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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Volume 15 - Number 7
July 2011
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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.
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© 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.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Jean-Loup Huret
(Poitiers, France)
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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Solid Tumours Section
Genes Section
Genes / Leukaemia Sections
Solid Tumours Section
Leukaemia Section
Deep Insights Section
Solid Tumours Section
Genes / Deep Insights Sections
Leukaemia Section
Genes / Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia / Solid Tumours Sections
Solid Tumours Section
Solid Tumours Section
Cancer-Prone Diseases / Deep Insights Sections
Cancer-Prone Diseases Section
Genes / Leukaemia Sections
Deep Insights Section
Leukaemia Section
Genes / Deep Insights Sections
Deep Insights Section
Solid Tumours Section
Solid Tumours Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Leukaemia Sections
Cancer-Prone Diseases Section
Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Solid Tumours Sections
Deep Insights Section
Genes / Leukaemia Section
Genes Section
Cancer-Prone Diseases Section
Education Section
Genes Section
Genes / Leukaemia Sections
Genes / Cancer-Prone Diseases Sections
Education Section
Solid Tumours Section
Leukaemia Section
Leukaemia Section
Genes / Leukaemia Sections
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Volume 15, Number 7, July 2011
Table of contents
Gene Section
EIF3A (eukaryotic translation initiation factor 3, subunit A)
Ji-Ye Yin, Zizheng Dong, Jian-Ting Zhang
ERG (v-ets erythroblastosis virus E26 oncogene like (avian))
Roopika Menon, Martin Braun, Sven Perner
ETV4 (ets variant 4)
Yasuyoshi Miyata
GPC5 (glypican 5)
Khin Thway, Joanna Selfe, Janet Shipley
GSDMA (gasdermin A)
Norihisa Saeki, Hiroki Sasaki
IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)
Theoni Trangas, Panayotis Ioannidis
MTA3 (metastasis associated 1 family, member 3)
Ansgar Brüning, Ioannis Mylonas
NMT1 (N-myristoyltransferase 1)
Ponniah Selvakumar, Sujeet Kumar, Jonathan R Dimmock, Rajendra K Sharma
PAEP (progestagen-associated endometrial protein)
Hannu Koistinen, Markku Seppälä
SHBG (sex hormone-binding globulin)
Nicoletta Fortunati, Maria Graziella Catalano
SLC39A6 (solute carrier family 39 (zinc transporter), member 6)
Shin Hamada, Kennichi Satoh, Tooru Shimosegawa
TRPV1 (transient receptor potential cation channel, subfamily V, member 1)
Massimo Nabissi, Giorgio Santoni
WRAP53 (WD repeat containing, antisense to TP53)
Marianne Farnebo
YBX1 (Y box binding protein 1)
Valentina Evdokimova, Alexey Sorokin
ZBTB33 (zinc finger and BTB domain containing 33)
Michael R Dohn, Albert B Reynolds
Leukaemia Section
Jean-Loup Huret
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Deep Insight Section
Role of HB-EGF in cancer
Rosalyn M Adam
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
EIF3A (eukaryotic translation initiation factor 3,
subunit A)
Ji-Ye Yin, Zizheng Dong, Jian-Ting Zhang
Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of
Medicine, Indianapolis, IN, USA (JYY, ZD, JTZ)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/EIF3AID40425ch10q26.html
DOI: 10.4267/2042/45982
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
spectrin domain, and a 10-amino acid repeat domain
(Pincheira et al., 2001b). It has phosphorylation sites at
Ser-881, Ser-1198, Ser-1336 and Ser-1364 (Damoc et
al., 2007). The PCI domain spans from amino acid 405
to 495, which contains purely alpha-helix (Pincheira et
al., 2001b). Since most of the proteins containing this
domain are part of a multi-protein complex, it is
tempting to speculate that this domain may be involved
in the interaction of eIF3a with other molecules in eIF3
(Hofmann and Bucher, 1998). The spectrin domain,
which consists of 112 amino acids, is a sequence
almost identical to spectrin, an actin-binding protein
(Pascual et al., 1997). Although the exact function of
this domain remains unknown, it may be responsible
for the binding of eIF3a to actin filaments (Pincheira et
al., 2001a). The 10-amino acid repeat domain spanning
925-1172 amino acids is the largest domain of eIF3a. It
can be divided into about 25 repeats of
DDDRGPRRGA (Johnson et al., 1997; Pincheira et al.,
2001b). This domain has been suggested to contribute
to interaction of eIF4B and eIF3a (Methot et al., 1996).
