinol. 2004
Jan;18(1):228-40
Necela BM, Su W, Thompson EA. Peroxisome proliferatoractivated receptor gamma down-regulates follistatin in
intestinal epithelial cells through SP1. J Biol Chem. 2008 Oct
31;283(44):29784-94
Stove C, Vanrobaeys F, Devreese B, Van Beeumen J, Mareel
M, Bracke M. Melanoma cells secrete follistatin, an antagonist
of activin-mediated growth inhibition. Oncogene. 2004 Jul
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MM, Werner S, Kögel H. Keratinocyte-derived follistatin
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Kojima I. Assessment of the function of the betaC-subunit of
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ovarian endometriosis. Hum Reprod. 2009 Oct;24(10):2600-6
Yao HH, Matzuk MM, Jorgez CJ, Menke DB, Page DC, Swain
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Jun;230(2):210-5
Hayashi K, Yamaguchi T, Yano S, Kanazawa I, Yamauchi M,
Yamamoto M, Sugimoto T. BMP/Wnt antagonists are
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1135
Gene Section
Review
Rosalyn M Adam, Joshua R Mauney
Urological Diseases Research Center, Children's Hospital Boston and Harvard Medical School, Boston, MA
02115, USA (RMA, JRM)
Online updated version : http://AtlasGeneticsOncology.org/Genes/GATA6ID40690ch18q11.html
DOI: 10.4267/2042/44915
family members. The non-coding exons possess
regulatory capability and may act to promote
transcription. Two isoforms of GATA6 are expressed
from two distinct open reading frames and distinct
initiator Met codons as a result of leaky ribosome
scanning.
There are no apparent differences in the amounts or
sites of expression of the two transcripts that result
from initiation at different Met codons.
Identity
Other names: GATA-6
HGNC (Hugo): GATA6
Location: 18q11.2
Local order: GATA-6 is flanked in the direction of the
centromere by:
LOC100128893, hypothetical protein LOC100128893 RNU7-17P, RNA U7 small nuclear 17 pseudogene LOC100287318 - RPL34P32, ribosomal protein L34
pseudogene 32 - MIB1, mindbomb homolog 1 - MIR12 - MIR133A1.
GATA6 is flanked in the direction of the telomere by:
CTAGE1, cutaneous T-cell lymphoma-associated
antigen 1 - RPS4P18, ribosomal protein S4X
pseudogene 18 - RBBP8, retinoblastoma binding
protein 8 - CABLES1, Cdk5 and Abl enzyme substrate
1 - C18orf45, chromosome 18 open reading frame 45 RIOK3, RIO kinase 3.
Note: GATA6 is one of a family of 6 related GATA
binding proteins. All six proteins possess zinc fingertype DNA binding domains and act as transcription
factors.
Protein
Description
The GATA6 protein products that result from different
initiation codons comprise a long isoform of 595 aa (64
kDa) and a short isoform of 449 aa (52 kDa).
Both isoforms possess an N-terminal transactivation
domain and two zinc finger domains, all of which are
essential for activity (Takeda et al., 2004). The two
isoforms display different transactivation potential on
GATA6-dependent promoters with long GATA6
showing higher activity than short GATA6.
Expression
GATA6 is expressed predominantly in tissues of
mesodermal and endodermal origin. In early
development, high levels are detected in the precardiac
mesoderm, embryonic heart tube and primitive gut. As
development proceeds GATA6 expression is observed
in vascular smooth muscle cells, the developing
airways, urogenital ridge and bladder (Morrisey et al.,
1996).
DNA/RNA
Description
Genomic DNA encoding GATA6 encompasses 33088
bp on the long arm of chromosome 18. The gene is
encoded on the plus (forward) strand.
Transcription
Localisation
The pre-mRNA comprises 7 exons, one of which is
non-coding, and 6 introns. The mouse and human
GATA6 genes contain two alternative non-coding
upstream exons, transcribed from two distinct
promoters (Brewer et al., 1999), similar to other GATA
Nuclear.
Function
GATA6 binds to a 5'-(T/A)GATA(A/G)-3' consensus
sequence in the promoters of target genes to regulate
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Adam RM, Mauney JR
their transcription. GATA6 is post-translationallly
modified by MEK/Erk-dependent phosphorylation at
Ser120 (S266 in long GATA6). Ser120Ala mutation
abolished GATA6 DNA-binding activity and GATA6mediated Nox1 promoter activation, and also
suppressed growth of CaCo-2 colon carcinoma cells
(Adachi et al., 2008). GATA6 activity is also regulated
through interaction with members of the Friend of
GATA (FOG) family of proteins. Two FOG proteins
have been identified in mice and humans, FOG-1 and
FOG-2, and their interaction with GATA factors can
promote or inhibit GATA activity, depending on
context (Cantor and Orkin, 2005).
GATA6 is essential for normal development, since
genetic knockout in mice leads to embryonic lethality
as early as E6.5. The underlying defect in GATA6-null
mice was determined to be a failure of endoderm
differentiation resulting in attenuated expression of
GATA6 target genes including GATA4, HNF3beta and
HNF4 (Morrisey et al., 1998). GATA6 was shown
subsequently to be essential for early extraembryonic
development (Koutsourakis et al., 1999). Partial rescue
of GATA6-deficient embryos by tetraploid embryo
complementation demonstrated additional functions for
GATA6 in liver development. The early lethality in
GATA6-null embryos could be overcome by providing
wild type extraembryonic endoderm and allowed
embryos to proceed through gastrulation. However,
although hepatic specification occurred normally in
rescued GATA6-/- embryos, normal differentiation did
not occur and hepatic development arrested at E10.5
(Zhao et al., 2005).
Early development of other organ systems was
unaffected in rescued GATA6-null embryos, including
the heart and vasculature. Interestingly, conditional
deletion of GATA6 using SM22alpha promoter-driven
Cre recombinase led to perinatal lethality as a result of
cardiovascular defects emerging later in embryonic
development. In that analysis, the underlying
mechanism was determined to be diminished
expression of the vascular and neuronal guidance
molecule semaphorin 3C, a direct target of GATA6
(Lepore et al., 2006). Consistent with GATA6dependent regulation of Sema3C in mice, mutations in
GATA6 were found to cause cardiac outflow tract
defects in humans by dysregulating semaphorindependent signaling (Kodo et al., 2009). In general,
GATA6 does not act alone in regulating developmental
processes, but rather achieves its effects through
physical and functional interaction with other
transcription factors and signaling molecules, including
FOG factors, GATA4 (Xin et al., 2006; Zhao et al.,
2008), Tbx5 (Maitra et al., 2009), members of the
Nkx2 family (Peterkin et al., 2003) and Wnt family
proteins. The complexity of these interactions is
exemplified by the functional cooperation of Wnt2 and
GATA6 in regulating heart development. In this case,
GATA6 not only regulates Wnt2 transcription during
heart development through direct binding to the Wnt2
promoter (Alexandrovich et al., 2006), but is itself
regulated by a Wnt2-dependent mechanism, since
GATA6 expression is markedly reduced in Wnt2-null
mice (Tian et al., 2010).
GATA6 has also been implicated in regulating
development of other organs including the lung and
pancreas. In the lung, GATA6 has been shown to
regulate specification, differentiation and maturation of
the pulmonary epithelium as well as branching
morphogenesis (Keijzer et al., 2001; Yang et al., 2002;
Liu et al., 2002; Zhang et al., 2008). Inhibition of
GATA6 at E6.0 prevented alveolar maturation and also
diminished expression of surfactant proteins required
for normal pulmonary function. In the pancreas,
GATA6 is co-expressed with GATA4 in the epithelium
early in development, but as development progresses is
expressed only in endocrine cells. Ablation of GATA6
function using a dominant inhibitory engrailed fusion
protein strategy led to a reduction or complete loss of
pancreatic tissue, consistent with a critical role for
GATA6 in pancreatic development (Decker et al.,
2006).
GATA6 has also been implicated in postnatal
maintenance of the differentiated phenotype in various
tissues including bladder smooth muscle (Kanematsu,
2007), gut mucosa (Fang, 2006) and airway epithelium
(Zhang, 2008).
Homology
GATA6 shares homology with the other 5 GATA
factors, all of which are evolutionarily conserved across
multiple species. All 6 GATA factors possess two zinc
fingers
of
the
Cys-X2-Cys-X17-Cys-X2-Cys
configuration. The C-terminal zinc finger mediates
high affinity DNA binding and the N-terminal zinc
finger stabilizes the interaction with DNA.
Mutations
Germinal
None known.
Somatic
Two mutations in GATA6 were identified in patients
with persistent truncus arteriosus, as follows (Kodo et
al., 2009).
GATA6-E486del resulted in conversion of P489 to a
stop codon, disruption of the nuclear localization signal
and truncation of the C-terminus by 100 aa. The
encoded protein showed abnormal nuclear localization,
no transcriptional activity against atrial natriuretic
factor and WNT2 promoters and was dominant
negative.
GATA6-N466H contained a point mutation in the Cterminal zinc finger domain. Despite normal nuclear
localization, the encoded protein had no transcriptional
activity against atrial natriuretic factor and WNT2
promoters.
1137
Adam RM, Mauney JR
histone deacetylase activity with trichostatin A restored
GATA6 and GATA4 expression in cell lines (Caslini et
al., 2006).
Prognosis
Loss of GATA6 expression precedes neoplastic
transformation in ovarian surface epithelia (Cai et al.,
2009) and is correlated with loss of markers of
differentiated epithelia (Capo-chichi et al., 2003).
Although a majority of ovarian carcinomas retained
GATA4 expression, most had either aberrantly
localized or absent GATA6 expression. Cytoplasmic
expression of GATA6 showed a correlation with
overall survival, but this association did not reach
statistical significance (McEachin, 2008).
Implicated in
Pancreatic cancer, pancreatobiliary
cancer
Disease
Genomic profiling of pancreatic and bile duct cancers
revealed focal amplification at 18q11.2 that encoded
GATA6. Amplification led to overexpression of
GATA6 at both mRNA and protein levels in nearly
50% of tumor samples, whereas no normal pancreatic
tissues showed overexpression (Kwei et al., 2008; Fu et
al., 2008). Consistent with an oncogenic role for
GATA6 in pancreatic cancer, RNAi-mediated silencing
in pancreatic cancer cell lines in which GATA6 was
amplified decreased cell cycle transit, growth and
clonogenic ability (Kwei et al., 2008). Conversely
forced expression of GATA6 in a pancreatic cancer cell
line stimulated anchorage-independent growth and
proliferation (Fu et al., 2008).
Prognosis
GATA6 silencing by RNAi in pancreatic cancer cells in
vitro reduced proliferation, cell cycle transit and colony
formation, whereas forced overexpression promoted
colony formation in soft agar and enhanced
proliferation, consistent with a role for GATA6 in
driving the tumorigenic phenotype.
Cytogenetics
Focal amplification of the locus encoding GATA6 at
18q11.2 was identified by array-based genomic
profiling and validated by fluorescence in situ
hybridization, quantitative PCR, immunohistochemical
analysis and immunoblotting.
Gastrointestinal cancer
Disease
Expression of GATA6 has been linked, both positively
and negatively, to development of gastrointestinal tract
tumors.
Prognosis
GATA6 expression was found to be decreased in colon
carcinoma compared to normal intestinal tissue or
benign intestinal lesions (Haveri et al., 2008), which
showed robust expression, especially in cells with
proliferative capacity. Conversely GATA6 was
reported to be overexpressed in human colon cancer
cells, where it contributes to silencing of 15lipoxygenase-1 (Shureiqi et al., 2007). The biological
significance of this discrepancy in GATA6 expression
between colon cancer cells and tissues has not been
determined. Expression profiling of Barrett's esophagus
and adenocarcinoma to identify genes whose
expression correlated with disease progression revealed
changes in GATA6 expression among other genes,
consistent with upregulation of GATA6 in the
transition from normal esophageal epithelium to
carcinoma (Kimchi et al., 2005).
Ovarian cancer
Disease
Consistent with their expression in the mouse ovary,
GATA6, GATA4 and FOG2 are also expressed in
human ovary and in tumors derived from granulosa and
thecal cells (Laitinen, 2000). Under normal conditions,
both GATA4 and GATA6 are robustly expressed in
ovarian surface epithelial cells. However, in a majority
of ovarian carcinomas, GATA6 is lost or mislocalized
to the cytoplasm (Capo-chichi et al., 2003; McEachin et
al., 2008), leading to irreversible epithelial
dedifferentiation (Capo-chichi et al., 2003). Expression
of GATA4 and GATA6 was shown to correlate with
specific histological subtypes of ovarian cancer. In
particular, although expression of both factors was lost
in the over 80% of endometrioid, clear cell and serous
tumors, GATA4 and GATA6 expression persisted in
mucinous carcinomas (Cai et al., 2009). Loss of GATA
factor expression preceded neoplastic transformation,
consistent with an important role for these proteins in
tumor development. The mechanism underlying loss of
GATA6 and GATA4 expression in ovarian cancer cell
lines was demonstrated to be histone deacetylation at
the GATA factor promoter regions. Inhibition of
Lung cancer
Disease
Despite substantial evidence linking GATA6 to
pulmonary development, only one study has
investigated the potential role of GATA6 in lung
cancer. Specifically, expression of GATA6 was
evaluated in malignant mesothelioma and pleural
metastases of lung adenocarcinomas and staining
patterns correlated with biological and clinical
outcomes. Nuclear immunoreactivity for GATA-6 was
stronger and more frequent in malignant mesothelioma
than in metastatic lung adenocarcinoma (Lindholm et
al., 2009). However, no relationship was found
between GATA6 expression and growth or apoptotic
endpoints.
Prognosis
Prognosis was better in malignant mesothelioma
patients whose tumors expressed GATA-6 compared to
1138
Adam RM, Mauney JR
those whose tumors had no GATA-6 expression, and
the relationship was highly statistically significant.
Reciprocal changes in the expression of transcription factors
GATA-4 and GATA-6 accompany adrenocortical tumorigenesis
in mice and humans. Mol Med. 1999 Jul;5(7):490-501
Adrenocortical cancer
Koutsourakis M, Langeveld A, Patient R, Beddington R,
Grosveld F. The transcription factor GATA6 is essential for
early extraembryonic development. Development. 1999
May;126(9):723-32
Disease
GATA6 has been implicated in development of the
normal adrenal gland. GATA6 mRNA, although
expressed in the normal adrenal cortex was found to be
absent from experimental mouse adrenocortical tumors,
whereas GATA-4 showed the opposite pattern (Kiiveri,
1999; Rahman et al., 2001). GATA-6 expression was
also decreased in human adrenocortical carcinomas
compared to normal adrenal tissue and adenomas
(Kiiveri et al., 2004). The physiologic relevance of
altered GATA6 expression in adrenocortical
tumorigenesis has not yet been elucidated. However,
based on expression of the CDK inhibitor p21 and
proliferation marker Ki67, GATA-6 expression in
adrenocortical tumors does not appear to be linked to
regulation of cell proliferation.
Prognosis
The prognostic significance of GATA-6 in
adrenocortical tumors has not been determined.
Laitinen MP, Anttonen M, Ketola I, Wilson DB, Ritvos O,
Butzow R, Heikinheimo M. Transcription factors GATA-4 and
GATA-6 and a GATA family cofactor, FOG-2, are expressed in
human ovary and sex cord-derived ovarian tumors. J Clin
Endocrinol Metab. 2000 Sep;85(9):3476-83
Keijzer R, van Tuyl M, Meijers C, Post M, Tibboel D, Grosveld
F, Koutsourakis M. The transcription factor GATA6 is essential
for branching morphogenesis and epithelial cell differentiation
during fetal pulmonary development. Development. 2001
Feb;128(4):503-11
Rahman NA, Kiiveri S, Siltanen S, Levallet J, Kero J, Lensu T,
Wilson DB, Heikinheimo MT, Huhtaniemi IT. Adrenocortical
tumorigenesis in transgenic mice: the role of luteinizing
hormone receptor and transcription factors GATA-4 and
GATA-61. Reprod Biol. 2001 Jul;1(1):5-9
Liu C, Morrisey EE, Whitsett JA. GATA-6 is required for
maturation of the lung in late gestation. Am J Physiol Lung Cell
Mol Physiol. 2002 Aug;283(2):L468-75
Yang H, Lu MM, Zhang L, Whitsett JA, Morrisey EE. GATA6
regulates differentiation of distal lung epithelium. Development.
2002 May;129(9):2233-46
Germ cell tumors
Disease
Germ cell tumors comprise a heterogeneous group of
lesions, including teratomas, yolk sac tumors and
embryonal carcinoma. Using in situ hybridization and
immunohistochemical staining, GATA6 was evaluated
in pediatric germ cell tumors and was found to be
expressed in a majority of yolk sac tumors. GATA6
expression was also evident in distinct cell types
comprising teratomas, including gut and airway
epithelia (Siltanen et al., 2003), but was variable in
carcinoma in situ of the testis and absent from
embryonal carcinomas and choriocarcinomas (Salonen
et al., 2010).
Prognosis
The prognostic role of GATA6 in germ cell tumors is
unknown.
Capo-chichi CD, Roland IH, Vanderveer L, Bao R, Yamagata
T, Hirai H, Cohen C, Hamilton TC, Godwin AK, Xu XX.
Anomalous expression of epithelial differentiation-determining
GATA factors in ovarian tumorigenesis. Cancer Res. 2003 Aug
15;63(16):4967-77
Peterkin T, Gibson A, Patient R. GATA-6 maintains BMP-4 and
Nkx2 expression during cardiomyocyte precursor maturation.
EMBO J. 2003 Aug 15;22(16):4260-73
Siltanen S, Heikkilä P, Bielinska M, Wilson DB, Heikinheimo M.
Transcription factor GATA-6 is expressed in malignant
endoderm of pediatric yolk sac tumors and in teratomas.
Pediatr Res. 2003 Oct;54(4):542-6
Takeda M, Obayashi K, Kobayashi A, Maeda M. A unique role
of an amino terminal 16-residue region of long-type GATA-6. J
Biochem. 2004 May;135(5):639-50
Cantor AB, Orkin SH. Coregulation of GATA factors by the
Friend of GATA (FOG) family of multitype zinc finger proteins.
Semin Cell Dev Biol. 2005 Feb;16(1):117-28
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Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K,
Takahashi T, Matsuoka R, Yamagishi H. GATA6 mutations
cause human cardiac outflow tract defects by disrupting
semaphorin-plexin signaling. Proc Natl Acad Sci U S A. 2009
Aug 18;106(33):13933-8
Kanematsu A, Ramachandran A, Adam RM. GATA-6 mediates
human bladder smooth muscle differentiation: involvement of a
novel enhancer element in regulating alpha-smooth muscle
actin gene expression. Am J Physiol Cell Physiol. 2007
Sep;293(3):C1093-102
Lindholm PM, Soini Y, Myllärniemi M, Knuutila S, Heikinheimo
M, Kinnula VL, Salmenkivi K. Expression of GATA-6
transcription factor in pleural malignant mesothelioma and
metastatic pulmonary adenocarcinoma. J Clin Pathol. 2009
Apr;62(4):339-44
Shureiqi I, Zuo X, Broaddus R, Wu Y, Guan B, Morris JS,
Lippman SM. The transcription factor GATA-6 is
overexpressed in vivo and contributes to silencing 15-LOX-1 in
vitro in human colon cancer. FASEB J. 2007 Mar;21(3):743-53
Maitra M, Schluterman MK, Nichols HA, Richardson JA, Lo
CW, Srivastava D, Garg V. Interaction of Gata4 and Gata6 with
Tbx5 is critical for normal cardiac development. Dev Biol. 2009
Feb 15;326(2):368-77
Adachi Y, Shibai Y, Mitsushita J, Shang WH, Hirose K, Kamata
T. Oncogenic Ras upregulates NADPH oxidase 1 gene
expression through MEK-ERK-dependent phosphorylation of
GATA-6. Oncogene. 2008 Aug 21;27(36):4921-32
Salonen J, Rajpert-De Meyts E, Mannisto S, Nielsen JE,
Graem N, Toppari J, Heikinheimo M. Differential
developmental expression of transcription factors GATA-4 and
GATA-6, their cofactor FOG-2 and downstream target genes in
testicular carcinoma in situ and germ cell tumors. Eur J
Endocrinol. 2010 Mar;162(3):625-31
Fu B, Luo M, Lakkur S, Lucito R, Iacobuzio-Donahue CA.
Frequent genomic copy number gain and overexpression of
GATA-6 in pancreatic carcinoma. Cancer Biol Ther. 2008
Oct;7(10):1593-601
Haveri H, Westerholm-Ormio M, Lindfors K, Mäki M, Savilahti
E, Andersson LC, Heikinheimo M. Transcription factors GATA4 and GATA-6 in normal and neoplastic human gastrointestinal
mucosa. BMC Gastroenterol. 2008 Apr 11;8:9
Tian Y, Yuan L, Goss AM, Wang T, Yang J, Lepore JJ,
D, Schwartz RJ, Patel V, Cohen ED, Morrisey
Characterization and in vivo pharmacological rescue
Wnt2-Gata6 pathway required for cardiac inflow
development. Dev Cell. 2010 Feb 16;18(2):275-87
Kwei KA, Bashyam MD, Kao J, Ratheesh R, Reddy EC, Kim
YH, Montgomery K, Giacomini CP, Choi YL, Chatterjee S,
Karikari CA, Salari K, Wang P, Hernandez-Boussard T,
Swarnalata G, van de Rijn M, Maitra A, Pollack JR. Genomic
profiling identifies GATA6 as a candidate oncogene amplified
in pancreatobiliary cancer. PLoS Genet. 2008 May
23;4(5):e1000081
Zhou
EE.
of a
tract
Adam RM, Mauney JR. GATA6 (GATA binding protein 6).
1140
Gene Section
Review
Dirk Sombroek, Thomas G Hofmann
Deutsches Krebsforschungszentrum (dkfz.), Cellular Senescence Unit A210, Cell and Tumor Biology
Program, Heidelberg, Germany (DS, TGH)
Online updated version : http://AtlasGeneticsOncology.org/Genes/HIPK2ID40824ch7q34.html
DOI: 10.4267/2042/44916
Identity
HIPK2-202 [ENST00000342645]; 2757 bp linear
mRNA; 918 amino acids.
Other names: DKFZp686K02111, FLJ23711, hHIPk2,
PRO0593
HGNC (Hugo): HIPK2
Location: 7q34
Pseudogene
DNA/RNA
Description
Nothing known.
Protein
HIPK2 is a protein kinase of 1198 amino acids (131
kDa); posttranslational modifications: phosphorylation,
ubiquitination, sumoylation at K25, caspase cleavage at
D916 and D977.
Contains several motifs and domains (from N- to Cterminus): a nuclear localisation signal (NLS)1 (97157), a kinase domain (192-520), an interaction domain
for homeodomain transcription factors (583-798), a
NLS2 (780-840) and a NLS3 within a speckle-retention
signal (SRS) (860-967), a PEST sequence (839-934)
and an autoinhibitory domain (935-1050).
Description
Zhang et al. (2005) reported 13 exons that span around
60 kb; however, up to 15 exons are listed in different
databases.
Transcription
Around 15 kb mRNA (full-length); 3594 bp open
reading frame.
At least two alternative transcripts.
Entrez Nucleotide:
[NM_022740.4] Homo sapiens HIPK2, transcript
variant 1; 15245 bp linear mRNA; full-length isoform,
[NM_001113239.2] Homo sapiens HIPK2, transcript
variant 2; 15164 bp linear mRNA; this variant lacks an
internal segment in the CDS, the resulting isoform is
shorter.
UniProtHB/Swiss-Prot [Q9H2X6]:
[Q9H2X6-1] full-length isoform (1),
[Q9H2X6-2] isoform (2),
[Q9H2X6-3] isoform (3).
Ensemble Gene [ENSG00000064393]; 4 transcripts:
mRNA; 1198 amino acids,
Expression
HIPK2 is ubiquitously expressed (high mRNA levels in
neuronal tissues, heart, muscle and kidney); but barely
detectable at protein levels in unstressed cells. Protein
levels increase upon genotoxic stress.