Regulatory role in gene expression: eIF3a not only
functions as a regular translation initiation factor and
participates in translation initiation of global mRNAs, it
also regulates the translation of a subset of mRNAs
which are involved in cell cycle, tumorigenesis and
DNA repair (Yin et al., 2010). It has been observed that
overexpression of ectopic eIF3a increases the
expression of ribonucleotide reductase
Other names: EIF3; EIF3S10; KIAA0139; P167;
TIF32; eIF3-p170; eIF3-theta; p180; p185
HGNC (Hugo): EIF3A
Location: 10q26.11
The eIF3a gene spans over a region of 46 kbp DNA
including 22 coding exons and 2 non-coding exons
(exon 2 and exon 10).
The eIF3a mRNA consists of about 5256 nucleotides
with an open reading frame (ORF) of 4149 bases.
No pseudogene has been identified.
Structure: The eIF3a protein consists of 1382 amino
acid residues with an apparent molecular weight of
~170 kDa as determined using SDS-PAGE (Pincheira
et al., 2001b). Its primary sequence contains a PCI
(Proteasome, COP9, Initiation factor 3) domain, a
Schematic presentation of eIF3a domain structure. Human eIF3a consists of 1382 amino acid residues with three putative domains of
PCI, spectrin, and 10-amino acid repeat.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
EIF3A (eukaryotic translation initiation factor 3, subunit A)
Yin JY, et al.
be associated with higher risk of breast cancers (Olson
et al., 2009).
M2 (RRM2) and alpha-tubulin, but decreases that of
p27kip without affect their mRNA levels (Dong and
Zhang, 2003; Dong et al., 2004). Recently, it has also
been found that eIF3a suppresses the synthesis of DNA
repair proteins including: XPA, XPC, RPA 14, RPA 32
and RPA 70 KDa (Yin et al., unpublished data).
Although the detailed mechanism of eIF3a regulation
in translational control is yet to be determined, it is
thought that eIF3a may regulate these genes at their 5'and 3'-UTRs (Dong and Zhang, 2003; Dong et al.,
Binding with other molecule: Since eIF3a is the
largest subunit of the eIF3 complex, the interaction
between eIF3a and other subunits of eIF3 were
intensively studied. It can bind with eIF3b (Methot et
al., 1997), eIF3c (Valasek et al., 2002), eIF3f (Asano et
al., 1997), eIF3h (Asano et al., 1997), eIF3j (Valasek et
al., 1999) and eIF3k (Mayeur et al., 2003). During the
translation initiation, the amino terminal domain of
eIF3a can bind with 40S protein RPS0A, while the C
terminal domain binds with the 18S rRNA (Valasek et
al., 2003). Apart from above molecule, eIF3a has also
been shown to interact with eIF4B (Methot et al.,
1996), actin (Pincheira et al., 2001a), and cytokeratin 7
(Lin et al., 2001).
Implicated in
Breast cancer
eIF3a was overexpressed in breast cancer tissues.
The eIF3a was highly expressed in all tested tissues
from breast cancer patients compared with normal
control tissues, which indicated that it may contribute
to the oncogenesis of breast cancer (Bachmann et al.,
Cervical carcinoma
eIF3a was found to be a molecular parameter of
predicting cervical carcinoma progression and
Patients with high eIF3a expression have better
prognosis than those with lower ones, thus it will be
useful in predicting cervical cancer prognosis (Dellas et
al., 1998).
Gastric carcinoma
eIF3a is ubiquitously expressed in all human tissues
(Nagase et al., 1995; Scholler and Kanner, 1997;
Pincheira et al., 2001b). However, its expression is
higher in proliferating tissues such as bone marrow,
thymus and fetal tissues (Pincheira et al., 2001b).
eIF3a is an early tumor maker of gastric carcinoma.
eIF3a was highly expressed in well differentiated, early
invasive stage and no-metastases gastric carcinoma
(Chen and Burger, 2004).
eIF3a has been found in both cytoplasmic and
membrane fractions and the cytoplasmic eIF3a appears
to be phosphorylated at its serine residues (Pincheira et
al., 2001a). However, 70-80% of eIF3a is cytoplasmic.
Lung cancer
eIF3a is highly expressed in lung cancer compared with
normal tissues.
eIF3a expression in human lung cancers negatively
correlates with patient response to platinum-based
chemotherapy, suggesting that lung cancer patients
with higher eIF3a expression level respond better to
platinum-based chemotherapy (Yin et al., unpublished
eIF3a was over-expressed in all types of human lung
cancer. Furthermore, it is ubiquitously highly
expressed in proliferating and developing tissues. This
suggested eIF3a may be involved in oncogenesis of
lung cancer (Pincheira et al., 2001b).
Centrosomin A and B have strong homology to eIF3a.
The spectrin domain is essentially identical to spectrin.
Esophagus squamous-cell carcinoma
eIF3a has been shown to play important roles in the
biological processes: translational initiation (including
generation of ribosomal subunit from 80S ribosomes,
43S pre-initiation complex formation and 48S preinitiation complex formation) (Dong and Zhang, 2006),
regulation of mRNA translation (Dong and Zhang,
2003; Dong et al., 2004), differentiation and
development (Liu et al., 2007), apoptosis (Nakai et al.,
2005), cell cycle regulation (Dong et al., 2009),
oncogenesis (Dong and Zhang, 2006; Zhang et al.,
2007), and drug response (unpublished observations).
eIF3a may be a biomaker of esophagus squamous-cell
Patients with higher eIF3a expression have better
Two SNPs (rs10787899 and rs3824830) were found to
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
EIF3A (eukaryotic translation initiation factor 3, subunit A)
Yin JY, et al.
Pincheira R, Chen Q, Zhang JT. Identification of a 170-kDa
protein over-expressed in lung cancers. Br J Cancer. 2001b
Jun 1;84(11):1520-7
overall survival and fewer tumor metastases than those
with lower ones (Chen and Burger, 1999).
Valásek L, Nielsen KH, Hinnebusch AG. Direct eIF2-eIF3
contact in the multifactor complex is important for translation
initiation in vivo. EMBO J. 2002 Nov 1;21(21):5886-98
Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N.
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genes. IV. The coding sequences of 40 new genes (KIAA0121KIAA0160) deduced by analysis of cDNA clones from human
cell line KG-1. DNA Res. 1995 Aug 31;2(4):167-74, 199-210
Dong Z, Zhang JT. EIF3 p170, a mediator of mimosine effect
on protein synthesis and cell cycle progression. Mol Biol Cell.
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Dong Z, Zhang JT. Initiation factor eIF3 and regulation of
mRNA translation, cell growth, and cancer. Crit Rev Oncol
Hematol. 2006 Sep;59(3):169-80
Méthot N, Song MS, Sonenberg N. A region rich in aspartic
acid, arginine, tyrosine, and glycine (DRYG) mediates
eukaryotic initiation factor 4B (eIF4B) self-association and
interaction with eIF3. Mol Cell Biol. 1996 Oct;16(10):5328-34
Valásek L, Mathew AA, Shin BS, Nielsen KH, Szamecz B,
Hinnebusch AG. The yeast eIF3 subunits TIF32/a, NIP1/c, and
eIF5 make critical connections with the 40S ribosome in vivo.
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Asano K, Vornlocher HP, Richter-Cook NJ, Merrick WC,
Hinnebusch AG, Hershey JW. Structure of cDNAs encoding
human eukaryotic initiation factor 3 subunits. Possible roles in
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Chen G, Burger MM. p150 overexpression in gastric
carcinoma: the association with p53, apoptosis and cell
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Bachmann F, Bänziger R, Burger MM. Cloning of a novel
protein overexpressed in human mammary carcinoma. Cancer
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Dong Z, Liu LH, Han B, Pincheira R, Zhang JT. Role of eIF3
p170 in controlling synthesis of ribonucleotide reductase M2
and cell growth. Oncogene. 2004 May 6;23(21):3790-801
Johnson KR, Merrick WC, Zoll WL, Zhu Y. Identification of
cDNA clones for the large subunit of eukaryotic translation
initiation factor 3. Comparison of homologues from human,
Saccharomyces cerevisiae. J Biol Chem. 1997 Mar
Nakai Y, Shiratsuchi A, Manaka J, Nakayama H, Takio K,
Zhang JT, Suganuma T, Nakanishi Y. Externalization and
recognition by macrophages of large subunit of eukaryotic
translation initiation factor 3 in apoptotic cells. Exp Cell Res.