Localisation
Mainly nuclear localisation, in nuclear bodies; but also
found in nucleoplasm and cytoplasm.
Function
HIPK2 is a potential tumour suppressor; in vivo data
suggest at least a role as an haploinsufficient tumour
suppressor in the skin of mice.
HIPK2 is a protein kinase that interacts with numerous
transcription factors (such as p53, AML1(RUNX1),
PAX6, c-MYB or NK3) as well as transcriptional
1141
Sombroek D, Hofmann TG
regulators (such as CBP, p300, Groucho, CtBP,
HMGA1 or Smads). In this way HIPK2 can activate or
repress
transcription
and
thereby
influence
differentiation, development and the DNA damage
response.
HIPK2 is an unstable protein in unstressed cells. It is
constantly degraded via the ubiquitin-proteasome
system (mediated by the E3 ubiquitin ligases
SIAH1/SIAH2, WSB1 and MDM2). Various types of
DNA damage (e.g. UV, IR or chemotherapeutics) lead
to stabilisation of the kinase and an HIPK2-mediated
induction of apoptosis or presumably also senescence.
HIPK2 can promote the apoptotic program via p53dependent and -independent pathways through
phosphorylation of p53 at Ser46 or phosphorylation of
the anti-apoptotic co-repressor CtBP at Ser422 (both
actions leading to the transcription of pro-apoptotic
target genes).
HIPK2 plays a role in the transcriptional regulation at
low oxigen concentrations (hypoxia).
Interestingly, HIPK2 also seems to have pro-survival
functions, at least in dopamine neurons.
Epithelial tumours (with altered beta4
integrin expression)
Oncogenesis
HIPK2 was reported to repress beta4 integrin
expression and thereby beta4-mediated tumour
progression in a p53-dependent manner. Beta4
overexpression correlates in vivo with a cytoplasmic
relocalisation of HIPK2, at least in breast cancer:
HIPK2 showed a cytoplasmic pattern in 62.5% of the
beta4-positive tumours (Bon et al., 2009).
Juvenile pilocytic astrocytomas (JPA)
Note
Benign childhood brain tumors.
Disease
A frequent amplification of HIPK2 along with BRAF
rearrangements in JPA (35 out of 53 cases) through
7q34 duplication was reported. This duplication was
more specific for JPA that originated from the
cerebellum or the optic chiasm. It was absent in other
brain tumours. If (and how) HIPK2 contributes to JPA
development is currently unclear (Jacob et al., 2009).
Homology
Cervical cancer
HIPK2 is conserved from flies to man.
Note
Surprisingly, a significant overexpression of HIPK2 in
cervical cancer was reported. But if (and how) HIPK2
contributes to the development of cervical carcinomas
remains unclear. No correlation between HIPK2
expression and grade or prognosis of the disease could
be demonstrated so far (Al-Beiti et al., 2008).
Mutations
Somatic
HIPK2 is rarely mutated (2 out of 130 cases) in acute
myeloid leukemia (AML) and myelodyplastic
syndrome (MDS) patients. Two missense mutations
(R868W and N958I) within the speckle-retention signal
(SRS) were reported. These mutations led to a changed
nuclear localisation of HIPK2 and a decreased
transactivation potential in AML1- and p53-dependent
transcription. The mutants showed dominant-negative
effects (Li et al., 2007).
AML(RUNX1)-associated leukemias
Oncogenesis
HIPK2 is inactivated on protein level by relocalisation
through a PEBP2-beta-SMMHC fusion protein.
Targeting of HIPK2 to cytoplasmic filaments and
thereby prevention of AML1(RUNX1) activation was
reported. Specifically, phosphorylation of RUNX1 and
its cofactor p300 seems to be inhibited by HIPK2
relocalisation (Wee et al., 2008).
Implicated in
Thyroid and breast cancer
Oncogenesis
HIPK2 is frequently inactivated by transcriptional
downregulation in thyroid carcinomas (8 out of 14
cases) and breast carcinomas (8 out of 20 cases)
(Pierantoni et al., 2002).
References
Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y. Homeodomaininteracting protein kinases, a novel family of co-repressors for
homeodomain transcription factors. J Biol Chem. 1998 Oct
2;273(40):25875-9
Breast cancer
Choi CY, Kim YH, Kwon HJ, Kim Y. The homeodomain protein
NK-3 recruits Groucho and a histone deacetylase complex to
repress
transcription.
J
Biol
Chem.
1999
Nov
19;274(47):33194-7
Oncogenesis
HIPK2 is inactivated on protein level by cytoplasmic
relocalisation through HMGA1. Overexpression of
HMGA1 was reported to inhibit p53-mediated
apoptosis by removing HIPK2 from the nucleus and
retaining it in the cytoplasm. Observations could be
correlated with in vivo data, at least in breast cancer.
WT p53-expressing breast carcinomas showed a low
spontaneous apoptotic index in case of HIPK2relocalisation (Pierantoni et al., 2007).
Kim YH, Choi CY, Kim Y. Covalent modification of the
homeodomain-interacting protein kinase 2 (HIPK2) by the
ubiquitin-like protein SUMO-1. Proc Natl Acad Sci U S A. 1999
Oct 26;96(22):12350-5
Hofmann TG, Mincheva A, Lichter P, Dröge W, Schmitz ML.
Human homeodomain-interacting protein kinase-2 (HIPK2) is a
member of the DYRK family of protein kinases and maps to
chromosome 7q32-q34. Biochimie. 2000 Dec;82(12):1123-7
1142
Pierantoni GM, Fedele M, Pentimalli F, Benvenuto G, Pero R,
Viglietto G, Santoro M, Chiariotti L, Fusco A. High mobility
group I (Y) proteins bind HIPK2, a serine-threonine kinase
protein which inhibits cell growth. Oncogene. 2001 Sep
27;20(43):6132-41
Gresko E, Roscic A, Ritterhoff S, Vichalkovski A, del Sal G,
Schmitz ML. Autoregulatory control of the p53 response by
caspase-mediated processing of HIPK2. EMBO J. 2006 May
3;25(9):1883-94
Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M,
Nakagawara A, Koseki H. Overlapping roles for homeodomaininteracting protein kinases hipk1 and hipk2 in the mediation of
cell growth in response to morphogenetic and genotoxic
signals. Mol Cell Biol. 2006 Apr;26(7):2758-71
Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin
K, Hug H. Isolation and characterization of cDNAs for the
protein kinase HIPK2. Biochim Biophys Acta. 2001 Mar
19;1518(1-2):168-72
D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y,
Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio
G, Fanciulli M, Appella E, Soddu S. Homeodomain-interacting
protein kinase-2 phosphorylates p53 at Ser 46 and mediates
apoptosis. Nat Cell Biol. 2002 Jan;4(1):11-9
Kim EA, Noh YT, Ryu MJ, Kim HT, Lee SE, Kim CH, Lee C,
Kim YH, Choi CY. Phosphorylation and transactivation of Pax6
by homeodomain-interacting protein kinase 2. J Biol Chem.
2006 Mar 17;281(11):7489-97
Dauth I, Krüger J, Hofmann TG. Homeodomain-interacting
protein kinase 2 is the ionizing radiation-activated p53 serine
46 kinase and is regulated by ATM. Cancer Res. 2007 Mar
1;67(5):2274-9
Hofmann TG, Möller A, Sirma H, Zentgraf H, Taya Y, Dröge W,
Will H, Schmitz ML. Regulation of p53 activity by its interaction
with homeodomain-interacting protein kinase-2. Nat Cell Biol.
2002 Jan;4(1):1-10
Li XL, Arai Y, Harada H, Shima Y, Yoshida H, Rokudai S,
Aikawa Y, Kimura A, Kitabayashi I. Mutations of the HIPK2
gene in acute myeloid leukemia and myelodysplastic syndrome
impair AML1- and p53-mediated transcription. Oncogene. 2007
Nov 8;26(51):7231-9
Pierantoni GM, Bulfone A, Pentimalli F, Fedele M, Iuliano R,
Santoro M, Chiariotti L, Ballabio A, Fusco A. The
homeodomain-interacting protein kinase 2 gene is expressed
late in embryogenesis and preferentially in retina, muscle, and
neural tissues. Biochem Biophys Res Commun. 2002 Jan
25;290(3):942-7
Pierantoni GM, Rinaldo C, Mottolese M, Di Benedetto A,
Esposito F, Soddu S, Fusco A. High-mobility group A1 inhibits
p53 by cytoplasmic relocalization of its proapoptotic activator
HIPK2. J Clin Invest. 2007 Mar;117(3):693-702
Harada J, Kokura K, Kanei-Ishii C, Nomura T, Khan MM, Kim
Y, Ishii S. Requirement of the co-repressor homeodomaininteracting protein kinase 2 for ski-mediated inhibition of bone
morphogenetic protein-induced transcriptional activation. J Biol
Chem. 2003 Oct 3;278(40):38998-9005
Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A,
Moretti F, Soddu S. MDM2-regulated degradation of HIPK2
prevents p53Ser46 phosphorylation and DNA damage-induced
apoptosis. Mol Cell. 2007 Mar 9;25(5):739-50
Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman
RH. Homeodomain interacting protein kinase 2 promotes
apoptosis by downregulating the transcriptional corepressor
CtBP. Cell. 2003 Oct 17;115(2):177-86
Wei G, Ku S, Ma GK, Saito S, Tang AA, Zhang J, Mao JH,
Appella E, Balmain A, Huang EJ. HIPK2 represses betacatenin-mediated transcription, epidermal stem cell expansion,
and skin tumorigenesis. Proc Natl Acad Sci U S A. 2007 Aug
7;104(32):13040-5
Di Stefano V, Rinaldo C, Sacchi A, Soddu S, D'Orazi G.
Homeodomain-interacting protein kinase-2 activity and p53
phosphorylation are critical events for cisplatin-mediated
apoptosis. Exp Cell Res. 2004 Feb 15;293(2):311-20
Zhang J, Pho V, Bonasera SJ, Holtzman J, Tang AT, Hellmuth
J, Tang S, Janak PH, Tecott LH, Huang EJ. Essential function
of HIPK2 in TGFbeta-dependent survival of midbrain dopamine
neurons. Nat Neurosci. 2007 Jan;10(1):77-86
Doxakis E, Huang EJ, Davies AM. Homeodomain-interacting
protein kinase-2 regulates apoptosis in developing sensory and
sympathetic neurons. Curr Biol. 2004 Oct 5;14(19):1761-5
Al-Beiti MA, Lu X. Expression of HIPK2 in cervical cancer:
correlation with clinicopathology and prognosis. Aust N Z J
Obstet Gynaecol. 2008 Jun;48(3):329-36
Kanei-Ishii C, Ninomiya-Tsuji J, Tanikawa J, Nomura T, Ishitani
T, Kishida S, Kokura K, Kurahashi T, Ichikawa-Iwata E, Kim Y,
Matsumoto K, Ishii S. Wnt-1 signal induces phosphorylation
and degradation of c-Myb protein via TAK1, HIPK2, and NLK.
Genes Dev. 2004 Apr 1;18(7):816-29
Choi DW, Seo YM, Kim EA, Sung KS, Ahn JW, Park SJ, Lee
SR, Choi CY. Ubiquitination and degradation of homeodomaininteracting protein kinase 2 by WD40 repeat/SOCS box protein
WSB-1. J Biol Chem. 2008 Feb 22;283(8):4682-9
Choi CY, Kim YH, Kim YO, Park SJ, Kim EA, Riemenschneider
W, Gajewski K, Schulz RA, Kim Y. Phosphorylation by the
DHIPK2 protein kinase modulates the corepressor activity of
Groucho. J Biol Chem. 2005 Jun 3;280(22):21427-36
Wee HJ, Voon DC, Bae SC, Ito Y. PEBP2-beta/CBF-betadependent phosphorylation of RUNX1 and p300 by HIPK2:
implications for leukemogenesis. Blood. 2008 Nov
1;112(9):3777-87
Gresko E, Möller A, Roscic A, Schmitz ML. Covalent
modification of human homeodomain interacting protein kinase
2 by SUMO-1 at lysine 25 affects its stability. Biochem Biophys
Res Commun. 2005 Apr 22;329(4):1293-9
Winter M, Sombroek D, Dauth I, Moehlenbrink J,
Scheuermann K, Crone J, Hofmann TG. Control of HIPK2
stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM
and ATR. Nat Cell Biol. 2008 Jul;10(7):812-24
Zhang D, Li K, Erickson-Miller CL, Weiss M, Wojchowski DM.
DYRK gene structure and erythroid-restricted features of
DYRK3 gene expression. Genomics. 2005 Jan;85(1):117-30
Bon G, Di Carlo SE, Folgiero V, Avetrani P, Lazzari C, D'Orazi
G, Brizzi MF, Sacchi A, Soddu S, Blandino G, Mottolese M,
Falcioni R. Negative regulation of beta4 integrin transcription
by homeodomain-interacting protein kinase 2 and p53 impairs
tumor progression. Cancer Res. 2009 Jul 15;69(14):5978-86
Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y,
Schmitz ML, Koseki H, Kitabayashi I. Roles of HIPK1 and
HIPK2 in AML1- and p300-dependent transcription,
hematopoiesis and blood vessel formation. EMBO J. 2006 Sep
6;25(17):3955-65
1143
Calzado MA, de la Vega L, Möller A, Bowtell DD, Schmitz ML.
An inducible autoregulatory loop between HIPK2 and Siah2 at
the apex of the hypoxic response. Nat Cell Biol. 2009
Jan;11(1):85-91
Nardinocchi L, Puca R, Guidolin D, Belloni AS, Bossi G,
Michiels C, Sacchi A, Onisto M, D'Orazi G. Transcriptional
regulation of hypoxia-inducible factor 1alpha by HIPK2
suggests a novel mechanism to restrain tumor growth. Biochim
Biophys Acta. 2009 Feb;1793(2):368-77
Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A,
Serre D, Hauser P, Garami M, Bognar L, Hanzely Z, Montes
JL, Atkinson J, Farmer JP, Bouffet E, Hawkins C, Tabori U,
Jabado N. Duplication of 7q34 is specific to juvenile pilocytic
astrocytomas and a hallmark of cerebellar and optic pathway
tumours. Br J Cancer. 2009 Aug 18;101(4):722-33
Sombroek D, Hofmann TG. HIPK2 (homeodomain interacting
protein kinase 2). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(12):1141-1144.
1144
Gene Section
Review
Vivian Chan
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong,
China (VC)
Online updated version : http://AtlasGeneticsOncology.org/Genes/RAD9AID42031ch11q13.html
DOI: 10.4267/2042/44917
hRad9 forms ring-shape heterotrimeric complex with
hRad1 and hHus1 proteins (9-1-1 complex). All 3
proteins have sequence homology with proliferating
cell nuclear antigen (PCNA). The 9-1-1 complex is
recruited onto DNA-lesion by RAD17 and ATR triggering checkpoint signaling pathway and acts to
repair DNA damage (Volkmer and Karnitz, 1999;
Rauen et al., 2000; Zou et al., 2002; Medhurst et al.,
2008). Phosphorylation of hRad9 by protein kinase C
delta (PKCD) is necessary for the formation of the 9-11 complex (Yoshida et al., 2003).
NH2 terminus of hRad9 contains BH3-like domain
which binds antiapoptotic proteins BCL2 and Bcl-x2,
thereby promoting apoptosis (Komatsu et al., 2000).
This interaction of hRad9 to Bcl2 is regulated also by
PKCdelta (Yoshida et al., 2003).
RAD9, like P53 can regulate P21 at the transcriptional
level.
Overexpression of hRad was shown to cause an
increase in P21 RNA and the encoded protein level in
P53-null H1299 cells (Yin et al., 2004). This suggests
that hRAD9 and P53 coregulate P21 to direct cell cycle
progression. hRAD9 may also modulate transcription
of other down-stream target genes.
C-terminal region of hRad9 protein acts to transport 91-1 complex into the nucleus (Hirai and Wang, 2002;
Sohn and Cho, 2009).
Identity
Other names: RAD9, hRAD9
HGNC (Hugo): RAD9A
Location: 11q13.2
Note: Accession No. NM_004584.
DNA/RNA
Description
6461 bp, 11 exons.
Transcription
The transcript length is 1176 bp, full open reading
frame cDNA clone, encodes a 391 amino acid, 42520
Da protein (Lieberman et al., 1996).
Protein
Function
The gene product is highly similar to Rad9 protein
from S pombe. A cell cycle checkpoint protein with
multiple functions for preserving genomic integrity
(Ishikawa et al., 2006), such as the regulation of DNA
damage response, cell cycle checkpoint, DNA repair,
apoptosis, transcriptional regulation, exonuclease
activity, ribonucleotide synthesis and embryogenesis.
1145
Chan V
(Adapted from Ishikawa K et al., Current Genomics.2006:7:477-80).
hRad9 and ATM rapidly colocalize to regions
containing DNA double-stranded breaks after DNAdamage (Greer et al., 2003; Medhurst et al., 2008) and
Atm can phosphorylate Rad9 directly at Ser-272 during
ionizing radiation (IR)-induced G1/S checkpoint
activation (Chen et al., 2001).
The 9-1-1 complex may attract DNA polymerase beta
to sites of DNA damage, thus connecting checkpoint
and DNA repair (Toueille et al., 2004).
Thr-292 of hRad9 is subject to CDC2-dependent
phosphorylation in mitosis. Four other hRad9
phosphorylation sites (Ser-277, Ser-328, Ser-336 and
Thr-355) are regulated in part by Cdc2 (St Onge et al.,
2001; St Onge et al., 2003; Ishikawa et al., 2006).
Phosphorylation sites of the C-terminal region of
hRad9 are essential for CHK1 activation following
hydroxyurea, ionizing radiation and ultraviolet
treatment (Roos-Mattjus et al., 2003).
Crystal structure of the human Rad9-Hus1-Rad1
complex reveals a single repair enzyme binding site
(Doré et al., 2009) and suggests that the C-terminal end
of Rad9 protein is involved in the regulation of the
complex in DNA binding (Sohn and Cho, 2009).
hRad9 possesses 3'-5' exonuclease activity which may
contribute to its role in sensing and repairing DNA
damage (Bessho and Sancar, 2000). The exact
mechanism of this exonucleolytic processing is still
unclear.
Implicated in
Various cancers
Oncogenesis
Checkpoint genes are known to be involved in the
maintenance of genomic integrity and their aberrant
expression can lead to cancer. Paralogue of human
HRad9 is called HRad9B. Gene product is structurally
related to hRad9 protein (55% similar and 35%
identical). HRad9B gene is expressed predominantly in
the testis and found in decreased amount in testicular
tumours, particularly seminomas (Hopkins et al., 2003).
Prostate cancer
Oncogenesis
Carboxy terminus of hRad9 contains a FXXLF motif
which interrupts the androgen-induced interaction
between the C and N terminus of androgen receptor
(AR), acting as a co-regulator to suppress androgen-AR
transactivation in prostrate cancer cells (Wang et al.,
2004). This denotes a possible tumour suppressor
function of hRad9.
Recent study has confirmed that high levels of Rad9
expression is found in prostate cancer cells and the high
protein levels in prostate adenocarcinomas were
generally associated with more advanced disease (Zhu
et al., 2008). Similar to previous findings in breast
1146
Chan V
cancer (Cheng et al., 2005), the increased expression of
Rad9 in prostate cancer cells was in part due to aberrant
methylation or gene amplification (Zhu et al., 2008).
The study failed to show that the role of Rad9 in
prostate tumorigenesis was androgen dependent, since
both androgen dependent CWR22 and LNCaP cell
lines as well as androgen independent DU145 and PC-3
cell lines were found to contain high levels of Rad9
protein (Zhu et al., 2008).
mutations lead to hereditary non-polyposis colorectal
cancer (HNPCC) (Avdievich et al., 2008; Peltomäki et
al., 2004) and various types of tumours (Avdievich et
al., 2008; Hu et al., 2008). However, hRad9's function
in MMR is not in the 9-1-1-complex form (He et al.,
2008).
References
Lieberman HB, Hopkins KM, Nass M, Demetrick D, Davey S. A
human homolog of the Schizosaccharomyces pombe rad9+
checkpoint control gene. Proc Natl Acad Sci U S A. 1996 Nov
26;93(24):13890-5
Lung cancer
Oncogenesis
Presence of hyperphosphorylated forms of hRad9 has
been found in the nuclei of surgically resected primary
lung carcinoma cells (Maniwa et al., 2005). No
mutation of the hRad9 gene was found in lung cancer
cells, but a nonsynonymous single nucleotide
polymorphism (SNP), His239Arg was found in 8 out of
50 lung adenocarcinoma patients, suggesting a possible
association of this SNP with the development of cancer
(Maniwa et al., 2006).
St Onge RP, Udell CM, Casselman R, Davey S. The human
G2 checkpoint control protein hRAD9 is a nuclear
phosphoprotein that forms complexes with hRAD1 and hHUS1.
Mol Biol Cell. 1999 Jun;10(6):1985-95
Volkmer
E,
Karnitz
LM.
Human
homologs
of
Schizosaccharomyces pombe rad1, hus1, and rad9 form a
DNA damage-responsive protein complex. J Biol Chem. 1999
Jan 8;274(2):567-70
Bessho T, Sancar A. Human DNA damage checkpoint protein
hRAD9 is a 3' to 5' exonuclease. J Biol Chem. 2000 Mar
17;275(11):7451-4
Breast cancer
Oncogenesis
Over-expression of hRad9 mRNA was found in breast
cancer, which was shown to be correlated with tumour
size (p = 0.037) and local recurrence (p = 0.033). Overexpression of Rad9 mRNA was partly due to increase
in RAD9 gene amplification and aberrant DNA
methylation at a putative Sp 1/3 binding site within the
second intron of the RAD9 gene. Promoter assays
indicate that the Sp 1/3 site in intron 2 may act as a
silencer. Further experiments in silencing Rad9
expression by RNAi inhibit the proliferation of MCF-7
cell line in vitro. These findings suggested that Rad9 is
a new oncogene candidate on Ch11q13 with a role in
breast cancer progression (Cheng et al., 2005).
In contrast to previous findings in testicular tumours,
increased hRad9 protein was found in the nuclei of
breast cancer cells. These were shown to exist as
hyperphosphorylated forms, with molecular weights of
65 and 50 kDa. Since the theoretical molecular weight
of hRad9 is 45 kDa (Lindsey-Boltz et al., 2001), these
larger forms most likely represent hyperphosphorylated
hRad9 and its hRad9-hRad1-hHus1 complex (Chan et
al., 2008; St Onge et al., 1999). Localization of
hyperphosphorylated forms of hRad in the nucleus of
cancer cells is in keeping with its function in
ameliorating DNA instability, whereby it inadvertently
assists tumour growth.
Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W,
Cuddeback S, Yamada M, Lieberman HB, Wang HG. Human
homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL
and promotes apoptosis. Nat Cell Biol. 2000 Jan;2(1):1-6
Rauen M, Burtelow MA, Dufault VM, Karnitz LM. The human
checkpoint protein hRad17 interacts with the PCNA-like
proteins hRad1, hHus1, and hRad9. J Biol Chem. 2000 Sep
22;275(38):29767-71
Chen MJ, Lin YT, Lieberman HB, Chen G, Lee EY. ATMdependent phosphorylation of human Rad9 is required for
ionizing radiation-induced checkpoint activation. J Biol Chem.
2001 May 11;276(19):16580-6
Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A.