2005 Sep 10;309(1):137-48
Méthot N, Rom E, Olsen H, Sonenberg N. The human
homologue of the yeast Prt1 protein is an integral part of the
eukaryotic initiation factor 3 complex and interacts with p170. J
Biol Chem. 1997 Jan 10;272(2):1110-6
Mayeur GL, Fraser CS, Peiretti F, Block KL, Hershey JW.
Characterization of eIF3k: a newly discovered subunit of
mammalian translation initiation factor elF3. Eur J Biochem.
2003 Oct;270(20):4133-9
Pascual J, Castresana J, Saraste M. Evolution of the spectrin
repeat. Bioessays. 1997 Sep;19(9):811-7
Damoc E, Fraser CS, Zhou M, Videler H, Mayeur GL, Hershey
JW, Doudna JA, Robinson CV, Leary JA. Structural
characterization of the human eukaryotic initiation factor 3
protein complex by mass spectrometry. Mol Cell Proteomics.
2007 Jul;6(7):1135-46
Scholler JK, Kanner SB. The human p167 gene encodes a
unique structural protein that contains centrosomin A homology
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1997 Apr;16(4):515-31
Liu Z, Dong Z, Yang Z, Chen Q, Pan Y, Yang Y, Cui P, Zhang
X, Zhang JT. Role of eIF3a (eIF3 p170) in intestinal cell
differentiation and its association with early development.
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Dellas A, Torhorst J, Bachmann F, Bänziger R, Schultheiss E,
Burger MM. Expression of p150 in cervical neoplasia and its
potential value in predicting survival. Cancer. 1998 Oct
Hofmann K, Bucher P. The PCI domain: a common theme in
three multiprotein complexes. Trends Biochem Sci. 1998
Zhang L, Pan X, Hershey JW. Individual overexpression of five
subunits of human translation initiation factor eIF3 promotes
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in squamous-cell carcinoma of the esophagus. Int J Cancer.
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Dong Z, Liu Z, Cui P, Pincheira R, Yang Y, Liu J, Zhang JT.
Role of eIF3a in regulating cell cycle progression. Exp Cell
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Valásek L, Hasek J, Trachsel H, Imre EM, Ruis H. The
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This article should be referenced as such:
Yin JY, Dong Z, Zhang JT. EIF3A (eukaryotic translation
initiation factor 3, subunit A). Atlas Genet Cytogenet Oncol
Haematol. 2011; 15(7):544-546.
Pincheira R, Chen Q, Huang Z, Zhang JT. Two subcellular
localizations of eIF3 p170 and its interaction with membranebound microfilaments: implications for alternative functions of
p170. Eur J Cell Biol. 2001a Jun;80(6):410-8
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
ERG (v-ets erythroblastosis virus E26 oncogene
like (avian))
Roopika Menon, Martin Braun, Sven Perner
Institute of Pathology, University Hospital Tuebingen, Liebermeisterstr. 8, D-72076 Tuebingen, Germany
(RM, MB, SP)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/ERGID53ch21q22.html
DOI: 10.4267/2042/45991
This article is an update of :
Rainis-Ganon L, Izraeli S. ERG (v-ets erythroblastosis virus E26 oncogene like (avian)). Atlas Genet Cytogenet Oncol Haematol
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Other names: erg-3; p55
HGNC (Hugo): ERG
Location: 21q22.2
The ERG gene belongs to the erythroblast
transformation-specific (ETS) family of transcriptions
factors. The ERG gene (ETS related gene 1) is located
on chromosome 21, and consists of 17 exons,
approximately 300 kb DNA in length.
The ERG gene forms 20 known transcripts (ranging
from 560 to 5034 bp in length), amongst which 15 are
coding for proteins, and 5 are non-coding. 8 alternative
splice variants are known.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
No observed pseudogenes.
ERG gene locus on the q-arm of chromosome 21 (21q22.2) spanning from 39751949 to 40033704 (according to UCSC genome browser,
Feb. 2009 GRCh37/hg19, and Ensemble, Aug. 2010).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
ERG (v-ets erythroblastosis virus E26 oncogene like (avian))
Menon R, et al.
Implicated in
Ewing's sarcoma
Amongst the 20 known transcripts of the ERG gene, 15
are protein coding. The 15 proteins range from 171 to
486 amino acids in length, and up to 55 kDa in weight.