Purification and characterization of human DNA damage
checkpoint Rad complexes. Proc Natl Acad Sci U S A. 2001
Sep 25;98(20):11236-41
St Onge RP, Besley BD, Park M, Casselman R, Davey S. DNA
damage-dependent and -independent phosphorylation of the
hRad9 checkpoint protein. J Biol Chem. 2001 Nov
9;276(45):41898-905
Hirai I, Wang HG. A role of the C-terminal region of human
Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint
complex. J Biol Chem. 2002 Jul 12;277(28):25722-7
Zou L, Cortez D, Elledge SJ. Regulation of ATR substrate
selection by Rad17-dependent loading of Rad9 complexes
onto chromatin. Genes Dev. 2002 Jan 15;16(2):198-208
Greer DA, Besley BD, Kennedy KB, Davey S. hRad9 rapidly
binds DNA containing double-strand breaks and is required for
damage-dependent topoisomerase II beta binding protein 1
focus formation. Cancer Res. 2003 Aug 15;63(16):4829-35
Colorectal cancer
Hopkins KM, Wang X, Berlin A, Hang H, Thaker HM,
Lieberman HB. Expression of mammalian paralogues of
HRAD9 and Mrad9 checkpoint control genes in normal and
cancerous testicular tissue. Cancer Res. 2003 Sep
1;63(17):5291-8
Oncogenesis
Rad9 interacts physically within the DNA mismatch
repair (MMR) protein MLH1. Disruption of the
interaction by a single point mutation in Rad9 leads to
significantly reduced mismatch repair activity (He et
al., 2008). The Rad9-MHL1 interaction might be a
hotspot for mutation in tumour cells. The hMLH1
Roos-Mattjus P, Hopkins KM, Oestreich AJ, Vroman BT,
Johnson KL, Naylor S, Lieberman HB, Karnitz LM.
Phosphorylation of human Rad9 is required for genotoxin-
1147
Chan V
activated checkpoint signaling. J Biol Chem. 2003 Jul
4;278(27):24428-37
Maniwa Y, Yoshimura M, Bermudez VP, Okada K, Kanomata
N, Ohbayashi C, Nishimura Y, Hayashi Y, Hurwitz J, Okita Y.
His239Arg SNP of HRAD9 is associated with lung
adenocarcinoma. Cancer. 2006 Mar 1;106(5):1117-22
St Onge RP, Besley BD, Pelley JL, Davey S. A role for the
phosphorylation of hRad9 in checkpoint signaling. J Biol Chem.
2003 Jul 18;278(29):26620-8
Yoshida K, Wang HG, Miki Y, Kufe D. Protein kinase Cdelta is
responsible for constitutive and DNA damage-induced
phosphorylation of Rad9. EMBO J. 2003 Mar 17;22(6):1431-41
Avdievich E, Reiss C, Scherer SJ, Zhang Y, Maier SM, Jin B,
Hou H Jr, Rosenwald A, Riedmiller H, Kucherlapati R, Cohen
PE, Edelmann W, Kneitz B. Distinct effects of the recurrent
Mlh1G67R mutation on MMR functions, cancer, and meiosis.
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4247-52
Peltomäki P, Vasen H. Mutations associated with HNPCC
predisposition -- Update of ICG-HNPCC/INSiGHT mutation
database. Dis Markers. 2004;20(4-5):269-76
Chan V, Khoo US, Wong MS, Lau K, Suen D, Li G, Kwong A,
Chan TK. Localization of hRad9 in breast cancer. BMC
Cancer. 2008 Jul 11;8:196
Toueille M, El-Andaloussi N, Frouin I, Freire R, Funk D,
Shevelev I, Friedrich-Heineken E, Villani G, Hottiger MO,
Hübscher U. The human Rad9/Rad1/Hus1 damage sensor
clamp interacts with DNA polymerase beta and increases its
DNA substrate utilisation efficiency: implications for DNA
repair. Nucleic Acids Res. 2004;32(11):3316-24
He W, Zhao Y, Zhang C, An L, Hu Z, Liu Y, Han L, Bi L, Xie Z,
Xue P, Yang F, Hang H. Rad9 plays an important role in DNA
mismatch repair through physical interaction with MLH1.
Nucleic Acids Res. 2008 Nov;36(20):6406-17
Hu Z, Liu Y, Zhang C, Zhao Y, He W, Han L, Yang L, Hopkins
KM, Yang X, Lieberman HB, Hang H. Targeted deletion of
Rad9 in mouse skin keratinocytes enhances genotoxininduced tumor development. Cancer Res. 2008 Jul
15;68(14):5552-61
Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang
C. Human checkpoint protein hRad9 functions as a negative
coregulator to repress androgen receptor transactivation in
prostate cancer cells. Mol Cell Biol. 2004 Mar;24(5):2202-13
Medhurst AL, Warmerdam DO, Akerman I, Verwayen EH,
Kanaar R, Smits VA, Lakin ND. ATR and Rad17 collaborate in
modulating Rad9 localisation at sites of DNA damage. J Cell
Sci. 2008 Dec 1;121(Pt 23):3933-40
Yin Y, Zhu A, Jin YJ, Liu YX, Zhang X, Hopkins KM, Lieberman
HB. Human RAD9 checkpoint control/proapoptotic protein can
activate transcription of p21. Proc Natl Acad Sci U S A. 2004
Jun 15;101(24):8864-9
Zhu A, Zhang CX, Lieberman HB. Rad9 has a functional role in
human prostate carcinogenesis. Cancer Res. 2008 Mar
1;68(5):1267-74
Cheng CK, Chow LW, Loo WT, Chan TK, Chan V. The cell
cycle checkpoint gene Rad9 is a novel oncogene activated by
11q13 amplification and DNA methylation in breast cancer.
Cancer Res. 2005 Oct 1;65(19):8646-54
Doré AS, Kilkenny ML, Rzechorzek NJ, Pearl LH. Crystal
structure of the rad9-rad1-hus1 DNA damage checkpoint
complex--implications for clamp loading and regulation. Mol
Cell. 2009 Jun 26;34(6):735-45
Maniwa Y, Yoshimura M, Bermudez VP, Yuki T, Okada K,
Kanomata N, Ohbayashi C, Hayashi Y, Hurwitz J, Okita Y.
Accumulation of hRad9 protein in the nuclei of nonsmall cell
lung carcinoma cells. Cancer. 2005 Jan 1;103(1):126-32
Sohn SY, Cho Y. Crystal structure of the human rad9-hus1rad1 clamp. J Mol Biol. 2009 Jul 17;390(3):490-502
Ishikawa K, Ishii H, Saito T, Ichimura K. Multiple functions of
rad9 for preserving genomic integrity. Curr Genomics.
2006;7(8):477-80
Chan V. RAD9A (RAD9 homolog A (S. pombe)). Atlas Genet
1148
Gene Section
Mini Review
Christos Kontos, Andreas Scorilas
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, 157 01,
Panepistimiopolis, Athens, Greece (CK, AS)
Online updated version : http://AtlasGeneticsOncology.org/Genes/SCAF1ID46074ch19q13.html
DOI: 10.4267/2042/44918
The human SCAF1 gene was shown to be expressed
widely in many normal tissues, but its mRNA levels
vary a lot. The highest levels of SCAF1 transcripts
were detected in the fetal brain and fetal liver and the
lowest in salivary gland, skin, heart, uterus and ovary.
In the mammary and prostate gland, SCAF1 mRNA
transcripts are constitutively present at relatively high
levels.
The mRNA levels of SCAF1 appear to increase in
cancer cell lines treated with various steroid hormones,
including estrogens, androgens and glucocorticoids,
and to a lesser extent with progestins (Scorilas et al.,
2001).
Identity
Other names: FLJ00034, SCAF, SFRS19, SRA1, SRA1,
HGNC (Hugo): SCAF1
Location: 19q13.33
Local order: Telomere to centromere.
Note: The first name of this gene, discovered and
cloned by Scorilas et al. was SR-A1. After the
establishment of the name "SRA1" for steroid receptor
RNA activator 1, the official name of SR-A1 gene has
changed into SCAF1, to avoid confusion.
Pseudogene
DNA/RNA
Not identified so far.
Description
Protein
Spanning 16.5 kb of genomic DNA, the SCAF1 gene
consists of 11 exons and 10 intervening introns
(Scorilas et al., 2001).
Description
The SCAF1 protein is composed of 1312 amino acids,
with a calculated molecular mass of 139.1 kDa and a
theoretical isoelectric point of 9.31.
Transcription
The unique transcript of SCAF1 gene is 4313 bp.
Schematic representation of the SCAF1 gene. Exons are shown as boxes and introns as connecting lines. Arrows show the positions
of the start codon, stop codon, and polyadenylation signal. Roman numerals indicate intron phases. The intron phase refers to the
location of the intron within the codon; I denotes that the intron occurs after the first nucleotide of the codon, II that the intron occurs after
the second nucleotide, and 0 that the intron occurs between distinct codons. The numbers inside boxes indicate exon lengths and the
vertical connecting lines show the intron lengths (in bp). Figure is not drawn to scale.
1149
Kontos C, Scorilas A
Schematic representation of the amino acid sequence of the SCAF1 protein. The Arg/Ser-rich domain is shown in bold and
underlined, and the CTD-binding domain is double-underlined. Additionally, the SCAF1 protein contains two areas with negatively
charged polyglutamic acid (E) stretches, shown as underlined with dashes, and an Arg/Asp-rich motif, which is normally underlined.
Various putative post-translational modification sites have also been identified, including numerous potential sites for either O- or Nglycosylation, and several possible sites of phosphorylation by cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and
casein kinase 2.
The SCAF1 protein contains an Arg/Ser-rich domain
(SR) as well as a CTD-binding domain, present only in
a subset of Arg/Ser-rich splicing factors.
Through interactions with the pre-mRNA and the Cterminal domain (CTD) of the large subunit of RNA
polymerase II, Arg/Ser-rich proteins have been shown
to regulate alternative splicing. In addition, we
identified two areas with negatively charged
polyglutamic acid (E) stretches and an Arg/Asp-rich
motif in the SCAF1 protein. This motif is also present
in a number of other RNA-binding proteins such as the
U1-70 K, the RD RNA-binding protein and the 68 kDa
human pre-mRNA cleavage factor Im.
Examination of the hydrophobicity profile of the
SCAF1 protein did not reveal regions with long
stretches of hydrophobic residues.
SCAF1 is predicted to be a nuclear protein with no
transmembrane region.
Various putative post-translational modification sites
have been identified, including numerous potential sites
for either O- or N-glycosylation, and several possible
sites of phosphorylation by cAMP-dependent protein
kinase (PKA), protein kinase C (PKC), and casein
kinase 2 (Scorilas et al., 2001).
Expression
Currently, there are no data concerning the in vivo
expression of the human SCAF1 protein.
Localisation
The SCAF1 protein is predicted to be localized to the
nucleus.
1150
Kontos C, Scorilas A
Function
Leukemia
SCAF1 interacts with the CTD domain of the RNA
polymerase II polypeptide A (POLR2A) and may be
involved in pre-mRNA splicing.
Prognosis
Alterations of SCAF1 mRNA expression have been
noticed in the human acute promyelocytic leukemia
cell line HL-60, after treatment with cisplatin and
bleomycin. mRNA levels of SCAF1 are modulated in
both cases as a response to apoptosis induction by each
drug, with up-regulation in bleomycin-induced
apoptosis and down-regulation in cisplatin-induced
apoptosis in HL-60 cells. This differential response of
SCAF1 mRNA levels to apoptosis induced by each
drug may be due to distinct apoptotic pathways and
therefore to distinct cellular needs for the splice
variants of specific genes.
Cytogenetics
No cytogenetic abnormalities have been identified so
far.
Hybrid/Mutated gene
Not identified so far.
Homology
Human SCAF1 shares 85% amino acid identity and
91% similarity with the mouse and rat Scaf1 protein.
Moreover, it shows 25% identity and 48% similarity
with the human PHRF1 protein ("PHD and RING
finger domain-containing protein 1", also known as
"CTD-binding SR-like protein rA9"), and to a lesser
extent with other Arg/Ser-rich splicing factors.
Mutations
No germinal or somatic mutations associated with
cancer have been identified so far.
Implicated in
Breast and ovarian cancer
References
Prognosis
Expression analysis of the SCAF1 gene has showed
that SCAF1 mRNA expression may be considered as a
new unfavorable prognostic marker for breast and
ovarian cancer. Expression of the SCAF1 gene in
breast cancer tissues is influenced by the tumor size
and the existence of lymph node metastases.
Furthermore, high SCAF1 expression is a significant
independent prognostic marker of disease-free survival
(DFS), and low mRNA expression of the gene is
associated with long DFS and overall survival (OS).
Regarding SCAF1 gene expression in ovarian cancer, it
is positively related to the histological grade and stage
of the disease, the size of the tumor, and the debulking
success. Additionally, high SCAF1 expression is a
significant independent prognostic marker of OS, and
low mRNA expression of the gene is related to long
DFS and OS.
Scorilas A, Kyriakopoulou L, Katsaros D, Diamandis EP.
Cloning of a gene (SR-A1), encoding for a new member of the
human Ser/Arg-rich family of pre-mRNA splicing factors:
overexpression in aggressive ovarian cancer. Br J Cancer.
2001 Jul 20;85(2):190-8
Mathioudaki K, Leotsakou T, Papadokostopoulou A,
Paraskevas E, Ardavanis A, Talieri M, Scorilas A. SR-A1, a
member of the human pre-mRNA splicing factor family, and its
expression in colon cancer progression. Biol Chem. 2004
Sep;385(9):785-90
Katsarou ME, Papakyriakou A, Katsaros N, Scorilas A.
Expression of the C-terminal domain of novel human SR-A1
protein: interaction with the CTD domain of RNA polymerase II.
Biochem Biophys Res Commun. 2005 Aug 19;334(1):61-8
Leoutsakou T, Talieri M, Scorilas A. Expression analysis and
prognostic significance of the SRA1 gene, in ovarian cancer.
Biochem Biophys Res Commun. 2006 Jun 2;344(2):667-74
Leoutsakou T, Talieri M, Scorilas A. Prognostic significance of
the expression of SR-A1, encoding a novel SR-related CTDassociated factor, in breast cancer. Biol Chem. 2006
Dec;387(12):1613-8
Colon cancer
Prognosis
SCAF1 mRNA expression seems also to be associated
with colon cancer progression, since its expression is
higher at the initial stages of tumorigenesis and is
reduced as cancer progresses.
Katsarou ME, Thomadaki H, Katsaros N, Scorilas A. Effect of
bleomycin and cisplatin on the expression profile of SRA1, a
novel member of pre-mRNA splicing factors, in HL-60 human
promyelocytic
leukemia
cells.
Biol
Chem.
2007
Aug;388(8):773-8
Kontos C, Scorilas A. SCAF1 (SR-related CTD-associated
factor 1). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(12):1149-1151.
1151
Gene Section
Review
SIRT1 (sirtuin (silent mating type information
regulation 2 homolog) 1 (S. cerevisiae))
Ruo-Chia Tseng, Yi-Ching Wang
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
(RCT, YCW)
Online updated version : http://AtlasGeneticsOncology.org/Genes/SIRT1ID44006ch10q21.html
DOI: 10.4267/2042/44919
Identity
with a predictive molecular weight of 81.7 kDa and an
isoelectric point of 4.55 (Alcaín and Villalba, 2009).
Other names: EC 3.5.1, hSIR2, hSIRT1, SIR2alpha,
SIR2L1
HGNC (Hugo): SIRT1
Location: 10q21.3
Transcription
SIRT1 transcription is under the control of at least two
negative feedback loops that keep its induction tightly
regulated under conditions of oxidative stress. SIRT1
promoter can be activated by E2F1 and HIC1 during
cellular stress.
E2F1 directly binds to the SIRT1 promoter at a
consensus site located at bp position -65 and appears to
regulate the basal expression level of SIRT1.
Such high levels of SIRT1 lead to a negative feedback
loop where E2F1 activity is inhibited by SIRT1mediated deacetylation.
DNA/RNA
Description
The SIRT1 gene spans about 34 kb including nine
exons. The SIRT1 promoter contains a CCAAT box
and a number of NFkappaB and GATA transcription
factor binding sites in addition to a small 350-bp CpG
island in the 5' flanking genomic region. The gene
encodes a 747 amino acids protein
SIRT1 gene expression is modulated at both transcriptional and posttranscriptional levels.
1152
By contrast, the tumor suppressor HIC1 and SIRT1
form a transcriptional repression complex that directly
binds SIRT1 promoter via its N-terminal POZ domain
and represses SIRT1 transcription thereby inhibiting
SIRT1-mediated p53 deacetylation and inactivation.
Two HIC1 binding sites have been assigned to base
pair positions -1116 and -1039 within the SIRT1
promoter. In addition, two functional p53 binding sites
(-178 bp and -168 bp), which normally repress SIRT1
expression, have been identified.
SIRT1 expression is also regulated at the
posttranscriptional level by HuR. It has been
demonstrated that HuR, a ubiquitously expressed RNA
binding protein, associates with the 3' UTR of the
SIRT1 mRNA under physiological conditions and
helps to stabilize the transcript. This interaction results
in increased SIRT1 mRNA stability and thus in
elevated protein levels. Conversely, the HuR-SIRT1
mRNA complex is being disrupted upon oxidative
stress, which finally leads to decreased mRNA stability
and therefore decreased SIRT protein levels.
Tseng RC, Wang YC
SIRT1 was the active regulator of SIRT1 (AROS). The
AROS protein is known to significantly enhance the
activity of SIRT1 on acetylated p53 both in vitro and in
cell lines thereby promoting the inhibitory effect of
SIRT1 on p53-mediated transcriptional activity of proapoptotic genes (e.g. Bax and p21Waf-1) under
conditions of DNA-damage. A negative regulator of
SIRT1, DBC-1 (deleted in breast cancer-1), has
recently been identified. DBC1 binds directly to the
catalytic domain of SIRT1, preventing substrate
binding to SIRT1 and inhibiting SIRT1 activity.
Reduction of DBC1 inhibits p53-mediated apoptosis
after induction of double-stranded DNA breaks owing
to SIRT1-mediated p53 deacetylation. Both factors
represent the first endogenous, direct regulators of
SIRT1 function.
Localisation
SIRT1 is predominately in the nucleus (although
SIRT1 does have some important cytoplasmic
functions as well). In addition to possessing two NLSs,
SIRT1 contains two nuclear export signals. Thus, the
exposure of nuclear localization signals versus nuclear
export signals may dictate the cytosolic versus nuclear
localization of SIRT1.
Pseudogene
None identified.
Protein
Function
Description
SIRT1 has been reported to play a key role in a variety
of physiological processes such as metabolism,
neurogenesis and cell survival due to its ability to
deacetylate both histone and numerous nonhistone
substrates.
(1) Lysines 9 and 14 in the amino-terminal tail of
histone H3 and lysine 16 of histone H4 are deacetylated
by yeast Sir2 and mammalian SIRT1 (Sir2alpha).
(2) Metabolic homeostasis is controlled by SIRT1mediated deacetylation and thus activation of the
peroxisome proliferation activating receptor (PPAR)gamma co-activator-1a (PGC-1a), which stimulates
mitochondrial activity and subsequently increases
glucose metabolism, which in turn improves insulin
sensitivity.
Human SIRT1 encodes 747 amino acids protein with a
nuclear localization signal (NLS) at the N-terminus (aa
41-46) and a sirtuin homology domain at the center (aa
261-447); this domain is a conserved catalytic domain
for deacetylation.
Expression
Expression appears to be ubiquitous in adult tissues
(although at different levels). Two proteins have been
identified to regulate the SIRT1 activity both positively
and negatively through complex formation in the
context of the cellular stress response. The first
identified direct regulator of
SIRT1 deacetylase activity is modulated through protein-protein interaction and sumoylation at its three protein domains (Liu T et al., 2009).
1153
SIRT1 represses PPAR-gamma, a key regulator of
adipogenesis, by docking with its cofactors NCoR
(nuclear receptor co-repressor) and SMRT (silencing
mediator of retinoid and thyroid hormone receptors).
The upregulation of SIRT1 triggers lipolysis and loss of
fat.
(3) The activation of SIRT1 appears to be
neuroprotective in animal models for Alzheimer's
disease and amyotrophic lateral sclerosis as well as
optic neuritis mainly due to decreased deacetylation of
the tumor suppressor p53 and PGC-1a.
(4) SIRT1 represses p53-dependent apoptosis in
response to DNA damage and oxidative stress and
promotes cell survival under cellular stress induced by
etoposide treatment or irradiation.
(5) SIRT1 activates FOXO1 and FOXO4, which
promote cell-cycle arrest by inducing p27kip1; SIRT1
also induces cellular resistance to oxidative stress by
increasing the levels of manganese superoxide
dismutase and GADD45 (growth arrest and DNA
damage-inducible protein 45).
(6) SIRT1 inhibits the transcriptional activity of NFkappaB by deacetylating NF-kappaB's subunit,
RelA/p65, at lysine 310. Thus, although SIRT1 is
capable of protecting cells from p53-induced apoptosis,
it may augment apoptosis by repressing NF-kappaB.
SIRT1 is reported to bind CTIP2 (BCL11B B-cell
CLL/lymphoma 11B) and accelerate the transcriptional
repression by this molecule. CTIP2 represses the
transcription of its target genes and is implicated in
hematopoietic cell development.
carcinoma patients with low p53 acetylation and SIRT1
expression mostly showed low HIC1 expression,
confirming deregulation HIC1-SIRT1-p53 circular loop
in clinical model. Expression of DBC1, which blocks
the interaction between SIRT1 deacetylase and p53, led
to acetylated p53 in lung adenocarcinoma patients.
Prognosis
Lung cancer patients with altered HIC1-SIRT1-p53
circular regulation showed poor prognosis.
Breast cancer
Note
The breast cancer associated protein, BCA3, when
neddylated (modified by NEDD8) interacts with SIRT1
and suppresses NF-kB-dependent transcription, also
sensitizes human breast cancer cells (such as MCF7) to
TNF-a-induced apoptosis. In addition, it has been
shown recently that SIRT7 levels of expression
increase significantly in breast cancer, and that SIRT7
and SIRT3 both are highly transcribed in lymph-node
positive breast biopsies, a stage in which the tumour
size is at least 2 mm and the cancer has already spread
to the lymph nodes.
Brain tumor
Note
SIRT2 resides in a genomic region frequently deleted
in human gliomas and ectopic expression of SIRT2 in
glioma-derived cell lines markedly reduces their
capacity to form colonies in vitro. Exogenously
expressed SIRT2 blocks chromosomal condensation
and hyperploidy in glioma cell lines, accompanied by
the presence of cyclin B/cdc2 activity in response to
mitotic stress. Thus, SIRT2 may be a novel metaphase
check-point protein that promotes genomic integrity
and inhibits the uncontrolled proliferation of
transformed cells.
Homology
SIRT1 is the mammalian homologue closest to yeast
NAD+-dependent deacetylase Sir2 (silent information
regulation 2). It was originally identified as a lifespan
extending gene when over-expressed in budding yeast,
Caenorhabditis elegans, and Drosophila melanogaster.
The SIR2 gene is broadly conserved in organisms
ranging from bacteria to humans. The accession
numbers for the amino acid sequences used are as
follows: yeast Sir2 (CAA25667), mouse Sir2alpha
(AAF24983), human Sirt1 (AAD40849). All of the
sirtuin proteins contain the ~275 residue sirtuin
homology domain. In many instances a highly
conserved protein domain represents a conserved
functional binding site for a metabolite or biomolecule
and such conserved binding site domains are often
found within enzymatic catalytic domains.
Kidney diseases
Note
SIRT1 attenuates TGF-beta (transforming growth
factor-beta) apoptotic signaling that is mediated by the
effector
molecule
Smad7.
SIRT1-dependent
deacetylation of Smad7 at Lys60 and Lys70 enhances
its ubiquitin-dependent proteasomal degradation via
Smurf1 (Smad ubiquitination regulatory factor 1), thus
protecting glomerular mesangial cells from TGF-betadependent apoptosis.
Cardiac hypertrophy
Implicated in
Note
Decreasing hypertrophy or apoptosis in cardiac
myocytes can ameliorate the disease, and there is
reason to suspect that SIRT1 activation may be useful
in this regard. SIRT1 protects primary cultured
myocytes from programmed cell death induced by
serum starvation or by the activation of PARP-1
[poly(ADP-ribose) polymerase-1] in a p53-dependent
manner. SIRT1 also deacetylates Lys115 and Lys121
Lung cancer
Note
Distinct status of p53 acetylation/deacetylation and
HIC1 alteration mechanism result from different
SIRT1-DBC1 (deleted in breast cancer 1) control and
epigenetic alteration in lung squamous cell carcinoma
and lung adenocarcinoma. The lung squamous cell
Tseng RC, Wang YC
1154
Tseng RC, Wang YC
of the histone variant H2A.Z, a factor known to
promote cardiac hypertrophy. In doing so, SIRT1
promotes the ubiquitination and proteosome-dependent
degradation of H2A.Z, which may help to protect
against heart failure.
transcription and cell survival by the SIRT1 deacetylase.
EMBO J. 2004 Jun 16;23(12):2369-80
References
Hisahara S, Chiba S, Matsumoto H, Horio Y. Transcriptional
regulation of neuronal genes and its effect on neural functions:
NAD-dependent histone deacetylase SIRT1 (Sir2alpha). J
Pharmacol Sci. 2005 Jul;98(3):200-4
Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor
suppressor HIC1 directly regulates SIRT1 to modulate p53dependent DNA-damage responses. Cell. 2005 Nov
4;123(3):437-48
Frye RA. Characterization of five human cDNAs with homology
to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize
NAD and may have protein ADP-ribosyltransferase activity.
Biochem Biophys Res Commun. 1999 Jun 24;260(1):273-9
Kobayashi Y, Furukawa-Hibi Y, Chen C, Horio Y, Isobe K,
Ikeda K, Motoyama N. SIRT1 is critical regulator of FOXOmediated transcription in response to oxidative stress. Int J Mol
Med. 2005 Aug;16(2):237-43
Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex
and SIR2 alone promote longevity in Saccharomyces
cerevisiae by two different mechanisms. Genes Dev. 1999 Oct
1;13(19):2570-80
Pillai JB, Isbatan A, Imai S, Gupta MP. Poly(ADP-ribose)
polymerase-1-dependent cardiac myocyte cell death during
heart failure is mediated by NAD+ depletion and reduced
Sir2alpha deacetylase activity. J Biol Chem. 2005 Dec
30;280(52):43121-30
Imai S, Armstrong CM, Kaeberlein M, Guarente L.
Transcriptional silencing and longevity protein Sir2 is an NADdependent histone deacetylase. Nature. 2000 Feb
17;403(6771):795-800
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM,
Puigserver P. Nutrient control of glucose homeostasis through
a complex of PGC-1alpha and SIRT1. Nature. 2005 Mar
3;434(7029):113-8
Brennan CM, Steitz JA. HuR and mRNA stability. Cell Mol Life
Sci. 2001 Feb;58(2):266-77
Gray SG, Ekström TJ. The human histone deacetylase family.
Exp Cell Res. 2001 Jan 15;262(2):75-83
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George WD, Shiels PG. Altered sirtuin expression is
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Yang X, Blethrow JD, Walker M, Shubert J, Gillespie DA,
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regulates SIRT1 expression. Mol Cell. 2007 Feb 23;25(4):54357
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6;101(27):10042-7
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Yamaguchi S, Nakano S, Katoh M, Ito H, Oshimura M. SIRT2,
a tubulin deacetylase, acts to block the entry to chromosome
condensation in response to mitotic stress. Oncogene. 2007
Feb 15;26(7):945-57
Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T,
Machado De Oliveira R, Leid M, McBurney MW, Guarente L.
Sirt1 promotes fat mobilization in white adipocytes by
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17;429(6993):771-6
Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F,
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peroxide stress and deacetylated by the longevity protein
hSir2(SIRT1). J Biol Chem. 2004 Jul 9;279(28):28873-9
Kim EJ, Kho JH, Kang MR, Um SJ. Active regulator of SIRT1
cooperates with SIRT1 and facilitates suppression of p53
activity. Mol Cell. 2007 Oct 26;28(2):277-90
Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye
RA, Mayo MW. Modulation of NF-kappaB-dependent
1155
Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isshiki
K, Isono M, Uzu T, Guarente L, Kashiwagi A, Koya D. SIRT1
inhibits transforming growth factor beta-induced apoptosis in
glomerular mesangial cells via Smad7 deacetylation. J Biol
Chem. 2007 Jan 5;282(1):151-8
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2009 Mar;19(3):283-94.
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senescence and cancer? Nat Rev Cancer. 2009 Feb;9(2):1238
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biological function. Biochem J. 2007 May 15;404(1):1-13
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Yamashita T. Zyxin is a novel interacting partner for SIRT1.
BMC Cell Biol. 2009 Jan 27;10:6
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activation confers neuroprotection in experimental optic
neuritis. Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3602-9
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histone deacetylase SIRT1 in cancer. Cancer Res. 2009 Mar
1;69(5):1702-5
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phylogenetically conserved psiKXEP motif in the tumor
suppressor HIC1 regulates transcriptional repression activity.
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and disease relevance. Annu Rev Pathol. 2010;5:253-95
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Nucleocytoplasmic shuttling of the NAD+-dependent histone
deacetylase SIRT1. J Biol Chem. 2007 Mar 2;282(9):6823-32
Tseng RC, Wang YC. SIRT1 (sirtuin (silent mating type
information regulation 2 homolog) 1 (S. cerevisiae)). Atlas
Genet Cytogenet Oncol Haematol. 2010; 14(12):1152-1156.
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regulation of the deacetylase SIRT1 by DBC1. Nature. 2008
Jan 31;451(7178):587-90
Zschoernig B, Mahlknecht U. SIRTUIN 1: regulating the
regulator. Biochem Biophys Res Commun. 2008 Nov
14;376(2):251-5
Tseng RC, Wang YC
1156
Gene Section
Mini Review
SLC16A3 (solute carrier family 16, member 3
(monocarboxylic acid transporter 4))
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho,
Campus of Gualtar, 4710-057 Braga, Portugal (CP, FB)
Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC16A3ID44573ch17q25.html
DOI: 10.4267/2042/44920
cells, chondrocytes, testis, lung, placenta, heart and
some mammalian cell lines (Halestrap and Meredith,
2004; Meredith and Christian, 2008).
Identity
Other names: MCT3,
MGC138474
HGNC (Hugo): SLC16A3
Location: 17q25.3
MCT4,
MGC138472,
Localisation
Plasma membrane.
Function
DNA/RNA
Note
SLC16A3 was first cloned from human circulating
blood by Price et al. (1998).
Proton-linked monocarboxylate transporter. Catalyzes
plasma membrane transport of monocarboxylates such
as lactate, pyruvate, branched-chain oxo acids derived
from leucine, valine and isoleucine, and the ketone
bodies acetoacetate, beta-hydroxybutyrate and acetate.
Description
Homology
11077 bp lenght, 5 exons.
Belongs to the major facilitator superfamily (MFS).
Monocarboxylate porter (TC 2.A.1.13) family. The
SLC16A3 gene is conserved in chimpanzee, dog, cow,
mouse, rat, chicken, zebrafish, and M. grisea.
Transcription
3 transcripts have been described for this gene (all with
protein product): SLC16A3-201, (5 exons; 2033 bps
transcript length; 465 residues translation length);
SLC16A3-202 (4 exons; 4222 bps transcript length;
465 residues translation length); SLC16A3-203 (5
exons; 2054 bps transcript length; 465 residues
translation length).
Implicated in
Colorectal carcinoma
Note
SLC16A3/MCT4 protein is overexpressed in colorectal
cancer (Pinheiro et al., 2008a).
Protein
Cervical cancer
Description
Note
SLC16A3/MCT4 protein is overexpressed in cervical
cancer (Pinheiro et al., 2008b). SLC16A3/MCT4
protein overexpression in cervical cancer correlated
with positivity for high-risk HPV (Pinheiro et al.,
2008b).
465 residues; 49469 Da; 12 transmembrane domains;
intracellular N- and C-terminals.
Expression
SLC16A3/MCT4 is expressed in tissues such as white
skeletal muscle fibres, astrocytes, white blood
1157
Protein diagram drawn following UniProtKB/Swiss-Prot database prediction, using TMRPres2D software.
a patient with a mitochondrial myopathy (Baker et al.,
2001).
Bladder cancer
Note
SLC16A3 gene expression was upregulated in some
bladder tumours and induced by hypoxia in bladder
cancer cell lines, but not in cultures of normal
urothelium (Ord et al., 2005).
Chronic obstructive pulmonary disease
Note
SLC16A3/MCT4 downregulation was described in the
vastus lateralis muscle of patients with chronic
obstructive pulmonary disease as compared with
healthy controls (Green et al., 2008).
Breast cancer
Note
Induction was also seen in two breast cancer cell lines.
Expression of SLC16A3 gene is higher in breast cancer
distant metastasis as compared to primary tumours or
regional metastasis. SLC16A3 gene was then included
in the 'VEGF profile' of breast cancer, associated with
promotion of vessel formation, survival under
anaerobic conditions and loss of dependence upon
fibroblasts (Hu et al., 2009).
References
Price NT, Jackson VN, Halestrap AP. Cloning and sequencing
of four new mammalian monocarboxylate transporter (MCT)
homologues confirms the existence of a transporter family with
an ancient past. Biochem J. 1998 Jan 15;329 ( Pt 2):321-8
Baker SK, Tarnopolsky MA, Bonen A. Expression of MCT1 and
MCT4 in a patient with mitochondrial myopathy. Muscle Nerve.
2001 Mar;24(3):394-8
Ovarian cancer
Halestrap AP, Meredith D. The SLC16 gene family-from
monocarboxylate transporters (MCTs) to aromatic amino acid
transporters and beyond. Pflugers Arch. 2004 Feb;447(5):61928
Note
SLC16A3 gene expression was described to be
downregulated in malignant ovarian tumours as
compared to normal ovarian surface epithelial cells.
Additionally, the non-tumorigenic cell line TOV-81D
presented higher expression that tumorigenic cell lines
(Wojnarowicz et al., 2008).
SLC16A3 gene, among other transporter genes, was
differentially expressed in a chemotherapy resistant
ovarian cancer cell line and tumour tissue as compared
to a chemosensitive cell line and tumour tissue. It was
suggested that these transporters might be involved in
drug influx/efflux, modulating chemotherapy response
(Cheng et al., 2010).
Ord JJ, Streeter EH, Roberts IS, Cranston D, Harris AL.
Comparison of hypoxia transcriptome in vitro with in vivo gene
expression in human bladder cancer. Br J Cancer. 2005 Aug
8;93(3):346-54
Green HJ, Burnett ME, D'Arsigny CL, O'Donnell DE, Ouyang J,
Webb KA. Altered metabolic and transporter characteristics of
vastus lateralis in chronic obstructive pulmonary disease. J
Appl Physiol. 2008 Sep;105(3):879-86
Meredith D, Christian HC. The SLC16 monocaboxylate
transporter family. Xenobiotica. 2008 Jul;38(7-8):1072-106
Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SM, Etlinger
D, Moreira MA, Jubé LF, Queiroz GS, Schmitt F, Baltazar F.
Increasing expression of monocarboxylate transporters 1 and 4
along progression to invasive cervical carcinoma. Int J Gynecol
Pathol. 2008 Oct;27(4):568-74
Mitochondrial myopathy
Note
SLC16A3/MCT4 overexpression was described in
1158
Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L,
Martins S, Pellerin L, Rodrigues M, Alves VA, Schmitt F,
Baltazar F. Increased expression of monocarboxylate
transporters 1, 2, and 4 in colorectal carcinomas. Virchows
Arch. 2008 Feb;452(2):139-46
Perou CM. A compact VEGF signature associated with distant
metastases and poor outcomes. BMC Med. 2009 Mar 16;7:9
Cheng L, Lu W, Kulkarni B, Pejovic T, Yan X, Chiang JH, Hood
L, Odunsi K, Lin B. Analysis of chemotherapy response
programs in ovarian cancers by the next-generation
sequencing
technologies.
Gynecol
Oncol.
2010
May;117(2):159-69
Wojnarowicz PM, Breznan A, Arcand SL, Filali-Mouhim A,
Provencher DM, Mes-Masson AM, Tonin PN. Construction of a
chromosome 17 transcriptome in serous ovarian cancer
identifies differentially expressed genes. Int J Gynecol Cancer.
2008 Sep-Oct;18(5):963-75
Pinheiro C, Baltazar F. SLC16A3 (solute carrier family 16,
member 3 (monocarboxylic acid transporter 4)). Atlas Genet
Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA,
Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M,
1159
Gene Section
Mini Review
SPAM1 (sperm adhesion molecule 1 (PH-20
hyaluronidase, zona pellucida binding))
Asli Sade, Sreeparna Banerjee
Department of Biology, Middle East Technical University, Ankara 06531, Turkey (AS, SB)
Online updated version : http://AtlasGeneticsOncology.org/Genes/SPAM1ID42361ch7q31.html
DOI: 10.4267/2042/44921
are clustered on chromosome 3p21.3 and the other
three (HYAL4, SPAM1 and HYALP1) are clustered on
chromosome 7q31.3. Of the three genes on
chromosome 7q31.3, HYALP1 is an expressed
pseudogene. The extensive homology between the six
hyaluronidase genes suggests an ancient gene
duplication event before the emergence of modern
mammals.
Identity
Other names: EC 3.2.1.35, HYA1, HYAL1, HYAL3,
HYAL5, Hyal-PH20, MGC26532, PH-20, PH20,
SPAG15
HGNC (Hugo): SPAM1
Location: 7q31.32
Local order: According to NCBI Map Viewer, genes
flanking SPAM1 in centromere to telomere direction
on 7q31.3 are:
HYALP1
7q31.3
hyaluronoglucosaminidase
pseudogene 1
- HYAL4 7q31.3 hyaluronoglucosaminidase 4
- SPAM1 7q31.3 sperm adhesion molecule 1
- TMEM229A 7q31.32 transmembrane protein 229A
- hCG_1651160 7q31.33 SSU72 RNA polymerase II
CTD phosphatase homolog pseudogene
Note: SPAM1 is a glycosyl-phosphatidyl inositol
(GPI)-anchored enzyme found in all mammalian
spermatozoa. The protein has a hyaluronidase activity
that enables sperm to penetrate the cumulus, a role in
zona pellucida binding and also participates in Ca2+
signaling associated acrosomal exocytosis.
Description
According to Entrez Gene, SPAM1 gene maps to locus
NC_000007 and spans a region of 46136 bp. According
to Spidey (mRNA to genomic sequence alignment
tool), SPAM1 has 7 exons, the sizes being 78, 112,
1160, 90, 441, 99 and 404.
Transcription
The SPAM1 mRNA has two isoforms; transcript
variant 1 (NM_003117) a 2395 bp mRNA and
transcript variant 2 (NM_153189) a 2009 bp mRNA.
The variant 2 uses an alternate in-frame splice site in
the 3' coding region, compared to variant 1, resulting in
a shorter C-terminus.
The promoter region of SPAM1 has been shown to
contain a CRE (cAMP-responsive element) sequence
which is a binding site for CREM (cAMP-responsive
element modulator) and thus Spam1 is under a cAMPdependent transcriptional regulation. No TATA or
CCAAT boxes were found in the promoter region of
SPAM1.
DNA/RNA
Note
The human genome contains six hyaluronidase like
genes. Three of them (HYAL1, HYAL2 and HYAL3)
The diagram of SPAM1 transcript variant 1. The red boxes represent the exons (in scale) and exon numbers are given below the
boxes.
1160
The testis-specific promoters of the human and mouse
SPAM1 genes are derived from a sequence that was
originally part of an ERV pol gene.
Sade A, Banerjee S
The human SPAM1 pseudogene HYALP1 is located on
chromosome 7q31.3.
responsible for local degradation of the cumulus ECM
during sperm penetration. Plasma membrane SPAM1
mediates HA-induced sperm signaling via the HA
binding domain. SPAM1 is also secreted by the
epithelial cells of the epididymis and has a role in
sperm maturation. In addition SPAM1 is implicated in
fluid reabsorption and urine concentration in kidney.
Protein
Homology
Pseudogene
- Pan troglodytes sperm adhesion molecule 1 (SPAM1)
- Canis lupus familiaris sperm adhesion molecule 1
(SPAM1)
- Bos taurus sperm adhesion molecule 1 (SPAM1)
- Mus musculus hyaluronoglucosaminidase 5 (Hyal5)
- Mus musculus sperm adhesion molecule 1 (SPAM1)
- Rattus norvegicus sperm adhesion molecule 1
(HYALP_RAT)
- Gallus gallus sperm adhesion molecule 1 (SPAM1)
- Danio rerio sperm adhesion molecule 1 (Spam1)
Note
Two sperm adhesion isoforms exist; one is 511 aa long
isoform 1 and the other 509 aa long isoform 2. When
the two isoforms are aligned the sequences are 100%
identical and no functional difference has been
reported.
Description
SPAM1 is a 68 kDa protein that belongs to glycosyl
hydrolase 56 family. This family of enzymes has
hyaluronidase activity which hydrolyses the glycosidic
bond between two or more carbohydrates, or between a
carbohydrate and a non-carbohydrate moiety. Sperm
hyaluronidase is active at neutral and acidic pHs which
results from different active sites in the hyaluronidase
domain at the N-terminus of the protein. The
hyaluronidase domain also contains a hyaluronic acid
(HA) binding site that plays a role in the signaling
pathway leading to acrosomal exocytosis. The protein
also contains a zona binding domain at the C-terminal
end.
Mutations
Note
According to dbSNP, one validated missense SNP for
SPAM1 is found in the 47th aa position causing a V to
A (rs34633019) substitution. Other SNPs causing
synonymous changes are: rs34404662 A/G substitution
at the 3rd amino acid residue (Val), rs2285996 A/G
substitution at the 184th amino acid residue (Lys) and
rs34978112 C/T substitution at the 330th amino acid
residue (Ala). No clinical associations with these SNPs
have been reported.
Expression
Germinal
According to GNF Expression Atlas 2 Data from
U133A and GNF1H Chips, SPAM1 expression is
widely limited to testis and epididymis but it was also
found to be expressed in murine kidney and female
reproductive tract. Both rare and abundant SPAM1
transcripts have been found in neoplastic breast tissue
and in a number of other cancers including pharyngeal
astatic melanomas and gliomas. In normal somatic cells
rare transcripts have been found in breast tissue and in
fetal, placental, and prostate cDNA libraries.
In mice bearing Robertsonian translocation Rb(6.15)
and (6.16), reduced Spam1 hyaluronidase activity was
found to cause sperm dysfunction. It was proposed that
entrapment of spontaneous Spam1 mutations, owing to
recombination suppression near the Rb junctions was
the major effect.
According to in vitro mutagenesis experiments the
following mutations were detected to have functional
consequences:
- D146N: 80% loss of activity
- E148Q: loss of activity
- R211G: 90% loss of activity
- E284Q: loss of activity
- R287T: loss of activity
Localisation
SPAM1 is located on the sperm surface and in the
lysosome-derived acrosome, where it is bound to the
inner acrosomal membrane. The acrosomal membrane
SPAM1 differs biochemically from the one on the
sperm surface.
Implicated in
Function
Breast cancer
SPAM1 is a multifunctional protein; a hyaluronidase
that acts in penetrating the cumulus, a receptor for
hyaluronic acid induced cell signaling which leads to
acrosomal exocytosis and a receptor for the zona
pellucida surrounding the oocyte. The zona pellucida
recognition function is ascribed to the inner acrosomal
membrane SPAM1. The neutral enzyme activity of
plasma membrane SPAM1, which is GPI anchored, is
Oncogenesis
Increased levels of SPAM1 are noted in invasive
and metastatic breast cancer compared to ductal
carcinoma in situ (DCIS). Tumors from African
American women with invasive and metastatic breast
cancer showed higher levels of SPAM1 than
Caucasians. Varying levels of SPAM1 in mammary
1161
Sade A, Banerjee S
tissue may contribute to early invasion and metastasis
of breast cancer.
dysfunction
in
Rb(6.16)24Lub
and
Rb(6.15)1Ald
heterozygotes. Mamm Genome. 1997 Feb;8(2):94-7
Laryngeal cancer
Sun L, Feusi E, Sibalic A, Beck-Schimmer B, Wüthrich RP.
Expression profile of hyaluronidase mRNA transcripts in the
kidney and in renal cells. Kidney Blood Press Res.
1998;21(6):413-8
Oncogenesis
SPAM1 expression was found to be significantly
elevated in primary laryngeal cancer tissue and even
higher in metastatic lesions compared with normal
laryngeal tissue. SPAM1 may therefore be a useful
tumor marker and prognostic tool for laryngeal cancer.
In squamous cell laryngeal carcinoma aberrant
expression of SPAM1 at late stages of cancer was
detected.
Zheng Y, Martin-Deleon PA. Characterization of the genomic
structure of the murine Spam1 gene and its promoter:
evidence for transcriptional regulation by a cAMP-responsive
element. Mol Reprod Dev. 1999 Sep;54(1):8-16
Godin DA, Fitzpatrick PC, Scandurro AB, Belafsky PC,
Woodworth BA, Amedee RG, Beech DJ, Beckman BS. PH20:
a novel tumor marker for laryngeal cancer. Arch Otolaryngol
Head Neck Surg. 2000 Mar;126(3):402-4
Colon Cancer
Cherr GN, Yudin AI, Overstreet JW. The dual functions of GPIanchored PH-20: hyaluronidase and intracellular signaling.
Matrix Biol. 2001 Dec;20(8):515-25
Oncogenesis
SPAM1 mRNA was present in mRNA from four
biopsies obtained from patients with colorectal cancers.
Normal colonic mucosal tissues obtained from the
same patients did not express SPAM1 mRNA. In
metastatic colon carcinoma cell lines but not in nonmetastatic cell lines, SPAM1 expression was detected.
Strong angiogenesis developed in four of five animals
injected with SPAM1+ colon carcinoma VAC05 cells.
However, only one of five animals injected with
SPAM1- VAC06 cells developed significant
angiogenesis.
Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes
in the human and mouse genomes. Matrix Biol. 2001
Dec;20(8):499-508
Vines CA, Li MW, Deng X, Yudin AI, Cherr GN, Overstreet JW.
Identification of a hyaluronic acid (HA) binding domain in the
PH-20 protein that may function in cell signaling. Mol Reprod
Dev. 2001 Dec;60(4):542-52
Zheng Y, Deng X, Zhao Y, Zhang H, Martin-DeLeon PA.
Spam1 (PH-20) mutations and sperm dysfunction in mice with
the Rb(6.16) or Rb(6.15) translocation. Mamm Genome. 2001
Nov;12(11):822-9
Beech DJ, Madan AK, Deng N. Expression of PH-20 in normal
and neoplastic breast tissue. J Surg Res. 2002 Apr;103(2):2037
Melanoma
Oncogenesis
SPAM1 expression is seen in metastatic melanoma but
not in non-metastatic melanoma cell lines (SMMU-2
and SMMU-1 respectively). SPAM1+ human
melanoma cell line SMMU-2 but not SPAM1- SMMU1 cells induced angiogenesis in mice cornea although
the exact mechanisms of how SPAM1 induces
angiogenesis is not known.
Evans EA, Zhang H, Martin-DeLeon PA. SPAM1 (PH-20)
protein and mRNA expression in the epididymides of humans
and macaques: utilizing laser microdissection/RT-PCR. Reprod
Biol Endocrinol. 2003 Aug 6;1:54
Zhang H, Martin-DeLeon PA. Mouse Spam1 (PH-20) is a
multifunctional protein: evidence for its expression in the
female reproductive tract. Biol Reprod. 2003 Aug;69(2):446-54
Dunn CA, Mager DL. Transcription of the human and rodent
SPAM1 / PH-20 genes initiates within an ancient endogenous
retrovirus. BMC Genomics. 2005 Apr 1;6(1):47
References
Christopoulos TA, Papageorgakopoulou N, Theocharis DA,
Mastronikolis NS, Papadas TA, Vynios DH. Hyaluronidase and
CD44 hyaluronan receptor expression in squamous cell
laryngeal carcinoma. Biochim Biophys Acta. 2006
Jul;1760(7):1039-45
Jones MH, Davey PM, Aplin H, Affara NA. Expression
analysis, genomic structure, and mapping to 7q31 of the
human sperm adhesion molecule gene SPAM1. Genomics.