The prognostic relevance of an ERG gene fusion or an
ERG overexpression in Ewing's sarcoma (EWS-ETS
fusion type) is yet to be determined. So far, no
prognostic relevance could be shown.
Hybrid/Mutated gene
If a gene fusion occurs in Ewing's sarcoma, most
frequently it is a fusion of EWS to FLI-1 (in app. 85%
of cases) or ERG (in app. 10% of cases). Other ETS
genes rarely serve as EWS gene fusion partners (in app.
5% of cases).
Abnormal protein
The EWS gene fuses with the carboxyl terminal of
ERG containing the ETS DNA binding domain of
ERG. Therefore, the resulting fusion protein
deregulates a large number of genes by so far poorly
defined mechanisms.
In a transgenic mouse model expression of the EWSERG in lymphoid progenitors induced T-cell leukemia.
On the protein level, ERG is mainly expressed in the
nucleus and is rarely seen in the cytoplasm. Basically,
in the GNF SymAtlas database, major ERG expression
was found to be in CD34+ cells (that include both
hematopoietic stem cells and endothelial cells). In
detail, ERG is reported to be expressed during early T
and B cell development, and down-regulated in later
stages of B and T cell differentiation. Also, ERG is
expressed in platelets, megakaryoblastic cell lines,
primary megakaryoblastic leukemia (AMKL or M7AML) in Down syndrome patients. Furthermore, ERG
is strongly expressed in ERG gene rearranged prostate
tissue (both in prostatic cancer tissue and adjacent
prostatic intraepithelial neoplasia lesions). Of note,
using immunohistochemistry, ERG expression is
regularly observed in lymphocytes and small blood
Acute myeloid leukemia (AML)
Several studies suggest a poorer prognosis for FUSERG gene fusion positive AML as compared to nonfused AML. Moreover, an ERG overexpression, not
necessarily due to the FUS-ERG gene fusion, predicts
an increased relapse risk and shorter survival in AML
patients. However, the exact contribution of ERG
overexpression to myeloid leukemiogenesis and
progression is still unknown.
Hybrid/Mutated gene
In the FUS-ERG gene fusion, the FUS gene fuses with
the carboxyl terminal of ERG containing the ETS DNA
binding domain of ERG. Of note, in a single case, a
gene fusion of ERG with the myeloid ELF-like factor 1
(ELF4) was detected.
The FUS-ERG fusion protein helps in activating the
oncogenic activity of transcription factors.
Predominantely nuclear and rarely cytoplasmic.
The ERG protein is a member of the ETS-family and is
known to bind to purine-rich sequences. ERG and other
members of the same family are downstream regulators
of mitogenic signal transduction pathways. They are
key regulators of embryonic development, cell
inflammation, and apoptosis. At the DNA level,
isoforms of ERG are known to regulate methylation.
Further, ERG is required for platelet adhesion to the
subendothelium, inducing vascular cell remodeling.
Moreover, hematopoesis, as well as the differentiation
and maturation of megakaryocytic cells are regulated
by ERG. Overexpression of the ERG protein is
suggested to aid in forming solid tumors. However, the
exact molecular mechanisms of ERG as a transcription
factor are still unknown.
Prostate cancer
The body of literature is controversial about the
prognostic relevance of ERG rearrangements in
prostate cancer. Some studies reported an association of
the ERG rearrangement with adverse clinical
parameters (i.e. time to prostate cancer specific death
and the development of hormone-refractory
A member of the ETS transcription factors, most
homologous to FLI1.
No known mutations.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
ERG (v-ets erythroblastosis virus E26 oncogene like (avian))
Menon R, et al.
Schematic displaying ERG rearrangement status (via FISH) in prostate cancer. The red-labelled centromeric and the green-labelled
telomeric probes span the ERG locus on chromosomes 21. If a break-apart occurs, the green signal is either lost (ERG rearrangement
through deletion) or translocated (ERG rearrangement through insertion). An ERG break-apart as determined by FISH accounts for a
fusion of ERG mainly with TMPRSS2 but also with other 5' fusion partners such as SLC45A3, HERPUD1, or NDRG1. A: Both alleles with
wild type (wt) ERG. B: One allele with ERG rearrangement through deletion (single red signal) and the other allele with wt ERG (yellow
signal). C: One allele with ERG rearrangement through insertion (separated red and green signal) and the other allele with wt ERG
(yellow signal).