1995 Oct 10;29(3):796-800
Liu D, Pearlman E, Diaconu E, Guo K, Mori H, Haqqi T,
Markowitz S, Willson J, Sy MS. Expression of hyaluronidase by
tumor cells induces angiogenesis in vivo. Proc Natl Acad Sci U
S A. 1996 Jul 23;93(15):7832-7
Grigorieva A, Griffiths GS, Zhang H, Laverty G, Shao M, Taylor
L, Martin-DeLeon PA. Expression of SPAM1 (PH-20) in the
murine kidney is not accompanied by hyaluronidase activity:
evidence for potential roles in fluid and water reabsorption.
Kidney Blood Press Res. 2007;30(3):145-55
Arming S, Strobl B, Wechselberger C, Kreil G. In vitro
mutagenesis of PH-20 hyaluronidase from human sperm. Eur J
Biochem. 1997 Aug 1;247(3):810-4
Deng X, Moran J, Copeland NG, Gilbert DJ, Jenkins NA,
Primakoff P, Martin-DeLeon PA. The mouse Spam1 maps to
proximal chromosome 6 and is a candidate for the sperm
Sade A, Banerjee S. SPAM1 (sperm adhesion molecule 1 (PH20 hyaluronidase, zona pellucida binding)). Atlas Genet
1162
Gene Section
Mini Review
Youngwoo Park
Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon,
Korea (YP)
Online updated version : http://AtlasGeneticsOncology.org/Genes/TMPRSS2ID42592ch21q22.html
DOI: 10.4267/2042/44922
Localisation
Identity
Subcellular location: Cell membrane; Single-pass type
II membrane protein.
Activated by cleavage and secreted.
Other names: FLJ41954, PP9284, PRSS10
HGNC (Hugo): TMPRSS2
Location: 21q22.3
Function
DNA/RNA
Two alternative splicing variants have been described,
producing transcripts of 3.25 kb and 3.21 kb,
respectively.
This gene was demonstrated to be up-regulated by
androgenic hormones in prostate cancer cells and
down-regulated in androgen-independent prostate
cancer tissue. To containing intra- and extracellular
domains, TMPRSS2 could work as a receptor for
specific ligand(s) mediating signals between the
environment and the cell. TMPRSS2 has been proposed
to regulate epithelial sodium currents in the lung
through proteolytic cleavage of the epithelial sodium
channel and inflammatory responses in the prostate via
the proteolytic activation of PAR-2.
Protein
Homology
Description
TMPRSS2 gene approximately extends 43.59 kb-long
on chromosome 21 in the region q22.3, containing 14
exons.
Transcription
TTPs (type II transmembrane serine proteases) contain
an integral transmembrane domain and remain cellsurface-associated, even after proteolytic activation of
the protease zymogen. Human TTSPs, which consists
of 17 members, were grouped into four subfamilies
based on similarity in domain structure and
phylogenetic
analysis of the serine protease domains, namely the
matriptase, corin, hepsin/TMPRSS and HAT/DESC
subfamilies.
Description
TMPRSS2 is a 492 amino acid type II transmembrane
serine proteases (TTSPs) which are expressed at the
cell surface and are thus ideally located to regulate cellcell and cell-matrix interactions.
Expression
TMPRSS2 is expressed in normal and diseased
human tissues. Especially, TMPRSS2 is highly
expressed in small intestine, but also in lower levels in
several other tissues. Also expressed in prostate, colon,
stomach and salivary gland.
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Park Y
TMPRSS2 is a 492 amino acid single-pass type II membrane protein. It contains a Serine protease domain (aa 255-492) of the S1 family,
followed by a Scavenger receptor cysteine-rich domain (SRDR, aa 149-242) of group A; an LDL receptor class A (LDLRA, aa 113-148)
domain forms a binding site for calcium; a predicted transmembrane domain (aa 84-106). Letters H, D and S in the serine protease
domain indicate the position of the three catalytic residues histidine, aspartate and serine, respectively.
Multidomain structure of human TTSPs. Human TTSPs were grouped into four subfamilies based on similarity in domain structure and
phylogenetic analysis of the serine protease domains, namely the matriptase, corin, hepsin/TMPRSS and HAT/DESC subfamilies.
Consensus domains are shown below. Each diagram was drawn using the web-based SMART software (http://smart.emblheidelberg.de) with TTSP amino acid sequences obtained from GenBank.
Abbreviations: CUB, Cls/Clr, urchin embryonic growth factor and bone morphogenic protein-1 domain; DESC1, differentially expressed
squamous cell carcinoma gene 1; FRZ, frizzled domain; HAT, human airway trypsin-like protease; LDLA, low-density lipoprotein receptor
domain class A; MAM, a meprin, A5 antigen and receptor protein phosphatase m domain; MSPL, mosaic serine protease long-form;
Polyserase-1, polyserine protease-1; SEA, a single sea urchin sperm protein, enteropeptidase, agrin domain; SR, scavenger receptor
cysteine-rich domain; TM, transmembrane domain. Letters H, D and S in the serine protease domain (active) indicate the position of the
three catalytic residues histidine, aspartate and serine, respectively. Letter A in the serine protease domain (inactive) indicates a serine to
alanine exchange.
however, its gene turned out to be expressed mainly in
the prostate in an androgen dependent manner.
In the prostate adenocarcinoma, TMPRSS2-EGR
fusion mRNAs is highly expressed. Because of its
location on the surface of prostatic cells, TMPRSS2 is a
potential new diagnostic marker for prostate cancer.
Implicated in
Prostate cancer
Prognosis
TMPRSS2 was originally reported to
smallintestine-associated serine protease.
be a
Later,
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Park Y
Breakpoints
References
Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C,
Antonarakis SE. Cloning of the TMPRSS2 gene, which
encodes a novel serine protease with transmembrane, LDLRA,
and SRCR domains and maps to 21q22.3. Genomics. 1997
Sep 15;44(3):309-20
Bugge TH, Antalis TM, Wu Q. Type II transmembrane serine
proteases. J Biol Chem. 2009 Aug 28;284(35):23177-81
Choi SY, Bertram S, Glowacka I, Park YW, Pöhlmann S. Type
II transmembrane serine proteases in cancer and viral
infections. Trends Mol Med. 2009 Jul;15(7):303-12
Vaarala MH, Porvari K, Kyllönen A, Lukkarinen O, Vihko P.
The TMPRSS2 gene encoding transmembrane serine
protease is overexpressed in a majority of prostate cancer
patients: detection of mutated TMPRSS2 form in a case of
aggressive disease. Int J Cancer. 2001 Dec 1;94(5):705-10
Barwick BG, Abramovitz M, Kodani M, Moreno CS, Nam R,
Tang W, Bouzyk M, Seth A, Leyland-Jones B. Prostate cancer
genes associated with TMPRSS2-ERG gene fusion and
prognostic of biochemical recurrence in multiple cohorts. Br J
Cancer. 2010 Feb 2;102(3):570-6
Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko
PT. Expression of transmembrane serine protease TMPRSS2
in mouse and human tissues. J Pathol. 2001 Jan;193(1):13440
Park Y. TMPRSS2 (transmembrane protease, serine 2). Atlas
1165
Gene Section
Review
Xueshan Qiu
Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China
Medical University, Shenyang, China (XQ)
Online updated version : http://AtlasGeneticsOncology.org/Genes/TMSB10ID42595ch2p11.html
DOI: 10.4267/2042/44923
Localisation
Identity
TMSB10 is expressed in cytoplasm.
Other names: MIG12, TB10, THYB10
HGNC (Hugo): TMSB10
Location: 2p11.2
Note: TMSB10 is a member of the beta-thymosin
family, which is an actin-sequestering protein involved
in cell motility. TMSB10 may be correlated with tumor
cells proliferation, apoptosis, metastasis and
angiogenesis.
Function
Overview: TMSB10 is a highly conserved small acid
protein. It is present in many tissues and cell types. It
can sequester actin monomers and bind to G-actin in a
1:1 complex.
Actin monomer sequestering protein: TMSB10 is
one of G-actin binding proteins, being expressed in all
mammalian species. It can sequester monomeric actin
and inhibit actin polymerization. It participates in the
regulation of cancer cell motility.
Development: The expression of TMSB10 is
associated with the development of several tissues. It is
involved in the development of the oral cavity and its
annexes. TMSB10 plays an important role in early
neuroembryogenesis. It is present in the developing
nervous, and has a specific physiological function
during cerebellum development. TMSB10 is only
present at very low levels in a very small subpopulation
of glia in the adult cerebellum. In young animals, most
of the TMSB10 is localized in granule cells, Golgi
neurons and Purkinje cells. In old animals, TMSB10
signal is detected faintly in a few Purkinje cells.
Apoptosis: TMSB10 regulates apoptosis. For example,
upregulation of TMSB10 in M. bovis-infected
macrophages is linked with increased cell death due to
apoptosis.
DNA/RNA
Description
The cDNA sequence for human TMSB10 is 482
nucleotides long comprising 3 exons. The open reading
frame of the coding region is 135 bp.
Protein
Description
Protein length (NP_066926.1): 44 amino acids.
(madkpdmgeiasfdkaklkktetqekntlptketieqekrseis)
Molecular weight: 4.9 kDa. TMSB10 is a small G-actin
binding protein, and it induces depolymerization of
intracellular F-actin pools by sequestering actin
monomers.
Expression
TMSB10 is found in human, rat, mouse, cat, and rabbit.
TMSB10 is one of the most abundant beta-thymosins.
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Qiu X
TMSB10 can disrupt F-actin stress fibers, markedly
decrease ovarian cancer cells growth, and a high rate of
apoptosis. TMSB10 plays a significant role in cell
apoptosis possibly by acting as an actin-mediated
tumor suppressor, perhaps functions as a neoapoptotic
influence during embryogenesis, and may mediate
some of the pro-apoptotic anticancer actions of
retinoids.
Angiogenesis: TMSB10 may be an effective inhibitor
of angiogenesis by inhibiting endothelial migration,
tube formation, VEGF, VEGFR-1 and integrin alphaV
expression in HCAECs. TMSB10 is not only a
cytoskeletal regulator, it also acts as a potent inhibitor
of angiogenesis and tumor growth by interaction with
Ras.
Cancers: Elevated expression of TMSB10 is
associated with invasion and metastasis of several
kinds of tumors. It may be considered a potential tool
for the diagnosis of several human neoplasias.
TMSB10 is detected mainly in the malignant tissue,
particularly in the cancerous cells, whereas the normal
cell population around the lesions showed very weak
staining. Also, the intensity of staining in the cancerous
cells is proportionally increased with the increasing
grade of the lesions.
Breast cancer
Note
TMSB10 plays a key role in sequestration of Gactin as well as in breast cancer cell motility.
Ovarian cancer
Note
TMSB10 inhibits angiogenesis and tumor growth by
interfering Ras signal transduction and expression of
VEGF.
Thyroid neoplasias
Note
TMSB10 overexpression is a general event of thyroid
cell neoplastic transformation. An increased expression
of TMSB10 mRNA in thyroid carcinomas is found.
The evaluation of TMSB10 gene expression may be
considered a promising means of human thyroid
hyperproliferative diagnosis. By decreasing TMSB10
expression, the thyroid cancer cells growth in soft agar
is inhibited.
Renal cell carcinoma
Note
The TMSB10 gene is deregulated in renal cell
carcinoma and it may be a new molecular marker for
renal-cell carcinoma.
Homology
Homolog to thymosin beta 4 and thymosin beta 15.
Cutaneous melanoma
Implicated in
Note
TMSB10 can be considered as a new progression
marker for human cutaneous melanoma.
Pancreatic cancer
Note
TSMB10 is expressed in human pancreatic carcinoma,
but not in non-neoplastic pancreatic tissue, suggesting a
role for TMSB10 in the carcinogenesis of pancreatic
carcinoma. It is a promising marker and a novel
therapeutic target for pancreatic cancer. Exogenous
TMSB10 causes the phosphorylation of JNK and
increases the secretion of cytokines interleukin (IL)-7
and IL-8 in BxPC-3 pancreatic cancer cells.
References
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Non-small cell lung cancer
Goodall GJ, Horecker BL. Molecular cloning of the cDNA for
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Note
TMSB10 might induce microvascular and lymphatic
vessel formation by up-regulating vascular endothelial
growth factor and vascular endothelial growth factor-C
in lung cancer tissues, thus promoting the distant and
lymph node metastases and being implicated in the
progression of non-small cell lung cancer.
McCreary V, Kartha S, Bell GI, Toback FG. Sequence of a
human kidney cDNA clone encoding thymosin beta 10.
Biochem Biophys Res Commun. 1988 Apr 29;152(2):862-6
Hall AK, Hempstead J, Morgan JI. Thymosin beta 10 levels in
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Lin SC, Morrison-Bogorad M. Developmental expression of
mRNAs encoding thymosins beta 4 and beta 10 in rat brain
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Califano D, Monaco C, Santelli G, Giuliano A, Veronese ML,
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M, Viglietto G, Fusco A. Thymosin beta-10 gene
overexpression correlated with the highly malignant neoplastic
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Hall AK. Retinoic acid and serum modulation of thymosin beta10 gene expression in rat neuroblastoma cells. J Mol Neurosci.
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Carpintero P, Anadón R, Gómez-Márquez J. Expression of the
thymosin beta10 gene in normal and kainic acid-treated rat
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Hall AK, Chen SC, Hempstead JL, Morgan JI. Retinoic acid
regulates thymosin beta 10 levels in rat neuroblastoma cells. J
Neurochem. 1991 Feb;56(2):462-8
Santelli G, Califano D, Chiappetta G, Vento MT, Bartoli PC,
Zullo F, Trapasso F, Viglietto G, Fusco A. Thymosin beta-10
gene overexpression is a general event in human
carcinogenesis. Am J Pathol. 1999 Sep;155(3):799-804
Lin SC, Morrison-Bogorad M. Cloning and characterization of a
testis-specific thymosin beta 10 cDNA. Expression in postmeiotic male germ cells. J Biol Chem. 1991 Dec
5;266(34):23347-53
Vassiliadou I, Leondiadis L, Ferderigos N, Ithakissios DS,
Evangelatos GP, Livaniou E. Investigation of the epitopic
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Peptides. 1999;20(3):411-4
Lugo DI, Chen SC, Hall AK, Ziai R, Hempstead JL, Morgan JI.
Developmental regulation of beta-thymosins in the rat central
nervous system. J Neurochem. 1991 Feb;56(2):457-61
Viglietto G, Califano D, Bruni P, Baldassarre G, Vento MT,
Belletti B, Fedele M, Santelli G, Boccia A, Manzo G, Santoro
M, Fusco A. Regulation of thymosin beta10 expression by TSH
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Condon MR, Hall AK. Expression of thymosin beta-4 and
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1992;3(3):165-70
Anadón R, Rodríguez Moldes I, Carpintero P, Evangelatos G,
Livianou E, Leondiadis L, Quintela I, Cerviño MC, GómezMárquez J. Differential expression of thymosins beta(4) and
beta(10) during rat cerebellum postnatal development. Brain
Res. 2001 Mar 16;894(2):255-65
Hall AK. Retinoids and a retinoic acid receptor differentially
modulate thymosin beta 10 gene expression in transfected
neuroblastoma cells. Cell Mol Neurobiol. 1992 Feb;12(1):45-58
Border BG, Lin SC, Griffin WS, Pardue S, Morrison-Bogorad
M. Alterations in actin-binding beta-thymosin expression
accompany neuronal differentiation and migration in rat
cerebellum. J Neurochem. 1993 Dec;61(6):2104-14
Bani-Yaghoub M, Felker JM, Ozog MA, Bechberger JF, Naus
CC. Array analysis of the genes regulated during neuronal
differentiation of human embryonal cells. Biochem Cell Biol.
2001;79(4):387-98
Nachmias VT. Small actin-binding proteins: the beta-thymosin
family. Curr Opin Cell Biol. 1993 Feb;5(1):56-62
Weterman MA, van Muijen GN, Ruiter DJ, Bloemers HP.
Thymosin beta-10 expression in melanoma cell lines and
melanocytic lesions: a new progression marker for human
cutaneous melanoma. Int J Cancer. 1993 Jan 21;53(2):278-84
Koutrafouri V, Leondiadis L, Avgoustakis K, Livaniou E,
Czarnecki J, Ithakissios DS, Evangelatos GP. Effect of
thymosin peptides on the chick chorioallantoic membrane
angiogenesis model. Biochim Biophys Acta. 2001 Nov
7;1568(1):60-6
Yu FX, Lin SC, Morrison-Bogorad M, Atkinson MA, Yin HL.
Thymosin beta 10 and thymosin beta 4 are both actin
monomer sequestering proteins. J Biol Chem. 1993 Jan
5;268(1):502-9
Lee SH, Zhang W, Choi JJ, Cho YS, Oh SH, Kim JW, Hu L, Xu
J, Liu J, Lee JH. Overexpression of the thymosin beta-10 gene
in human ovarian cancer cells disrupts F-actin stress fiber and
leads to apoptosis. Oncogene. 2001 Oct 11;20(46):6700-6
Hall AK. Amplification-independent overexpression of thymosin
beta-10 mRNA in human renal cell carcinoma. Ren Fail.
1994;16(2):243-54
Vasile E, Tomita Y, Brown LF, Kocher O, Dvorak HF.
Differential expression of thymosin beta-10 by early passage
and senescent vascular endothelium is modulated by
VPF/VEGF: evidence for senescent endothelial cells in vivo at
sites of atherosclerosis. FASEB J. 2001 Feb;15(2):458-66
Yu FX, Lin SC, Morrison-Bogorad M, Yin HL. Effects of
thymosin beta 4 and thymosin beta 10 on actin structures in
living cells. Cell Motil Cytoskeleton. 1994;27(1):13-25
Gómez-Márquez J, Anadón R. The beta-thymosins, small
actin-binding peptides widely expressed in the developing and
adult cerebellum. Cerebellum. 2002 Apr;1(2):95-102
Hall AK. Thymosin beta-10 accelerates apoptosis. Cell Mol Biol
Res. 1995;41(3):167-80
Gutiérrez-Pabello JA, McMurray DN, Adams LG. Upregulation
of thymosin beta-10 by Mycobacterium bovis infection of
bovine macrophages is associated with apoptosis. Infect
Immun. 2002 Apr;70(4):2121-7
Voisin PJ, Pardue S, Morrison-Bogorad M. Developmental
characterization of thymosin beta 4 and beta 10 expression in
enriched neuronal cultures from rat cerebella. J Neurochem.
1995 Jan;64(1):109-20
Otto AM, Müller CS, Huff T, Hannappel E. Chemotherapeutic
drugs change actin skeleton organization and the expression
of beta-thymosins in human breast cancer cells. J Cancer Res
Clin Oncol. 2002 May;128(5):247-56
Carpintero P, Franco del Amo F, Anadón R, Gómez-Márquez
J. Thymosin beta10 mRNA expression during early
postimplantation mouse development. FEBS Lett. 1996 Sep
23;394(1):103-6
Santelli G, Bartoli PC, Giuliano A, Porcellini A, Mineo A,
Barone MV, Busiello I, Trapasso F, Califano D, Fusco A.
Thymosin beta-10 protein synthesis suppression reduces the
Verghese-Nikolakaki S, Apostolikas N, Livaniou E, Ithakissios
DS, Evangelatos GP. Preliminary findings on the expression of
thymosin beta-10 in human breast cancer. Br J Cancer. 1996
Nov;74(9):1441-4
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growth of human thyroid carcinoma cells in semisolid medium.
Thyroid. 2002 Sep;12(9):765-72
Mu H, Ohashi R, Yang H, Wang X, Li M, Lin P, Yao Q, Chen
C. Thymosin beta10 inhibits cell migration and capillary-like
tube formation of human coronary artery endothelial cells. Cell
Motil Cytoskeleton. 2006 Apr;63(4):222-30
Takano T, Hasegawa Y, Miyauchi A, Matsuzuka F, Yoshida H,
Kuma K, Amino N. Quantitative analysis of thymosin beta-10
messenger RNA in thyroid carcinomas. Jpn J Clin Oncol. 2002
Jul;32(7):229-32
Maelan AE, Rasmussen TK, Larsson LI. Localization of
thymosin beta10 in breast cancer cells: relationship to actin
cytoskeletal remodeling and cell motility. Histochem Cell Biol.
2007 Jan;127(1):109-13
Tokuriki M, Noda I, Saito T, Narita N, Sunaga H, Tsuzuki H,
Ohtsubo T, Fujieda S, Saito H. Gene expression analysis of
human middle ear cholesteatoma using complementary DNA
arrays. Laryngoscope. 2003 May;113(5):808-14
Gu Y, Wang C, Wang Y, Qiu X, Wang E. Expression of
thymosin beta10 and its role in non-small cell lung cancer.
Hum Pathol. 2009 Jan;40(1):117-24
Chiappetta G, Pentimalli F, Monaco M, Fedele M, Pasquinelli
R, Pierantoni GM, Ribecco MT, Santelli G, Califano D,
Pezzullo L, Fusco A. Thymosin beta-10 gene expression as a
possible tool in diagnosis of thyroid neoplasias. Oncol Rep.
2004 Aug;12(2):239-43
Li M, Zhang Y, Zhai Q, Feurino LW, Fisher WE, Chen C, Yao
Q. Thymosin beta-10 is aberrantly expressed in pancreatic
cancer and induces JNK activation. Cancer Invest. 2009
Mar;27(3):251-6
Liu CR, Ma CS, Ning JY, You JF, Liao SL, Zheng J. Differential
thymosin beta 10 expression levels and actin filament
organization in tumor cell lines with different metastatic
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Nemolato S, Messana I, Cabras T, Manconi B, Inzitari R,
Fanali C, Vento G, Tirone C, Romagnoli C, Riva A, Fanni D, Di
Felice E, Faa G, Castagnola M. Thymosin beta(4) and beta(10)
levels in pre-term newborn oral cavity and foetal salivary
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Sribenja S, Li M, Wongkham S, Wongkham C, Yao Q, Chen C.
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E, Lohr M, Jesnowski R, Baretton G, Ockert D, Saeger HD,
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Zhang T, Li X, Yu W, Yan Z, Zou H, He X. Overexpression of
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Res. 2009;41(1):36-43
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Lee JH. Thymosin {beta}(10) inhibits angiogenesis and tumor
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Qiu X. TMSB10 (thymosin beta 10). Atlas Genet Cytogenet
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1169
Gene Section
Review
Irene V Bijnsdorp, Godefridus J Peters
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands (IVB, GJP)
Online updated version : http://AtlasGeneticsOncology.org/Genes/TYMPID40397ch22q13.html
DOI: 10.4267/2042/44924
is involved in nucleotide synthesis and thymidine
phosphorolysis.
Identity
Other names: ECGF1,
PDECGF, TP
HGNC (Hugo): TYMP
Location: 22q13.33
hPD-ECGF,
MNGIE,
Description
Thymidine phosphorylase is located at chromosome 22
in the region of q13.33. cDNA is approximately 1.8 kb
long, consisting of 10 exons in a 4.3 kb region
(Hagiwara et al., 1991; Stenman et al., 1992). TP was
first cloned and sequenced in 1989 (Ishikawa et al.,
1989). The nucleic acid sequence of TP is highly
conserved, the human TP shares 39% sequence identity
with that of E. coli (Barton et al., 1992).
DNA/RNA
Note
The TP gene encodes an angiogenic factor which
promotes angiogenesis both in vitro and in vivo and
TYMP is located on chromosome 22 of which 3 transcripts have been identified.
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Bijnsdorp IV, Peters GJ
pyrimidine nucleoside to another pyrimidine base.
Subsequently a new pyrimidine nucleoside is formed.
The sugars that are formed by degradation of thymidine
are thought to play a role in the induction of
angiogenesis. Deoxyribose-1-P can be converted to
deoxyribose-5-phosphate or degraded to deoxyribose.
Deoxyribose can be secreted, and possibly attract
endothelial cells to form new blood vessels (reviewed
in de Bruin et al., 2006; Liekens et al., 2007;
Bronckaers et al., 2009). TP in some cancer cells can
also increase their invasive potential, although the exact
mechanism remains unclear.
TP can also activate or inactivate several pyrimidines
or pyrimidine nucleoside analogs with antiviral and
antitumoral activity, such as inactivation of
trifluorothymidine (TFT) (Heidelberger et al., 1964)
and 5-fluoro-2'-deoxyruidine (van Laar et al., 1998), or
activation of 5-fluorouracil (5-FU) (Schwartz et al.,
1995) and 5-fluoro-5'-deoxyuridine (5'DFUR).
Transcription
The promoter region of the TP gene has no TATA box
or CCAAT box, but has a high G-C content and seven
copies of the SP-1 binding site upstream from the
transcription start site.
Exact TP gene regulation is unknown, but has been
described to be (indirectly) regulated by NFkB, TNFalpha and IFN-gamma (Waguri et al., 1997; Zhu et al.,
2002; Zhu et al., 2003; Eda et al., 1993; de Bruin et al.,
2004).
Protein
Note
Thymidine phosphorylase was first identified as the
platelet-derived endothelial cell growth factor, because
it was related to endothelial cell growth (Miyazono et
al., 1987; Ishikawa et al., 1989). Later on, it was found
that it was identical to thymidine phosphorylase
(Furukawa et al., 1992). Thymidine phosphorylase (TP)
is the most correct name to refer to this protein, since it
catalyzes the phopshorolysis of thymidine to thymine.
TP undergoes limited post-translational modification
and is not glycosylated. Covalent linkage between
serine residues of TP and phosphate groups of
nucleotides has been observed, which may facilitate
secretion of the protein (Usuki et al., 1991). However,
TP does not contain a classical secretion signal
(Ishikawa et al., 1989). TP is a dimer, consisting of two
identical subunits that are non-covalently associated
(Desgranges et al., 1981) with its dimeric molecular
mass ranging from 90 kD in Escherichia coli to 110 kD
in mammals (Schwartz, 1978; Desgranges et al., 1981).
Homology
The TYMP gene is conserved in chimpanzee, mouse,
rat, and zebrafish.
Mutations
Note
Mutations in this gene have been associated with
mitochondrial
neurogastrointestinal
encephalomyopathy (MNGIE). Multiple alternatively
spliced variants, encoding the same protein, have been
identified.
Implicated in
Description
Various cancer
TP protein does not contain a known receptor binding
region or a secretion signal (Ishikawa et al., 1989). It is
implicated in nucleotide synthesis and degradation of
thymidine. TP is also implicated in angiogenesis
(reviewed in de Bruin et al., 2006; Liekens et al., 2007;
Bronckaers et al., 2009).
Note
TP in tumor sites can be expressed in the cancer cells,
in the most malignant cells, tumor stromal cells (such
as macrophages) or in the invasive part of the tumor
(van Triest et al., 1999). A high TP expression and
activity have been related to a poor outcome and
increased angiogenesis. The TP gene is regulated by
many other factors that are implicated in cancer, such
as NFkB (de Bruin et al., 2004). TP regulates the
expression of IL-8, and possibly also that of other
genes, although the exact mechanism of this regulation
is still unclear (Brown et al., 2000; Bijnsdorp et al.,
2008). The high TP activity in the tumor can selectively
activate the 5FU prodrug 5'-deoxy-5-fluorouridine to
5FU. 5'deoxy-5-fluorouridine is an intermediate of the
oral 5FU prodrug Capecitabine (Xeloda) (de Bruin et
al., 2006). On the other hand TP can inactivate the
fluoropyrimidine trifluorothymidine (TFT), which is
registered as the antiviral drug Viroptic® (De Clercq,
2004). An inhibitor of TP, TPI, will prevent
inactivation of TFT. TAS-102 is a combination of TFT
and TPI (in a molar ratio of 1:0.5) which is developed
as an anticancer drug (Temmink et al., 2007).
Expression
TP is highly expressed in liver tissues. Furthermore, TP
is often overexpressed in tumor sites and is involved in
inflammatory diseases, such as rheumatoid arthritis.
Localisation
TP is expressed in the cytoplasm and the nucleus (Fox
et al., 1995).
Function
TP catalyzes the phosphorolysis of thymidine (TdR) to
thymine and 2-deoxy-alpha-D-ribose 1-phosphate (dR1-P). TP can also catalyze the formation of thymidine
from thymine and dR-1-P. TP also catalyzes the
phosphorolysis of deoxyuridine to uracil and dR-1-P.
TP also has deoxyribosyl transferase activity by which
the deoxyribosyl moiety is transferred from a
1171
glomeruli) where it probably plays a critical role in the
progression of interstitial fibrosis (Wang et al., 2006).
Disease
Gastrointestinal tumors (Fox et al., 1995; Yoshikawa et
al., 1999; Kimura et al., 2002; Takebayashi et al.,
1996), breast cancer (Moghaddam et al., 1995), bladder
cancer (O'Brien et al., 1996).
Prognosis
High expression is often related to a poor prognosis, an
increased microvessel density and increased metastasis.
Abnormal protein
No fusion protein has been described.
Mitochondrial neurogastrointestinal
encephalomyopathy (MNGIE)
Note
An autosomal recessive disorder involving DNA
alterations (Bardosi et al., 1987). Gene mutations in the
TP gene include missense, splice sites microdeletions
and single nucleotide insertions (Spinazzola et al.,
2002; Nishino et al., 2000). These mutations are
associated with a severe reduction in TP activity. This
leads to increased thymidine plasma levels, and
increased deoxyuridine levels (which is also a substrate
for TP).
Prognosis
Not determined.
Rheumatoid arthritis
Note
Elevated levels of (circulating) PD-ECGF (TP) were
found in rheumatoid arthritis patients (Asai et al.,
1993). In the sera and synovial fluids of patients
suffering from rheumatoid arthritis PD-ECGF (TP) was
detected at high levels (Asai et al., 1993). In addition,
there was a significant positive correlation between
PD-ECGF (TP) levels in synovial fluid and in serum
(Asai et al., 1993). The elevated PD-ECGF (TP) levels
presumably arise through induction of PD-ECGF (TP)
in synoviocytes, resulting from aberrant production of
cytokines like TNF-alpha and IL-1 (Waguri et al.,
1997).
References
HEIDELBERGER C, ANDERSON SW. FLUORINATED
PYRIMIDINES. XXI. THE TUMOR-INHIBITORY ACTIVITY OF
5-TRIFLUOROMETHYL-2'-DEOXYURIDINE. Cancer Res.
1964 Dec;24:1979-85
Schwartz M. Thymidine phosphorylase from Escherichia coli.
Methods Enzymol. 1978;51:442-5
Desgranges C, Razaka G, Rabaud M, Bricaud H. Catabolism
of thymidine in human blood platelets: purification and
properties of thymidine phosphorylase. Biochim Biophys Acta.
1981 Jul 27;654(2):211-8
Atherosclerosis
Note
TP is expressed in atherosclerosis. Macrophages, foam
cells and giant cells from both aortic and coronary
plaques expressed TP, suggesting that TP may play a
role in the pathogenesis of atherosclerosis (Boyle et al.,
2000).
Bardosi A, Creutzfeldt W, DiMauro S, Felgenhauer K, Friede
RL, Goebel HH, Kohlschütter A, Mayer G, Rahlf G, Servidei S.
Myo-, neuro-, gastrointestinal encephalopathy (MNGIE
syndrome) due to partial deficiency of cytochrome-c-oxidase. A
new mitochondrial multisystem disorder. Acta Neuropathol.
1987;74(3):248-58
Psoriasis
Miyazono K, Okabe T, Urabe A, Takaku F, Heldin CH.
Purification and properties of an endothelial cell growth factor
from human platelets. J Biol Chem. 1987 Mar 25;262(9):4098103
Note
Increased
PD-ECGF
(TP)
mRNA
and
immunoreactivity were found in lesional psoriasis
compared to the non-lesional skin (Creamer et al.,
1997). In another study it was reported that the
thymidine phosphorylase activity was twenty-fold
higher in psoriatic lesions than in normal skin
(Hammerberg et al., 1991).
Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C,
Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH.
Identification of angiogenic activity and the cloning and
expression of platelet-derived endothelial cell growth factor.
Nature. 1989 Apr 13;338(6216):557-62
Hagiwara K, Stenman G, Honda H, Sahlin P, Andersson A,
Miyazono K, Heldin CH, Ishikawa F, Takaku F. Organization
and chromosomal localization of the human platelet-derived
endothelial cell growth factor gene. Mol Cell Biol. 1991
Apr;11(4):2125-32
Inflammatory bowel disease
Note
In inflammatory bowel disease, TP has been found to
be overexpressed, predominantly in macrophages and
fibroblasts of the inflamed colonic mucosa. The grade
of expression augmented with an increasing grade of
inflammation. In addition, TP was found in the
endothelial cells of the inflamed colonic mucosa
(Giatromanolaki et al., 2003; Saito et al., 2003).
Hammerberg C, Fisher GJ, Voorhees JJ, Cooper KD. Elevated
thymidine phosphorylase activity in psoriatic lesions accounts
for the apparent presence of an epidermal "growth inhibitor,"
but is not in itself growth inhibitory. J Invest Dermatol. 1991
Aug;97(2):286-90
Usuki K, Miyazono K, Heldin CH. Covalent linkage between
nucleotides and platelet-derived endothelial cell
Chronic glomerulonephritis
growth factor. J Biol Chem. 1991 Oct 25;266(30):20525-31
Note
TP is upregulated in chronic glomerulonephritis (a
renal disease characterized by inflammation of the
Barton GJ, Ponting CP, Spraggon G, Finnis C, Sleep D.
Human platelet-derived endothelial cell growth factor is
homologous to Escherichia coli thymidine phosphorylase.
Protein Sci. 1992 May;1(5):688-90
1172
Furukawa T, Yoshimura A, Sumizawa T, Haraguchi M,
Akiyama S, Fukui K, Ishizawa M, Yamada Y. Angiogenic
factor. Nature. 1992 Apr 23;356(6371):668
Boyle JJ, Wilson B, Bicknell R, Harrower S, Weissberg PL, Fan
TP. Expression of angiogenic factor thymidine phosphorylase
and angiogenesis in human atherosclerosis. J Pathol. 2000
Oct;192(2):234-42
Stenman G, Sahlin P, Dumanski JP, Hagiwara K, Ishikawa F,
Miyazono K, Collins VP, Heldin CH. Regional localization of
the human platelet-derived endothelial cell growth factor
(ECGF1) gene to chromosome 22q13. Cytogenet Cell Genet.
1992;59(1):22-3
Brown NS, Jones A, Fujiyama C, Harris AL, Bicknell R.
Thymidine phosphorylase induces carcinoma cell oxidative
stress and promotes secretion of angiogenic factors. Cancer
Res. 2000 Nov 15;60(22):6298-302
Asai K, Hirano T, Matsukawa K, Kusada J, Takeuchi M,
Otsuka T, Matsui N, Kato T. High concentrations of
immunoreactive gliostatin/platelet-derived endothelial cell
growth factor in synovial fluid and serum of rheumatoid
arthritis. Clin Chim Acta. 1993 Sep 17;218(1):1-4
Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner
I, Hahn CD, Connolly AM, Verloes A, Guimarães J, Maillard I,
Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL,
Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I,
Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M.
Mitochondrial neurogastrointestinal encephalomyopathy: an
autosomal recessive disorder due to thymidine phosphorylase
mutations. Ann Neurol. 2000 Jun;47(6):792-800
Eda H, Fujimoto K, Watanabe S, Ura M, Hino A, Tanaka Y,
Wada K, Ishitsuka H. Cytokines induce thymidine
phosphorylase expression in tumor cells and make them more
susceptible to 5'-deoxy-5-fluorouridine. Cancer Chemother
Pharmacol. 1993;32(5):333-8
van Triest B, Pinedo HM, Blaauwgeers JL, van Diest PJ,
Schoenmakers PS, Voorn DA, Smid K, Hoekman K, Hoitsma
HF, Peters GJ. Prognostic role of thymidylate synthase,
thymidine phosphorylase/platelet-derived endothelial cell
growth factor, and proliferation markers in colorectal cancer.
Clin Cancer Res. 2000 Mar;6(3):1063-72
Takeuchi M, Otsuka T, Matsui N, Asai K, Hirano T, Moriyama
A, Isobe I, Eksioglu YZ, Matsukawa K, Kato T. Aberrant
production of gliostatin/platelet-derived endothelial cell growth
factor in rheumatoid synovium. Arthritis Rheum. 1994
May;37(5):662-72
Kimura H, Konishi K, Kaji M, Maeda K, Yabushita K, Miwa A.
Correlation between expression levels of thymidine
phosphorylase (dThdPase) and clinical features in human
gastric carcinoma. Hepatogastroenterology. 2002 MayJun;49(45):882-6
Fox SB, Moghaddam A, Westwood M, Turley H, Bicknell R,
Gatter KC, Harris AL. Platelet-derived endothelial cell growth
factor/thymidine phosphorylase expression in normal tissues:
an immunohistochemical study. J Pathol. 1995 Jun;176(2):18390
Spinazzola A, Marti R, Nishino I, Andreu AL, Naini A, Tadesse
S, Pela I, Zammarchi E, Donati MA, Oliver JA, Hirano M.
Altered thymidine metabolism due to defects of thymidine
phosphorylase. J Biol Chem. 2002 Feb 8;277(6):4128-33
Moghaddam A, Zhang HT, Fan TP, Hu DE, Lees VC, Turley H,
Fox SB, Gatter KC, Harris AL, Bicknell R. Thymidine
phosphorylase is angiogenic and promotes tumor growth. Proc
Natl Acad Sci U S A. 1995 Feb 14;92(4):998-1002
Zhu GH, Lenzi M, Schwartz EL. The Sp1 transcription factor
contributes to the tumor necrosis factor-induced expression of
the angiogenic factor thymidine phosphorylase in human colon
carcinoma cells. Oncogene. 2002 Dec 5;21(55):8477-85
Schwartz EL, Baptiste N, Wadler S, Makower D. Thymidine
phosphorylase mediates the sensitivity of human colon
carcinoma cells to 5-fluorouracil. J Biol Chem. 1995 Aug
11;270(32):19073-7
Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D,
Simopoulos C, Gatter KC, Harris AL, Koukourakis MI. Hypoxia
inducible factor 1alpha and 2alpha overexpression in
inflammatory bowel disease. J Clin Pathol. 2003
Mar;56(3):209-13
O'Brien TS, Fox SB, Dickinson AJ, Turley H, Westwood M,
Moghaddam A, Gatter KC, Bicknell R, Harris AL. Expression of
the angiogenic factor thymidine phosphorylase/platelet-derived
endothelial cell growth factor in primary bladder cancers.
Cancer Res. 1996 Oct 15;56(20):4799-804
Saito S, Tsuno NH, Sunami E, Hori N, Kitayama J, Kazama S,
Okaji Y, Kawai K, Kanazawa T, Watanabe T, Shibata Y,
Nagawa H. Expression of platelet-derived endothelial cell
growth factor in inflammatory bowel disease. J Gastroenterol.
2003;38(3):229-37
Takebayashi Y, Yamada K, Miyadera K, Sumizawa T,
Furukawa T, Kinoshita F, Aoki D, Okumura H, Yamada Y,
Akiyama S, Aikou T. The activity and expression of thymidine
phosphorylase in human solid tumours. Eur J Cancer. 1996
Jun;32A(7):1227-32
Zhu GH, Schwartz EL. Expression of the angiogenic factor
thymidine phosphorylase in THP-1 monocytes: induction by
autocrine tumor necrosis factor-alpha and inhibition by aspirin.
Mol Pharmacol. 2003 Nov;64(5):1251-8
Creamer D, Jaggar R, Allen M, Bicknell R, Barker J.
Overexpression of the angiogenic factor platelet-derived
endothelial cell growth factor/thymidine phosphorylase in
psoriatic epidermis. Br J Dermatol. 1997 Dec;137(6):851-5
de Bruin M, Peters GJ, Oerlemans R, Assaraf YG, Masterson
AJ, Adema AD, Dijkmans BA, Pinedo HM, Jansen G.
Sulfasalazine down-regulates the expression of the angiogenic
factors platelet-derived endothelial cell growth factor/thymidine
phosphorylase and interleukin-8 in human monocyticmacrophage THP1 and U937 cells. Mol Pharmacol. 2004
Oct;66(4):1054-60
Waguri Y, Otsuka T, Sugimura I, Matsui N, Asai K, Moriyama
A, Kato T. Gliostatin/platelet-derived endothelial cell growth
factor as a clinical marker of rheumatoid arthritis and its
regulation in fibroblast-like synoviocytes. Br J Rheumatol. 1997
Mar;36(3):315-21
van Laar JA, Rustum YM, Ackland SP, van Groeningen CJ,
Peters GJ. Comparison of 5-fluoro-2'-deoxyuridine with 5fluorouracil and their role in the treatment of colorectal cancer.
Eur J Cancer. 1998 Feb;34(3):296-306
De Clercq E. Antiviral drugs in current clinical use. J Clin Virol.
2004 Jun;30(2):115-33
de Bruin M, Temmink OH, Hoekman K, Pinedo H, Peters GJ..
Role of platelet derived endothelial cell growth factor/
thymidine phosphorylase in health and disease. Cancer
Therapy. 2006;4:99-124. (REVIEW)
Yoshikawa T, Suzuki K, Kobayashi O, Sairenji M, Motohashi H,
Tsuburaya A, Nakamura Y, Shimizu A, Yanoma S, Noguchi Y.
Thymidine phosphorylase/platelet-derived endothelial cell
growth factor is upregulated in advanced solid types of gastric
cancer. Br J Cancer. 1999 Mar;79(7-8):1145-50
Wang EH, Goh YB, Moon IS, Park CH, Lee KH, Kang SH,
Kang CS, Choi YJ. Upregulation of thymidine phosphorylase in
1173
chronic glomerulonephritis and its role in tubulointerstitial
injury. Nephron Clin Pract. 2006;102(3-4):c133-42
factor/thymidine phosphorylase in tumor behavior. Nucleosides
Nucleotides Nucleic Acids. 2008 Jun;27(6):681-91
Liekens S, Bronckaers A, Pérez-Pérez MJ, Balzarini J.
Targeting
platelet-derived
endothelial
cell
growth
factor/thymidine phosphorylase for cancer therapy. Biochem
Pharmacol. 2007 Dec 3;74(11):1555-67
Bronckaers A, Gago F, Balzarini J, Liekens S. The dual role of
thymidine phosphorylase in cancer development and
chemotherapy. Med Res Rev. 2009 Nov;29(6):903-53
Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ.
Therapeutic potential of the dual-targeted TAS-102 formulation
in the treatment of gastrointestinal malignancies. Cancer Sci.
2007 Jun;98(6):779-89
Bijnsdorp IV, Peters GJ. TYMP (thymidine phosphorylase).
Bijnsdorp IV, de Bruin M, Laan AC, Fukushima M, Peters GJ.
The role of platelet-derived endothelial cell growth
1174
Leukaemia Section
Mini Review
der(6)t(1;6)(q21-23;p21)
Adriana Zamecnikova
Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh,
70653, Kuwait (AZ)
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/der6t0106q21p21ID1546.html
DOI: 10.4267/2042/44925
Identity
Partial karyotypes showing the chromosomal translocation der(6)t(1;6)(q21-23;p21) identified by G-banding.
years old male, progressed to AML. From the known
data of 14 patients with myelofibrosis, median age was
65.5 years (range, 38-72 years).
Clinics and pathology
Disease
Clinics
Most frequently observed in chronic myeloproliferative
disorders, occurs with higher frequency in patients with
chronic idiopathic myelofibrosis, polycythemia vera
and post-polycythemic myelofibrosis; may be present
either at diagnosis or during transformation to
advanced stages of the disease.
In the largest study, the anomaly was associated with
splenomegaly, elevated WBC count, elevated levels of
alkaline phosphatase and lactate dehydrogenase;
median overall survival was 7.8 years: five patients
have died (one transformed to acute myeloid leukemia
and the others died because of sepsis or thrombosis).
Epidemiology
Described in 20 cases (11 males, 9 females): 1
biphenotypic leukemia (16 years old male); 1 B-cell
lymphoma (73 years old female); 2 acute myeloid
leukemia (AML) patients (1 male 71 years old, 1
female 28 years old); and in 16 patients with
myelofibrosis with myeloid metaplasia (9 males; 7
females): eleven patients had myelofibrosis with
myeloid metaplasia, three post-polycythemic myeloid
metaplasia, and one post-thrombocythemic myeloid
metaplasia; one of these patients, a 47
Cytogenetics
Cytogenetics morphological
Breakpoints may be controversial and difficult to
ascertain in poor quality preparations. Recently, the
same breakpoint on 6p21.3 and clustering of
breakpoints near the paracentric region 1q21-23 was
described in 14 patients with myelofibrosis with
myelocytic metaplasia.
1175
der(6)t(1;6)(q21-23;p21)
Zamecnikova A
the underlying molecular consequences
rearrangement remain to be determined.
Additional anomalies
Sole anomaly in 9 cases (2 AML and 7 cases with
myelofibrosis); no recurrent additional anomaly
observed in patients with complex karyotypes. 4
patients had two or more different clones (1 patient
with biphenotypic leukemia and 3 myelofibrosis cases);
among them 2 patients had 1q21-23 rearrangements
involving the homologous chromosome 1.
the
To be noted
Case Report
der(6)t(1;6)(q21;p21)
polycythemia vera.
in
myelofibrosis
following
References
Result of the chromosomal
anomaly
Mertens F, Johansson B, Heim S, Kristoffersson U, Mitelman
F. Karyotypic patterns in chronic myeloproliferative disorders:
report on 74 cases and review of the literature. Leukemia.
1991 Mar;5(3):214-20
Fusion protein
Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N,
Watmore A, Potter A. Cytogenetic abnormalities and their
prognostic significance in idiopathic myelofibrosis: a study of
106 cases. Br J Haematol. 1997 Jul;98(1):96-102
Oncogenesis
The presence of the der(6)t(1;6) results in partial
trisomy for 1q21-23 to 1qter and in loss of 6p21 to
6pter. The pathogenetic significance may be the
consequence of gain of gene(s) on 1q and/or haploinsufficiency of gene(s) from 6p and alternatively,
rearrangements of one or more genes at the
breakpoints. The significance of the 6p21 breakpoint is
unclear; however a number of published reports of
myelofibrosis with chromosome 6p breakpoints in the
region raise the possibility of a gene involved in the
pathogenesis of this hematologic disorder. The inability
to identify common breakpoints on 1q, suggests that an
increase in gene copy number is a pathogenetic event.
Whether trisomy 1q is a secondary event to a primary
(cryptic? e.g. JAK2 V617F mutation) anomaly as well
as the roles of methylation, cytotoxic treatments and
of
Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M,
Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis
following polycythemia vera. Cancer Genet Cytogenet. 2003
Jan 15;140(2):118-23
Dingli D, Grand FH, Mahaffey V, Spurbeck J, Ross FM,
Watmore AE, Reilly JT, Cross NC, Dewald GW, Tefferi A.
Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality
in myelofibrosis with myeloid metaplasia. Br J Haematol. 2005
Jul;130(2):229-32
Hussein K, Van Dyke DL, Tefferi A. Conventional cytogenetics
in myelofibrosis: literature review and discussion. Eur J
Haematol. 2009 May;82(5):329-38
Zamecnikova A. der(6)t(1;6)(q21-23;p21). Atlas
1176
Genet
Leukaemia Section
Short Communication
ins(9;4)(q33;q12q25)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ins0904q33q12q25ID1450.html
DOI: 10.4267/2042/44926
assembly (Fong et al., 2009); critical for centrosomal
localization of dynein throughout the cell cycle (Lee
and Rhee, 2010). CDK5RAP2-knockdown cells have
increased resistance to paclitaxel and doxorubicin
(Zhang et al., 2009). Homozygous mutations in
CDK5RAP2 can cause microcephaly (Bond et al.,
2005).