On the other hand, some studies demonstrated an
association of ERG rearrangement with parameters of
more favourable outcome, such as lower Gleason score,
stage, volume, better overall survival, or late
biochemical recurrence. Interestingly, a subset of
studies without any such association was reported as
Hybrid/Mutated gene
In approximately 50% of prostate cancers, the ERG
gene is rearranged, i.e. fused to another gene. In case of
a rearrangement, TMPRSS2 is the ERG 5' fusion
partner in the vast majority of cases (app. 85%). Other
known, but rarely occurring ERG fusion partners
include NDRG1, SLC45A3, and HERPUD1. The ERG
gene rearrangement either occurs due to a deletion, or
an insertion.
Abnormal protein
An ERG gene rearrangement in prostate cancer mainly
results in an androgen dependant ERG overexpression.
In-vitro models complement that over expression of
truncated ERG and various TMPRSS2-ERG isoforms
increase cell migration and invasion. In-vivo
recapitulation of ETS fusions by prostate specific
expression of truncated ERG in mice resulted in the
development of PIN but not carcinoma. Subsequent
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
work on transgenic TMPRSS2-ERG mice develop PIN
progressing to invasive cancer, but only in the context
of PI3-kinase pathway activation. TMPRSS2-ERGpositive human tumors are also enriched for PTEN
loss, suggesting cooperation in prostate tumorigenesis.
Acute lymphoblastic leukemia (ALL)
Overexpression of ERG was shown to be a risk factor
in adult T-ALL. ALL patients with ERG
overexpression were four times more likely to fail longterm recurrence free survival, indicating inferior
Studies assessing ERG overexpression in ALL have
shown that due to the involvement of ERG in T-cell
development, it may have an oncogenic potential.
Acute megakaryoblastic leukemia
Even though ERG is highly considered to be oncogenic
in AMKL, no prognostic relevance has been
ERG was found to be expressed megakaryoblastic
leukemic cell lines and in primary leukemic cells from
ERG (v-ets erythroblastosis virus E26 oncogene like (avian))
Menon R, et al.
DS patients. Moreover, in mouse models, expression of
ERG drove megakaryopoiesis and lead to a rapid
development of aggressive leukemia.
ERG involvement in endothelial
ERG has been reported to regulate genes involved in
chondrogenesis and angiogenesis and functions as a
modulator of endothelial cell differentiation. In an invitro study, the decrease of the ERG protein follows a
reduction in endothelial cell proliferation and vascular
tube formation. In human umbilical vein endothelial
cell lines, vascular endothelial growth factor (VEGF)
was seen to significantly up-regulate ERG expression.
Controversially, on the other hand, ERG expression
was shown to inhibit responsiveness to the VEGF
receptor in a Down Syndrome mouse model.
Alzheimer's disease (AD)
ERG has been linked to AD, due to an ERG protein
overexpression as compared to control patients. This is
further supported by experiments conducted on patients
suffering from Down syndrome, who gradually develop
AD-like symptoms, linked to ERG overexpression.
Down syndrome (DS)
DS is associated with trisomy of the chromosome 21,
where the ERG gene is located. The trisomy is
considered to be responsible for an ERG
overexpression. In a DS mouse model, an induced
functional disomy of the ERG allele corrects some
pathologic features of the disease, including
myeloproliferation and progenitor cell expansion,
suggesting a pathogenic effect of trisomy driven ERG
ERG involvement in lymphoid
ERG was reported to be expressed in during early T
and B cell development, and to be down-regulated in
later stages of B and T cell differentiation. In detail, the
ERG protein modulates the maturation of lymphoid
cells. Interestingly, ERG overexpression is associated
with T-ALL.
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Menon R, Braun M, Perner S. ERG (v-ets erythroblastosis
virus E26 oncogene like (avian)). Atlas Genet Cytogenet Oncol
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Mini Review
ETV4 (ets variant 4)
Yasuyoshi Miyata
Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501,
Japan (YM)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/ETV4ID133ch17q21.html
DOI : 10.4267/2042/45992
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Nuclear (Monté et al., 1994; Takahashi et al., 2005).
Ubiquitinated protein is localized in the dot-like
structure in the nuclear (Takahashi et al., 2005).
Other names: E1A-F; E1AF; PEA3; PEAS3
HGNC (Hugo): ETV4
Location: 17q21.31
ETV4 is capable of regulating transcription by binding
to the Ets-binding site in the promoter of its target
genes. Biologically, it contributes in a number of
processes including neuronal pathfinding, mammary
gland development, and male sexual function (Laing et
al., 2000; Ladle et al., 2002; Kurpios et al., 2003). In
various malignancies, its over-expression has been
observed and it was also associated with tumor
progression and outcome of patients with these
malignancies. As mechanism of such function,
regulation of hepatocyte growth factor (HGF)-induced
cell migration (Hakuma et al., 2005), HER2-mediated
malignant potential (Benz et al., 1997), and other
ETV4-related factors including cyclooxygenase
(COX)-2 and matrix metalloproteinases (MMPs) have
been reported (Higashino et al., 1995; Horiuchi et al.,
2003; Shindoh et al., 2004).
The gene spans approximately 30 kb and contained 14
exons. The largest exon (901 bp) contains the end of
the ETS domain, the carboxy-terminal domain and the
3'-untranslated region. The remaining exons varied
from 48 bp (exon 5) to 266 bp (exon 9).
ETV4 is a member of ets-oncogene family transcription
factors that were cloned by the ability to bind to
enhancer motifs of the adenovirus E1A gene (Lavia et
al., 2003). It is composed of 555 amino acids, which
has a molecular weight ranging 61~70 kDa.
GeneLoc map region.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
ETV4 (ets variant 4)
Miyata Y
In addition, ETV4 promotes cell cycle progression via
upregulation of cyclin D3 transcription in breast cancer
cell (MDA231 cell) (Jiang et al., 2007). In contrast,
ETV4 function as negative regulator of sonic hedgehog
expression (Mao et al., 2009).
ETV4 expression was not detected in normal lung
tissues. On the other hand, it is expressed in distal lung
epithelium during lung development and in human lung
cancer cells (Hiroumi et al., 2001; Liu et al., 2003). It
was reported to be associated with cell invasion
(Hiroumi et al., 2001) and metastasis via regulation of
caveolin-1 transcription (Sloan et al., 2009) and Metrelated factors (Hakuma et al., 2005).
Implicated in
Breast cancer
Malignant melanoma
Over-expression of ETV4 has been detected in human
cancer cell lines (Baert et al., 1997). In animal model
and human tissues, its over-expression was also found
and it was associated with malignant potential
including invasion and metastasis (Trimble et al., 1993;
De Launoit et al., 2000; Benz et al., 1997; Bièche et al.,
2004). Such ETV4-related functions are controlled via
regulation of cyclin D3 transcription (Jiang et al.,
2007), HER-2/Neu (Benz et al., 1997), and MMPs
(Bièche et al., 2004).
In cell lines, ETV4 plays important roles for malignant
behavior including invasion and metastasis thorough
up-regulation of MT1-MMP (Hata et al., 2008).
Prostate cancer
In human tissues, its expression in cancer cell was
significantly higher than that in normal cells and it was
also positively associated with pT stage. This finding
was influenced with regulation of MMP-7 and MMP-9,
but not of MMP-1, MMP-3, and MMP-14 (MT1MMP) (Maruta et al., 2009).
Gastric cancer
Correlated with tumor progression via up-regulation of
matrilysin in human tissues (Yamamoto et al., 2004).
Colorectal cancer
In early stage of colorectal carcinogenesis, its overexpression plays important roles through MMPs, COX2, and iNos (Nosho et al., 2005).
Lung cancer
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
ETV4 (ets variant 4)
Miyata Y
Bièche I, Tozlu S, Girault I, Onody P, Driouch K, Vidaud M,
Lidereau R. Expression of PEA3/E1AF/ETV4, an Ets-related
transcription factor, in breast tumors: positive links to MMP2,
NRG1 and CGB expression. Carcinogenesis. 2004
Trimble MS, Xin JH, Guy CT, Muller WJ, Hassell JA. PEA3 is
adenocarcinomas. Oncogene. 1993 Nov;8(11):3037-42
Shindoh M, Higashino F, Kohgo T. E1AF, an ets-oncogene
family transcription factor. Cancer Lett. 2004 Dec 8;216(1):1-8
Monté D, Baert JL, Defossez PA, de Launoit Y, Stéhelin D.
Molecular cloning and characterization of human ERM, a new
member of the Ets family closely related to mouse PEA3 and
ER81 transcription factors. Oncogene. 1994 May;9(5):1397406
Yamamoto H, Horiuchi S, Adachi Y, Taniguchi H, Nosho K,
Min Y, Imai K. Expression of ets-related transcriptional factor
E1AF is associated with tumor progression and overexpression of matrilysin in human gastric cancer.