Disease
Chronic eosinophilic leukemia
Epidemiology
One case to date, a 71-year-old female patient with
chronic eosinophilic leukemia in accelerated phase
(Walz et al., 2006).
anomaly
Prognosis
Remission was obtained with imatinib, but the patient
relapsed with imatinib-resistant acute myeloid
leukemia that was characterized by a normal karyotype,
absence of detectable CDK5RAP2-PDGFRA mRNA,
and a newly acquired G12D NRAS mutation.
Hybrid gene
Description
In-frame fusion between exon 13 of the CDK5RAP2, a
40 bp insert from an inverted sequence of PDGFRA
intron 9, and a truncated PDGFRA exon 12. No
reciprocal PDGFRA-CDK5RAP2 transcript.
Genes involved and proteins
Fusion protein
PDGFRA
Description
N-term CDK5RAP2 - C-term PDGFRA; 1003 amino
acids; contains 494 amino acids, including several
potential dimerization domains, of CDK5RAP2 and
509 amino acids from PDGFRA tyrosine kinase
domains.
Oncogenesis
Constitutive tyrosine kinase activity is likely.
Location
4q25
Protein
Receptor tyrosine kinase. Gain-of-function mutations
of PDGFRA are implicated in a subset of
gastrointestinal stromal tumors (Heinrich et al., 2003).
PDGFRA has also been involved in translocations,
making hybrid genes with STRN (2p22), FIP1L1
(4q12), KIF5B (10p11), ETV6 (12p13) and BCR
(22q11).
References
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ,
Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD,
Fletcher CD, Fletcher JA. PDGFRA activating mutations in
gastrointestinal stromal tumors. Science. 2003 Jan
31;299(5607):708-10
CDK5RAP2
Location
9q33
Protein
Centrosomal protein; regulates CDK5; binds EB1. The
CDK5RAP2-EB1 complex stimulates microtubule
Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins
J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM,
Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C,
1177
ins(9;4)(q33;q12q25)
Huret JL
Corry P, Walsh CA, Woods CG. A centrosomal mechanism
involving CDK5RAP2 and CENPJ controls brain size. Nat
Genet. 2005 Apr;37(4):353-5
Fong KW, Hau SY, Kho YS, Jia Y, He L, Qi RZ. Interaction of
CDK5RAP2 with EB1 to track growing microtubule tips and to
regulate microtubule dynamics. Mol Biol Cell. 2009
Aug;20(16):3660-70
Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G,
Schoch C, Lengfelder E, Erben P, Müller MC, Haferlach T,
Hochhaus A, Hehlmann R, Cross NC, Reiter A. Transient
response to imatinib in a chronic eosinophilic leukemia
associated with ins(9;4)(q33;q12q25) and a CDK5RAP2PDGFRA fusion gene. Genes Chromosomes Cancer. 2006
Oct;45(10):950-6
Zhang X, Liu D, Lv S, Wang H, Zhong X, Liu B, Wang B, Liao
J, Li J, Pfeifer GP, Xu X. CDK5RAP2 is required for spindle
checkpoint function. Cell Cycle. 2009 Apr 15;8(8):1206-16
Lee S, Rhee K. CEP215 is involved in the dynein-dependent
accumulation of pericentriolar matrix proteins for spindle pole
formation. Cell Cycle. 2010 Feb 15;9(4):774-83
Gotlib J, Cools J. Five years since the discovery of FIP1L1PDGFRA: what we have learned about the fusion and other
molecularly
defined
eosinophilias.
Leukemia.
2008
Nov;22(11):1999-2010
Huret JL. ins(9;4)(q33;q12q25). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(12):1177-1178.
1178
Solid Tumour Section
Short Communication
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Online updated version : http://AtlasGeneticsOncology.org/Tumors/t1922q13q12MyoCarcID6287.html
DOI: 10.4267/2042/44927
Genes involved and proteins
Disease
ZNF444
Myoepithelioma tumours of soft tissue cover a wide
range of tumours of various behaviour. While most are
of intermediate aggressivity, some metastasize. There is
no sex ratio predominance. Mean age at diagnosis is 38
years; with a range of 3-83 years. Of a hundred of cases
reviewed by Hornick and Fletcher (2003), 60% were
benign and classified as myoepitheliomas or mixed
tumors, and 40% were classified as myoepithelial
carcinomas or malignant mixed tumours.
Amongst cases with benign or low-grade cytology,
with a mean follow-up of 3 years, 20% recurred locally
and none metastasized. Amongst cytologically
malignant cases, with a mean follow-up of 4 years,
40% recurred locally, 1/3 metastasized, and 4 out of 31
patients died. Tumours are positive for epithelial
markers, and for S100 or GFAP, or myogenic markers
(Gleason and Fletcher, 2007).
Location
19q13
Protein
Possess a SCAN domain and 4 C2H2-type zinc fingers.
Transcription factor.
Epidemiology
anomaly
EWSR1
Location
22q12
Protein
From N-term to C-term: a transactivation domain
(TAD) containing multiple degenerate hexapeptide
repeats, 3 arginine/glycine rich domains (RGG
regions), a RNA recognition motif, and a RanBP2 type
Zinc finger. Role in transcriptional regulation for
specific genes and in mRNA splicing.
One case to date, a 40-year-old female patient. After
surgical removal, recurrences occured during 2 years,
and metastases appeared 3 years later. The patient
finally died 9.5 years after initial diagnosis (Brandal et
al., 2009).
Hybrid Gene
Description
5' EWSR1 - 3' ZNF444; fuses EWSR1 exon 8 to the
very near end of ZNF444 (at nucleotide 967, while the
full transcript of ZNF444 is 984 nt long!).
Cytogenetics
Cytogenetics Morphological
Fusion Protein
The t(19;22)(q13;q12) was found within a complex
karyotype.
Description
Truncated EWSR1 with 6 amino acids added from
1179
Huret JL
Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft
tissue in children: an aggressive neoplasm analyzed in a series
of 29 cases. Am J Surg Pathol. 2007 Dec;31(12):1813-24
ZNF444. This does not fit with the usual model of
carcinogenesis found with other EWSR1 translocations,
were there is fusion of the N terminal transactivation
domain of EWSR1 to the DNA binding domain of the
partner (e.g. FLI1).
Brandal P, Panagopoulos I, Bjerkehagen B, Heim S.
t(19;22)(q13;q12) Translocation leading to the novel fusion
gene EWSR1-ZNF444 in soft tissue myoepithelial carcinoma.
Genes Chromosomes Cancer. 2009 Dec;48(12):1051-6
References
Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: a
clinicopathologic and immunohistochemical study of 101 cases
with evaluation of prognostic parameters. Am J Surg Pathol.
2003 Sep;27(9):1183-96
Huret JL. t(19;22)(q13;q12) in myoepithelial carcinoma. Atlas
1180
Isabelle Meiers
Maidstone and Tunbridge Wells NHS Trust, Preston Hall Hospital, Royal British Legion Village, Aylesford,
Kent, ME20 7NJ, UK (IM)
Online updated version : http://AtlasGeneticsOncology.org/Deep/GSTP1inCancerID20084.html
DOI: 10.4267/2042/44928
the glutathione S-transferase family enzymes that
inactivates electrophilic carcinogens by conjugation
with glutathione (Toffoli et al., 1992; Jerónimo et al.,
2001). The regulatory sequence near the GST gene is
commonly affected by hypermethylation during the
early stages of carcinogenesis (Lee et al., 1994; Brooks
et al., 1998; Cairns et al., 2001; Jerónimo et al., 2002;
Henrique and Jerónimo, 2004).
Several classes of GST, including alpha, mu, pi, and
theta, were previously found in human tissue. For
example, compared with benign tissue, there is
increased expression of GST pi in cancers of the breast,
colon, stomach, pancreas, bladder, lung, head and neck,
ovary, and cervix, as well as soft tissue sarcoma,
testicular embryonal carcinoma, meningioma, and
glioma (Niitsu et al., 1989; Randall et al., 1990; Kantor
et al., 1991; Satta et al., 1992; Toffoli et al., 1992;
Green et al., 1993; Inoue et al., 1995; Bentz et al.,
2000; Tratche et al., 2002; Simic et al., 2005; Arai et
al., 2006).
However, hypermethylation of the GSTP1 promoter
has been associated with gene silencing in prostate
cancer and kidney cancer (Lee et al., 1994; Brooks et
al., 1998; Cairns et al., 2001; Jerónimo et al., 2002;
Dulaimi et al., 2004). Similarly, expression of GSTP1
is lower in invasive pituitary tumors than in
noninvasive pituitary tumors and methylation status
correlates with significant downregulation of GSTP1
expression; the frequency of GSTP1 methylation being
higher in invasive pituitary tumors with reducedGSTP1 expression than in pituitary adenomas with
normal or high GSTP1 expression. These data indicate
that
GSTP1
inactivation
through
CpG
hypermethylation is common in pituitary adenomas and
may contribute to aggressive pituitary tumor behavior
(Yuan et al., 2008). More recently, a study showed a
trend of increasing GSTP1 methylation frequency with
increasing grade of mammary phyllodes tumors. The
Running title: GSTP1 review
Key words: Glutathione S-transferase pi (GSTP1),
cancer, methylation analysis, antioxidants.
Pi-class glutathione-S-transferase (GSTP1) located on
chromosome 11q13 encodes a phase II metabolic
enzyme that detoxifies reactive electrophilic
intermediates. GSTP1 plays an important role in
protecting cells from cytotoxic and carcinogenic agents
and is expressed in normal tissues at variable levels in
different cell types. Altered GSTP1 activity and
expression have been reported in many tumors and this
is largely due to GSTP1 DNA hypermethylation at the
CpG island in the promoter-5'.
We review the potential novel role of glutathione Stransferase pi (GSTP1) and its related expression in
miscellaneous cancers. We focus on the rationale for
use of molecular assays for the detection of cancer,
emphasizing the role of the identification of epigenetic
alterations. Finally, we focus on the potential role of
GSTP1 in the pathway of prostate cancer, the most
GSTP1 DNA hypermethylation-related neoplasm
studied to date.
Advances in the epigenetic characterization of cancers
enabled the development of DNA methylation assays
that may soon be used in diagnostic testing of serum
and tissue for cancers. Inhibition of aberrant promoter
methylation could theoretically prevent carcinogenesis.
Reactive oxygen species that are generated by
physiologic processes such as cellular respiration,
exposure to chemical agents, or exposure to ionizing
radiation may overcome cellular antioxidant defense
and cause DNA damage (Bostwick et al., 2000). Such
damage may result in mutations and alteration of
oncogenes or tumor suppressor genes. The cytosolic
isoenzyme glutathione S-transferase pi (GSTP1) is an
important multifunctional detoxifying enzyme within
1181
Meiers I
authors
reported
that
GSTP1
promoter
hypermethylation was associated with loss of GSTP1
expression. These results suggest that phyllodes tumors
segregate into only two groups on the basis of their
methylation profiles: the benign group and the
combined borderline/malignant group (Kim et al.,
2009). Other investigators studied the role of
hypermethylation of the GSTP1 gene promoter region
in endometrial carcinoma and found that reduced
GSTP1 expression was associated with myometrial
invasion potential (Chan et al., 2005).
allowing quantitation or identification of partial
methylation. The CMSP assay is mainly used for
GSTP1 methylation detection in fluids. For instance,
GSTP1 methylation in serum of men with localized
prostate cancer prior to treatment carries a 4.4 fold
increased risk of biochemical recurrence following
surgery (Bastian et al., 2005).
The use of fluorescence-based real-time quantitative
methylation-specific PCR (QMSP) assay improved the
sensitivity of tumor detection. Continuous monitoring
of fluorescent signals during the PCR process enabled
quantification of methylated alleles of a single region
amongst unmethylated DNA because the fluorescence
emission of the reporter represents the number of
generated DNA fragments (Heid et al., 1996).
Epigenetic alterations: emerging
molecular markers for cancer detection
Cancer is a process fuelled both by genetic alterations
and epigenetic mechanisms. Epigenetics refer to
changes in gene expression that can be mitotically
inherited, but are not associated with the changes in the
coding sequence of the affected genes. In other words,
epigenetics refer to the inheritance of information
based on gene expression levels, in contrast to genetics
that refer to transmission of information based on gene
sequence (Esteller et al., 2000). DNA methylation, the
best understood mechanism in epigenetics, is an
enzyme-mediated chemical modification that adds
methyl (-CH3) groups at selected sites on DNA. In
humans and most mammals, DNA methylation only
affects the cytosine base (C), when it is followed by a
guanosine (G). Methylation of the cytosine nucleotide
residue located within the dinucleotide 5'-CpG-3' is the
most frequent epigenetic alteration in humans. These
CpG dinucleotides are not randomly distributed in the
genome. Indeed, there are CpG-rich regions called
"CpG islands" frequently associated with the 5'
regulatory regions of genes, including the promoter.
DNA methylation in the promoter regions is a powerful
mechanism for the suppression of gene activity.
GSTP1 hypermethylation: significance
and incidence related to prostate cancer
Epigenetic silencing of gluthathione-S-transferase pi
(GSTP1) is recognized as being a molecular hallmark
of human prostate cancer. Methylation of CpG islands
in the promoter of the pi class of glutathione Stransferase occurs in prostatic intraepithelial neoplasia
(PIN) and cancer (Gonzalgo et al., 2004). Other
hypermethylated regions relevant to prostate cancer
include the retinoic acid receptor beta 2 (Bastian et al.,
2007). These findings in prostate cancer suggest that
DNA methylation is among the early events in
tumorigenesis, but it remains to be seen whether DNA
methylation is a necessary or permissive event in
tumorigenesis.
The extensive methylation of deoxycytidine
nucleotides distributed throughout the 5' "CG island"
region of GSTP1 is not detected in benign prostatic
epithelium, but has been detected in intraepithelial
neoplasia, prostatic adenocarcinoma, and fluids
(plasma, serum, ejaculate, and urine) of patients with
prostate cancer by methylation-specific polymerase
chain reaction assay, and may be useful as a cancerspecific molecular biomarker (Lee et al., 1994; Cairns
et al., 2001; Henrique and Jerónimo, 2004; Crocitto et
al., 2004; Perry et al., 2006; Hopkins et al., 2007; Cao
and Yao, 2010).
Quantitative methylation-specific PCR (QMSP) reveals
that the epigenetic silencing (loss of expression) of the
GSTP1 gene is in fact the most common genetic
alteration in prostate cancer (>90%) and high-grade
prostatic intraepithelial neoplasia (PIN) (70%) (Lee et
al., 1994; Brooks et al., 1998; Cairns et al., 2001;
Harden et al., 2003; Henrique and Jerónimo, 2004) and
this somatic inactivation ("silencing") of GSTP1 is
directly associated with promoter methylation (Cairns
et al., 2001; Jerónimo et al., 2002; Henrique and
Jerónimo, 2004). Higher levels of GSTP1 promoter
methylation is associated with the transition from
prostatic intraepithelial neoplasia (PIN) to carcinoma
(Henrique et al., 2006).
During cancer development, GSTP1 does not appear to
function either as an oncogene or as a tumor suppressor
DNA methylation analysis: currently
available methods
Methylation of CpG islands is of interest for diagnostic
and prognostic reasons. Methylation of one or both
alleles of a region can serve as a biomarker of cancer or
silence gene expression when they are in a promoter
region (Verma and Srivastava, 2002). Assays for
methylation are appealing for translational research
since they can utilize amplification techniques, such as
methylation-specific polymerase chain reaction (PCR),
and thereby utilize small amounts of samples.
Due to its relative simplicity, safety, and sensitivity,
methylation-specific PCR is the most commonly
employed method for methylation analysis (Herman et
al., 1996).
The conventional methylation-specific PCR (CMSP)
assay uses two sets of primers specifically designed to
amplify the methylated or unmethylated sequence, and
the PCR products are run in a gel (Herman et al., 1996).
The results of CMSP at a particular DNA region are
simply reported as methylated or unmethylated, not
1182
Meiers I
gene, since induced GSTP1 expression in prostate
cancer cell lines failed to suppress cell growth. Instead,
GSTP1 was proposed to act as a "caretaker" gene.
When GSTP1 is inactivated, prostate cells appear to
become more vulnerable to somatic alterations upon
chronic exposure to genome-damaging stresses as
oxidants and electrophiles, that are contributed by
environment and lifestyle (Kinzler and Vogelstein,
1997; Cairns et al., 2001).
The significance of absent GSTP1 (GSTP1 silencing)
in high grade PIN and carcinoma is unclear. It may be
an epiphenomenon, simply reflecting disruption of the
basal cell layer with neoplastic progression. However,
Lee et al. considered the likelihood of a more
fundamental role (Lee et al., 1994). Two studies found
that a small proportion (3.5-5%) of cases retained
modest GSTP1 expression in carcinoma (Cookson et
al., 1997; Moskaluk et al., 1997). Cookson et al. also
recorded positivity in 1 of 17 cases of high grade PIN
(Cookson et al., 1997) . Unlike genetic alterations that
permanently and definitively change DNA sequence,
promoter methylation is a potentially reversible
modification. Hence, promoter methylation may be
amenable to therapeutic intervention aimed at
reactivating silenced cancer genes. This has important
implications for chemoprevention because, as
mentioned above, up to 70% of cases of high-grade
PIN display GSTP1 promoter methylation (Brooks et
al., 1998; Cairns et al., 2001; Jerónimo et al., 2002).
Indeed, recently some authors have investigated the
effects of green tea polyphenols (GTPs) on GSTP1 reexpression. They demonstrated that promoter
demethylation by green tea polyphenols leads to reexpression of GSTP1 in human prostate cancer cells,
therefore making green tea polyphenols excellent
candidates for the chemoprevention of prostate cancer
(Pandey et al., 2009).
Some investigators evaluated the impact of androgen
deprivation therapy on the detection of GSTP1
hypermethylation in prostate cancer (Kollermann et al.,
2006). In 87% (13/15) of the patients, there was no
alteration in GSTP1 hypermethylation detection
(Kollermann et al., 2006) and the authors suggested
that the change from positive to negative GSTP1
hypermethylation status in two patients may point to
partial androgen dependency (Kollermann et al., 2006).
In addition to the supposed hormonal interaction, other
possible explanations may be speculated to explain
why prostate cancer loses GSTP1 hypermethylation
after prolonged neoadjuvant hormonal therapy. First,
the lack of GSTP1 hypermethylation may be
attributable to technical problems (false negative
results). Furthermore, the possibility that both tumors
primarily lacked GSTP1 hypermethylation might be
raised. However, further studies are necessary to assess
the frequency and extent of hormonal interaction with
GSTP1 hypermethylation.
Anti-cancer effect of GSTP1 and future
prospects
Increased levels of GST pi may protect human cancer
cells against cytotoxic drugs. Several antineoplastic
drugs, particularly reactive electrophilic alkylating
agents, form conjugates with glutathione spontaneously
and in GST-catalyzed reactions (Awasthi et al., 1996).
The expression of particular subclasses of GST protects
cells from the cytotoxicities of these cancer drugs, and
overexpression of GST has been implicated in
antineoplastic drug resistance (Morrow et al., 1998).
Induction of the enzymes is thought to represent an
adaptive response to stress, and may be triggered by
exogenous chemical agents and probably also by
reactive oxygen metabolites (Hayes and Pulford, 1995).
GST enzymes have a broad substrate specificity that
includes substances with known mutagenic properties.
Elevated serum GST pi has been exploited as a serum
tumor marker for gastrointestinal cancer (Niitsu et al.,
1989) and non-Hodgkin's lymphoma (Katahira et al.,
2004) as a method of predicting sensitivity to
chemotherapy.
Inactivation of GSTP1 in prostate cancer occurs early
during carcinogenesis, leaving prostate cells with
inadequate defenses against oxidant and electrophile
carcinogens. Epigenetic mechanisms (see above) are
strongly implicated in progression (Rennie and Nelson,
1998). Unlike genetic alterations, changes in DNA
methylation are potentially reversible. Thus,
therapeutic interventions involving reversal of the
methylation process of several key genes in prostate
carcinogenesis might improve current therapeutic
options, thereby enhancing the anti-cancer effect of
GSTP1 gene in patients "at risk" with high-grade PIN
or in men with established prostate cancer. Nucleosideanalogue inhibitors of DNA methyltransferases, such as
5-aza-2'-deoxycytidine, are able to demethylate DNA
and restore silenced gene expression. Unfortunately,
the clinical utility of these compounds has not yet been
fully realized, mainly because of their side effects. The
anti-arrhythmia drug procainamide, a nonnucleoside
inhibitor of DNA methyltransferases (category of
enzymes that catalyse DNA methylation during cell
replication), reversed GSTP1 DNA hypermethylation
and restorted GSTP1 expression in LNCaP human
prostate cancer cells propagated in vitro or in vivo as
xenograft tumors in athymic nude mice (Cairns et al.,
2001). Some investigators tested the potential use of
procaine, an anesthetic drug related to procainamide.
Using the MCF-7 breast cancer cell line, they have
found that procaine produced a 40% reduction in 5methylcytosine DNA content as determined by highperformance capillary electrophoresis and total DNA
enzyme digestion. Procaine can also demethylate
densely hypermethylated CpG islands such as those
located in the promoter region of the RAR beta 2 gene,
1183
Meiers I
Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA,
Bova GS, Hsieh WS, Isaacs WB, Nelson WG. Cytidine
methylation of regulatory sequences near the pi-class
glutathione S-transferase gene accompanies human prostatic
carcinogenesis. Proc Natl Acad Sci U S A. 1994 Nov
22;91(24):11733-7
restoring gene expression of epigenetically silenced
genes. This property may be explained by binding of
procaine to CpG-enriched DNA. Finally, procaine also
has growth-inhibitory effects in these cancer cells,
causing mitotic arrest (Villar-Garea et al., 2003). Thus,
procaine and procainamide are promising candidate
agents for future cancer therapies based on epigenetics.
Li et al. reported that GSTP1 was upregulated in the
stromal compartment of hormone-independent prostate
cancer, which may contribute to chemoresistance of
advanced prostate cancer (Morrow et al., 1998).
Epidemiologic evidence has shown a reduced risk of
prostate cancer in men consuming selenium, suggesting
a role for antioxidants in protection against prostate
carcinogenesis. A systematic review and meta-analysis
of the literature confirm that selenium intake may
reduce the risk of prostate cancer (Etminan et al.,
2005). Vitamin E intake also may decrease DNA
damage and inhibit transformation through its
antioxidant function. Long-term supplementation with
alpha-tocopherol substantially reduced prostate cancer
incidence and mortality in male smokers (Heinonen et
al., 1998). Therapy directed at the induction or
preservation of GSTP1 activity in benign prostatic
epithelium may prevent or delay progression of
prostatic cancer.
GSTP1 has a protective role as an antioxidant agent in
transformation and progression of prostate cancer. The
interplay between altered or impaired expression of
GST appears to play a significant role in carcinogenesis
in the prostate. Inhibition of aberrant promoter
methylation could be an effective method of
chemoprevention.
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1185
Yi Yan, Charlton Cooper, Etienne Leygue
Manitoba Institute of Cell Biology, University of Manitoba, 770 Bannatyne Avenue, R3E0W3, Winnipeg,
Manitoba, Canada (YY, EL); Department of Biochemistry and Medical Genetics, University of Manitoba,
770 Bannatyne Avenue, R3E0W3, Winnipeg, Manitoba, Canada (YY, CC, EL)
Online updated version : http://AtlasGeneticsOncology.org/Deep/SRA1inCancerID20085.html
DOI: 10.4267/2042/44929
Abstract
The Steroid receptor RNA activator (SRA) gene has been implicated in estrogen receptor signaling pathway. First
identified as a RNA coregulator, SRA had been shown to increase steroid receptor activity. SRA RNA expression is
altered during breast tumorigenesis and its molecular role in underscoring these events has been suggested. The
subsequent identification of molecules capable of binding SRA, including RNA helicase p68, SRA stem-loop
interacting RNA binding protein (SLIRP), and steroidogenic factor 1 (SF1) indicates SRA function is not exclusively
limited to modulate steroid receptor activity. A recent genome-wide expression analysis by depleting SRA in cancer
cells has further expanded our understanding of a broader biological role played by SRA. In addition, several RNA
isoforms have been found to encode an endogenous protein (SRAP), which is well conserved among Chordata.
Interestingly, SRAP also modulates steroid receptor activity and functions as a co-regulator in estrogen receptor
signaling. The recent observation that a higher expression of SRAP protein is associated with poorer survival in breast
cancer patients treated with tamoxifen, highlights the potential relevance of this protein in cancer. Together, the SRA1
gene encodes both functional RNA and protein (SRAP) products, making it a unique member amongst the growing
population of steroid receptor co-regulators.
particularly interesting member within this family was
identified by Lanz et al. in 1999, as it was found not to
act as a protein molecule but as a functional RNA. This
nuclear co-regulator was therefore named Steroid
receptor RNA activator (SRA) (Lanz et al., 1999).
1. Introduction
It is now quite apparent that the end results of Estrogen
Receptor (ER) mediated signaling is not simply limited
to ER status and/or the presence of its naturally
occurring ligand estridiol. In addition to the two known
estrogen receptors, ERα and ERβ, ERs-mediated gene
transcription also requires transcription co-regulators,
which form complexes with estrogen receptors through
protein-protein interactions followed by dynamic
recruitment to specific gene promoters. Based on the
outcomes of their regulations, co-regulators are
categorized as either co-activators or co-repressors if
they either promote or prevent gene transcription
respectively. These complexes regulate the assembly
and activity of the transcription initiation complex
through chromatin remodeling (McKenna et al., 1999;
Jenuwein and Allis, 2001).
Since the characterization of the first co-regulator, the
steroid receptor co-activator 1 (SRC-1), this list of
factors has grown significantly to now include over 300
co-regulators (Lonard and O'Malley, 2007). One
2. Steroid Receptor RNA Activator
(SRA)
2.1 Discovery of SRA, an RNA Co-activator
In order to identify new potential co-regulators
interacting with AF-1 domain of the progesterone
receptor (PR), Lanz screened a human B-lymphocyte
library using AF-1 domain as bait in a
yeast-two-hybrid assay (Lanz et al., 1999). They
identified a new clone, they called SRA, for steroid
receptor RNA activator. This cDNA was unable to
encode a protein, but was required for the growth of the
yeast colony. Further experiment confirmed that the
potential co-activation role of SRA on PR was
mediated through a RNA transcript rather than any
protein product.
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Yan Y, et al.
2001; Deblois and Giguère, 2003; Coleman et al.,
2004; Klinge et al., 2004). SRA RNA has been shown
to co-activate the action of the AF-2 domain of both
ERα and ERβ in a ligand-dependent manner on some,
but not all estrogen receptor element (ERE) as measure
through luciferase reporters assay (Deblois and
Giguère, 2003; Coleman et al., 2004).
Interestingly, SRA can also enhance AF-1 domain of
ERα but not ERβ in a ligand-independent manner
(Coleman et al., 2004; Deblois and Giguère, 2003).
Overall, data suggest that the action of the two estrogen
receptors are differentially regulated by SRA and SRA
regulation of a given receptor is also specific of a given
ERE sequence (Leygue, 2007).
2.4 Emerging mechanisms of SRA RNA action
Several studies have been published discussing the
mechanism of SRA RNA action (Leygue, 2007).
2.2 Core sequence of SRA and predicted functional
region
In the incipient SRA study, a core sequence spanning
SRA exon 2 to exon 5 was found to be necessary and
sufficient for co-activation function of SRA RNA
(Figure 1, Lanz et al., 1999). Several predicted
secondary RNA structural motifs are distributed
throughout this core sequence, and are believed to form
the functional structures that impart SRA activities.
Site-directed mutagenesis experiment revealed six
secondary structural motifs (STR1, 7, 9, 10, 11, 12) that
independently participate in PR co-activation by SRA
(Lanz et al., 2002). It was found that silent mutations in
both SRT1 and STR7 of SRA could decrease by more
than 80% co-activation SRA's function (Lanz et al.,
1999).
2.3 Effect of SRA RNA on ERα and ERβ signaling
Several research groups have now confirmed that SRA
is able to increase estradiol induced gene transcription
by both full length ERs subtypes (Watanabe et al.,
Figure 1. SRA1 genomic structure and core sequence. A) SRA sequences were originally described, differing in their 5' and 3'
extremities, but sharing a central core sequence depicted in light blue (Lanz et al., 1999). One sequence has been registered with the
NCBI nucleotide database (AF092038). Alignment with chromosome 5q31.3 genomic sequence is provided. Introns and exons are
represented by black lines and blue boxes, respectively. B) Schematic profile of the predicted secondary structure of human core SRA
RNA. The secondary structure profile of SRA core sequence has been modeled using Mfold software (Zuker, 2003). Detailed structure of
STR1, 10, 7 (Lanz et al., 2002) is provided. C) By doing site-directed mutagenesis experiment, six secondary structural motifs (STR1, 9,
10, 7, 11, 12) have been identified to participate in co-activation respectively. Especially, silent mutations in both SRT1 and STR7 of SRA
could nullify above 80% SRA co-activation function (Lanz et al., 2002).
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Yan Y, et al.
(Zhao et al., 2004; Xu and Koenig, 2004) as well as the
activity of MyoD, a transcription factor involved in
skeletal myogenesis (Caretti et al., 2006; Caretti et al.,
2007); SF-1 and DAX-1, orphan NRs that plays critical
roles in the regulation of sex determination, adrenal
development steroidogenesis (Xu et al., 2009).
Recently, Foulds et al. investigated the global changes
in gene expression by microarray analyses in two
human cancer cell lines when SRA RNA was depleted
by small interfering RNAs (Foulds et al., 2010).
Unexpectedly, only a small subset of direct estrogen
receptor-target genes was affected in estradiol-treated
MCF-7 cells. However, they found many target genes
involved in diverse biological roles such as glucose
uptake, cellular signaling, T3 hormone generation were
altered upon SRA depletion. This suggests SRA has a
much broader upstream biological impact within the
cell than simply a corgualtor of ER-signaling.
2.6 SRA RNA expression and relevance to breast
cancer
Different SRA transcripts, detected by Northern blot,
have been observed in normal human tissues (Lanz et
al., 1999). SRA seems highly expressed in liver,
skeletal muscle, adrenal gland and the pituitary gland,
whereas intermediate expression levels are seen in the
placenta, lung, kidney and pancreas. Interestingly, brain
and other typical steroid-responsive tissues such as
prostate, breast, uterus and ovary contained low levels
of SRA RNA (Lanz et al., 1999). However, SRA RNA
expression, assessed by RT-PCR amplification, is
increased during breast and ovarian tumorigenesis
(Lanz et al., 2003; Leygue et al., 1999; Hussein-Fikret
and Fuller, 2005). Interestingly, SRA over-expression
might characterize particular subtypes of lesions among
different tumors. Indeed, serous ovarian tumors
expressed higher levels of SRA than granulosa cell
tumors (Hussein-Fikret and Fuller, 2005).
The involvement of SRA in ER action suggests
possible SRA role in breast tumor pathology. Indeed,
ER-α-positive/PR-negative breast tumors expressed
more SRA than ER-α-positive/PR-positive breast
tumors (Leygue et al., 1999), whereas Tamoxifensensitive and resistant breast tumors express similar
levels (Murphy et al., 2002). However, generation of
transgenic mice has however demonstrated that overexpression of the core SRA sequence in the mammary
gland only led to pre-neoplastic lesions but was not
sufficient per se to induce tumorigenesis (Lanz et al.,
2003). Notably, SRA gene depleted MDA-MB-231
cells are less invasive than control cells, indicating this
gene might be also critical for invasion (Foulds et al.,
2010).
Firstly, SRA's coactivation function is activated by two
pseudouridylases, Pus1p and Pus3p, which have also
been characterized as co-activators (Zhao et al., 2007).
This modification alters the secondary structure and
rigidity of the target SRA RNA molecules to promote
proper folding, resulting in synergized co-activation
function (Charette and Gray, 2000). The other positive
regulators include the receptor co-activator 1 (SRC-1)
(Lanz et al., 1999) and the RNA helicases P68/72
(Watanabe et al., 2001). SRC-1 belongs to p160 family
co-activators (SRC1, SRC2/TIF2 and SRC3/AIB1),
which can recruit other co-regulators to steroid
receptors as well as promote a functional synergy
between AF-1 and AF-2 domains (Louet and O'Malley,
2007; McKenna et al., 1999; Smith and O'Malley,
2004). Using co-immunoprecipitation from an
expression system consisting of Xenopus oocytes
programmed with in vitro generated RNA, SRA was
found to associate with SRC-1 (Lanz et al., 1999). The
p72/p68 proteins are DEAD-box RNA binding
helicases that can physically interact with p160 family
proteins and with ERα. AF-1 region (Caretti et al.,
2007). The p72/p68 is able to bind to SRA through a
well conserved motif in the DEAD box and synergizes
with SRA and SRC2/TIF2 to co-activate ERα activity
in the presence of estradiol (Caretti et al., 2006).
On the other side, SRA may also serve as a platform to
recruit some negative regulators consisting of the
SMRT/HDAC1 associated repressor protein (SHARP)
(Shi et al., 2001) and the SRA stem-loop interacting
RNA binding protein (SLIRP) (Hatchell et al., 2006).
SHARP was found to physically interact with
corepressors through its repression domain (RD)
whereas it interacts with SRA through a RNA
recognition motif (RRM) (Shi et al., 2001). Similarly,
SLIRP specifically binds to SRA STR-7 and attenuates
SRA-mediated transactivation of endogenous ER
(Hatchell et al., 2006).
The emerging model of SRA action on ERα signaling
had been summarized: Pus1p pseudouridylates specific
SRA RNA uridine residues, leading to an optimum
configuration of this RNA.
The resulting active form of SRA, could stabilize
complexes with p68 and SRC-1. In this case,
transcription of target genes with suitable ERE will
occur. In contrast, interaction with the negative
regulators SLIRP and SHARP with SRA RNA may
result in the inhibition of ER-mediated transcription. It
has been proposed that they might act by sequestrating
SRA by destabilizing the complex SRA/SRC-1 or by
recruiting the nuclear receptor corepressor N-CoR at
the promoter region of silenced genes (Leygue, 2007).
2.5 A broader biological role played by SRA
It has been previously established that SRA action is
not exclusively limited to increasing steroid
receptor activity. Indeed it was also confirmed that
SRA enhance the activity of other nuclear receptor
(NRs), such as retinoic acid receptors, thyroid receptors
3. Coding SRA and SRAP
3.1 Discovery of SRAP
Kawashima et al. reported in 2003 the cloning of a new
rat SRA cDNA mostly identical to the core SRA
sequence from exon 2 to exon 5. This cDNA was,
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Yan Y, et al.
unpublished results using mass spectrometry, MBD3
(methyl-CpG binding domain protein 3, a member of
the nucleosome remodeling and histone deacetylase
complex, Nurd), BAF 57 (a core subunit of SWI/SNF
chromatin remodeling complex) and YB-1 (Y-box
bindng protein, a general transcription factor) have
been found to interact with SRAP (Jung et al., 2005;
Chooniedass-Kothari et al., 2010). By using a similar
approach, Jung et al. also found that the transcription
regulators, such as, BAF 170 (BRG1 associated factor
170, also belonging to SWI/SNF chromatin remodeling
complex) and YB-1 are associated with SRAP (Jung et
al., 2005). It is necessary to point out that different cell
line models and antibodies were used in these two
groups. Jung et al. used Hela cell lines and 743
antibody (commercial available rabbit polyclonal
antibody) whereas Chooniedass-Kothari used MCF7
cells stably over-expressed V5 tagged SRAP and V5
antibody.
Interestingly, nobody has confirmed any proteinprotein interaction between SRAP and those potential
partners by co-immunoprecipitation experiments.
The observation that SRAP forms complexes with
transcription factors by mass spectrometric analysis led
us to investigate its direct association with transcription
factors.
By using recombinant SRAP and protein arrays,
Chooniedass-Kothari found that SRAP interact with
different transcription factors including ERα and ERβ
with different binding affinities (Chooniedass-Kothari
et al., 2010). To further validate the interaction between
ER and SRAP, we performed GST pull down assay and
a direct interaction between GST-SRAP and both full
length radio-labeled estrogen receptor α and β was
observed (Chooniedass-Kothari et al., 2010).
Interestingly, Kawashima showed that SRAP is also
able to directly interact with the AF-2 domain of AR in
vitro by doing GST pull down assay (Kawashima et al.,
2003).
3.3 Alternative RNA splicing of SRA gene in breast
cancer
The balance between co-activators and co-repressors
may ultimately controls estrogen action in a given
tissue (Lonard and O'Malley, 2006). A direct
participation of this balance during breast
tumorigenesis and cancer progression is now suspected,
and a search for possible means to control it has started
worldwide (Perissi and Rosenfeld, 2005; Hall and
McDonnell, 2005). Alternative splicing of SRA gene
might control the balance between the coding and noncoding SRA, and ultimately might function as the
potential mechanism to regulate the balance between
co-activators and co-repressors.
however translatable in vitro encoding a putative 16 kD
protein starting at the third methionine codon of the rat
SRA cDNA sequence (Kawashima et al., 2003). It
should be stressed that the existence of a corresponding
endogenous 16 kD SRAP has never been proved.
In the nucleotide database of the National Center for
Biotechnology Information (NCBI), most human SRA
sequences contain an intact core sequence (exon-2 to
exon-5) but differ in their 5'-extremity. Interestingly,
some variants having 5' end extention contain two start
codons with a large open reading frame potentially
encoding a 236/237 amino acid peptide. These cDNAs,
as opposed to the original SRA, were translatable in
vitro, as well as in vivo, leading to the production of a
protein localized both in the cytoplasm and the nucleus
(Emberley et al., 2003). In addition, sequence of SRAP
is highly conserved among chordate and the presence
of endogenous SRAP had been found in the testes,
uterus, ovary and prostate, as well as mammary gland,
lung and heart (Chooniedass-Kothari et al., 2004).
Altogether, accumulated data has demonstrated that
SRA1 gene products consist of two characteristic
entities: a functional RNA, which through its core
sequence, can co-activate transcription factor and a
protein whose function remains yet to be fully
understood.
3.2 Function of SRAP
Chooniedass-Kothari et al. reported the existence of
putative endogenous human SRA protein in breast
cancer cells (Chooniedass-Kothari et al., 2006). A
decreased response to ERα activity was observed in
MCF-7 cells stably transfected with SRAP suggested
that this protein might repress estrogen receptor
activities (Chooniedass-Kothari et al., 2006). This
result contrasts with Kawashima's results, who found
that the transient transfection of full length rat SRA
coding sequence and led to an activation of the
response to androgen (Kurisu et al., 2006). It should be
pointed out that, both coding sequence of SRA used by
these two groups also contains the functional core
sequence of SRA RNA proven to co-activate ERα.
Therefore, it is difficult to draw any conclusions
regarding the individual function of SRAP on estrogen
receptor activities when functional SRA RNA and
SRAP protein are co-expressed.
In order to understand the functional role of SRAP
independently of SRA RNA, two different groups have
investigated physical protein properties by tandem
mass spectrometric analysis of SRAP coimmunoprecipitation samples (Jung et al., 2005;
Chooniedass-Kothari et al., 2010). Interestingly, both
groups showed that SRAP is able to interact with
transcriptional regulators. In Chooniedass-Kothari's
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Yan Y, et al.
Figure 2: Coding and non-coding SRA transcripts in human breast cancer cells. SRA1 gene, located on chromosome 5q31.3,
consists of 5 exons (boxes) and 4 introns (plain lines). The originally described SRA sequence (AF092038) contains a core sequence
(light blue), necessary and sufficient for SRA RNAs to act as co-activators (Lanz et al., 1999). Three coding isoforms have now been
identified (SRA1, SRA2, SRA3), which mainly differ from AF092038 by an extended 5'-extremity containing AUG initiating codons
(vertical white bar in exon 1). The stop codon of the resulting open reading frame is depicted by a black vertical bar in exon5. Black stars
in exon 2 and 3 correspond to a point mutation (position 98 of the core: U to C) and a point mutation followed by a full codon (position
271 of the core: G to CGAC), respectively. Three non-coding SRA isoforms containing a differentially-spliced intron-1 have been
characterized: FI, full intron-1 retention; PI, partial intron-1 retention; AD, alternative 5' donor and partial intron retention. Thick straight
line, 60 bp of intron 1 retained in PI; triangulated lines represent splicing events (Modified from Cooper et al. 2009).
Both non-coding and coding SRA transcripts co-exist
in breast cells (Figure 2, Hube et al., 2006). Using a
previously validated triple-primer PCR (TP-PCR) assay
(Leygue et al., 1996), which allows co-amplification
and relative quantification of two transcripts sharing a
common region but differing in another, we found that
breast cancer cell lines co-expressed normally spliced
coding SRA RNA as well as SRA RNA containing
intron-1 (Hube et al., 2006). Interestingly, breast cancer
cell lines differ in their relative levels of coding/noncoding SRA transcripts. In particular, the three most
invasive cell lines (MDA-MB-231, 468, and BT-20)
expressed the highest, whereas the "closest to normal"
MCF-10A1 breast cells expressed the lowest relative
levels of SRA intron-1 RNA. This suggests that a
balance changed toward the production of non-coding
SRA1 RNA in breast cells might be associated with
growth and/or invasion properties (Hube et al., 2006).
Alternative splicing events result from the relative local
concentration of RNA binding proteins within the
microenvironnement surrounding the nascent premRNA (Mercatante et al., 2001). We were recently
able to artificially alter the balance between coding and
non-coding SRA1 RNAs in T5 breast cancer cells using
a
previously
described
splicing-switching
oligonucleotide strategy (Mercatante et al., 2001;
Mercatante and Kole, 2002). This approach resulted in
an increase in the production of intron retained
transcripts, decrease in the expression of SRAP,
resulting in an observed significant increase in the
expression of the urokinase plasminogen activator
(uPA, PLAU), gene intimately linked to invasion
mechanisms (Harbeck et al., 2004) as well as of ERβ,
involved, as highlighted earlier, in breast cancer cell
growth (Han et al., 2005).
3.4 SRAP expression and relevance to breast cancer
SRAP expression was assessed by Tissue Microarray
(TMA) analysis of 372 breast tumors (Yan et al., 2009).
SRAP levels were significantly higher in estrogen
receptor-alpha positive, in progesterone receptor
positive and in older patients (age > 64). When
considering ER+ tumors, PR+ tumors, or young
patients (≤ 64 years), patients with high SRAP
expression had a significantly worse breast cancer
specific survival (BCSS) than patients with low SRAP
levels. SRAP also appeared as a very powerful
indicator of poor prognostic for BCSS in the subset of
ER+, node negative and young breast cancer patients.
Altogether suggest that SRAP levels might provide
additional information on potential risk of recurrence
and negative outcome in a specific set of patients.
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Yan Y, et al.
SRA, functions as an RNA and is present in an SRC-1
complex. Cell. 1999 Apr 2;97(1):17-27
4. Conclusion
Accumulated data suggest that the bi-faceted
SRA/SRAP system, including SRA non-coding RNA
and SRA protein, regulates estrogen receptor signaling
pathways and plays a critical role in breast
tumorigenesis and tumor progression. SRA is the first
example of a new kind of molecules active at both
RNA as well as at the protein levels. Investigating and
understanding this bi-faceted system might open a new
era of novel preventive or therapeutic strategies for
breast cancer patients.
Leygue E, Dotzlaw H, Watson PH, Murphy LC. Expression of
the steroid receptor RNA activator in human breast tumors.
Cancer Res. 1999 Sep 1;59(17):4190-3
McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor
coregulators: cellular and molecular biology. Endocr Rev. 1999
Jun;20(3):321-44
Charette M, Gray MW. Pseudouridine in RNA: what, where,
how, and why. IUBMB Life. 2000 May;49(5):341-51
Jenuwein T, Allis CD. Translating the histone code. Science.
2001 Aug 10;293(5532):1074-80
Acknowledgements
Mercatante DR, Bortner CD, Cidlowski JA, Kole R. Modification
of alternative splicing of Bcl-x pre-mRNA in prostate and breast
cancer cells. analysis of apoptosis and cell death. J Biol Chem.
2001 May 11;276(19):16411-7
This work is supported by the Canadian Institute of
Health Research / the Canadian Breast Cancer
Research Alliance (MOP-129794) and the CancerCare
Manitoba Foundation (761017028). Y Yan has been
supported by the MHRC (Manitoba Health Research
Council) Studentship.
Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC, Hon
M, Evans RM. Sharp, an inducible cofactor that integrates
nuclear receptor repression and activation. Genes Dev. 2001
May 1;15(9):1140-51
Abbreviations
Watanabe M, Yanagisawa J, Kitagawa H, Takeyama K,
Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T,
Yoshikawa H, Masuhiro Y, Kato S. A subfamily of RNA-binding
DEAD-box proteins acts as an estrogen receptor alpha
coactivator through the N-terminal activation domain (AF-1)
with an RNA coactivator, SRA. EMBO J. 2001 Mar
15;20(6):1341-52
AF-1: activation function 1
AF-2: activation function 2
AR: androgen receptor
DAX-1:
dosage-sensitive
sex
reversal-adrenal
hypoplasia congenital critical region on X chromosome
gene 1; NR0B1
DBD: DNA binding domain
ER: estrogen receptor
ERE: estrogen receptor
GR: glucocorticoid receptor
LBD: ligand binding domain
MBD3: methyl-CpG binding domain protein 3
NRs: nuclear receptors
NCoR: nuclear co-repressor
PLAU: urokinase plasminogen activator
PR: progesterone receptor
Pus1p: pseudouridine synthase 1
Pus3p: pseudouridine syntheses 3
SERM: selective estrogen receptor modulators
SF-1: nuclear receptor steroidogenic factor 1
SDM: site-directed mutatagenesis
SHARP: SMRT/HDAC1 associated repressor protein
SLIRP: SRA stem-loop interacting RNA binding
protein
SRA: steroid receptor RNA activator
SRAP: steroid receptor RNA activator protein
SR: serine/arginine-rich proteins
SRC-1: steroid receptor co-activator 1
STR: secondary structural motif
YB-1: Y-box bindng protein
Lanz RB, Razani B, Goldberg AD, O'Malley BW. Distinct RNA
motifs are important for coactivation of steroid hormone
receptors by steroid receptor RNA activator (SRA). Proc Natl
Acad Sci U S A. 2002 Dec 10;99(25):16081-6
Mercatante DR, Kole R. Control of alternative splicing by
antisense oligonucleotides as a potential chemotherapy:
effects on gene expression. Biochim Biophys Acta. 2002 Jul
18;1587(2-3):126-32
Murphy LC, Leygue E, Niu Y, Snell L, Ho SM, Watson PH.
Relationship of coregulator and oestrogen receptor isoform
expression to de novo tamoxifen resistance in human breast
cancer. Br J Cancer. 2002 Dec 2;87(12):1411-6
Deblois G, Giguère V. Ligand-independent coactivation of
ERalpha AF-1 by steroid receptor RNA activator (SRA) via
MAPK activation. J Steroid Biochem Mol Biol. 2003 Jun;85(25):123-31
Emberley E, Huang GJ, Hamedani MK, Czosnek A, Ali D,
Grolla A, Lu B, Watson PH, Murphy LC, Leygue E.
Identification of new human coding steroid receptor RNA
activator isoforms. Biochem Biophys Res Commun. 2003 Feb
7;301(2):509-15
Kawashima H, Takano H, Sugita S, Takahara Y, Sugimura K,
Nakatani T. A novel steroid receptor co-activator protein
(SRAP) as an alternative form of steroid receptor RNAactivator gene: expression in prostate cancer cells and
enhancement of androgen receptor activity. Biochem J. 2003
Jan 1;369(Pt 1):163-71
Lanz RB, Chua SS, Barron N, Söder BM, DeMayo F, O'Malley
BW. Steroid receptor RNA activator stimulates proliferation as
well as apoptosis in vivo. Mol Cell Biol. 2003 Oct;23(20):716376
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1192
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