Carcinogenesis. 2004 Mar;25(3):325-32
Higashino F, Yoshida K, Noumi T, Seiki M, Fujinaga K. Etsrelated protein E1A-F can activate three different matrix
metalloproteinase gene promoters. Oncogene. 1995 Apr
Hakuma N, Kinoshita I, Shimizu Y, Yamazaki
Nishimura M, Dosaka-Akita H. E1AF/PEA3
Rho/Rho-associated kinase pathway to
malignancy potential of non-small-cell lung
Cancer Res. 2005 Dec 1;65(23):10776-82
Baert JL, Monté D, Musgrove EA, Albagli O, Sutherland RL, de
Launoit Y. Expression of the PEA3 group of ETS-related
transcription factors in human breast-cancer cells. Int J
Cancer. 1997 Mar 4;70(5):590-7
Nosho K, Yoshida M, Yamamoto H, Taniguchi H, Adachi Y,
Mikami M, Hinoda Y, Imai K. Association of Ets-related
transcriptional factor E1AF expression with overexpression of
matrix metalloproteinases, COX-2 and iNOS in the early stage
Benz CC, O'Hagan RC, Richter B, Scott GK, Chang CH, Xiong
X, Chew K, Ljung BM, Edgerton S, Thor A, Hassell JA.
HER2/Neu and the Ets transcription activator PEA3 are
coordinately upregulated in human breast cancer. Oncogene.
1997 Sep 25;15(13):1513-25
Takahashi A, Higashino F, Aoyagi M, Yoshida K, Itoh M,
Kobayashi M, Totsuka Y, Kohgo T, Shindoh M. E1AF
degradation by a ubiquitin-proteasome pathway. Biochem
Biophys Res Commun. 2005 Feb 11;327(2):575-80
de Launoit Y, Chotteau-Lelievre A, Beaudoin C, Coutte L,
Netzer S, Brenner C, Huvent I, Baert JL. The PEA3 group of
ETS-related transcription factors. Role in breast cancer
metastasis. Adv Exp Med Biol. 2000;480:107-16
Jiang J, Wei Y, Liu D, Zhou J, Shen J, Chen X, Zhang S, Kong
X, Gu J. E1AF promotes breast cancer cell cycle progression
via upregulation of Cyclin D3 transcription. Biochem Biophys
Res Commun. 2007 Jun 22;358(1):53-8
Laing MA, Coonrod S, Hinton BT, Downie JW, Tozer R,
Rudnicki MA, Hassell JA. Male sexual dysfunction in mice
bearing targeted mutant alleles of the PEA3 ets gene. Mol Cell
Biol. 2000 Dec;20(24):9337-45
Hata H, Kitamura T, Higashino F, Hida K, Yoshida K, Ohiro Y,
Totsuka Y, Kitagawa Y, Shindoh M. Expression of E1AF, an
ets-oncogene transcription factor, highly correlates with
malignant phenotype of malignant melanoma through upregulation of the membrane-type-1 matrix metalloproteinase
gene. Oncol Rep. 2008 May;19(5):1093-8
Hiroumi H, Dosaka-Akita H, Yoshida K, Shindoh M, Ohbuchi T,
Fujinaga K, Nishimura M. Expression of E1AF/PEA3, an Etsrelated transcription factor in human non-small-cell lung
cancers: its relevance in cell motility and invasion. Int J
Cancer. 2001 Sep;93(6):786-91
Ladle DR, Frank E. The role of the ETS gene PEA3 in the
development of motor and sensory neurons. Physiol Behav.
2002 Dec;77(4-5):571-6
Mao J, McGlinn E, Huang P, Tabin CJ, McMahon AP. Fgfdependent Etv4/5 activity is required for posterior restriction of
Sonic Hedgehog and promoting outgrowth of the vertebrate
limb. Dev Cell. 2009 Apr;16(4):600-6
Horiuchi S, Yamamoto H, Min Y, Adachi Y, Itoh F, Imai K.
Association of ets-related transcriptional factor E1AF
expression with tumour progression and overexpression of
MMP-1 and matrilysin in human colorectal cancer. J Pathol.
2003 Aug;200(5):568-76
Maruta S, Sakai H, Kanda S, Hayashi T, Kanetake H, Miyata
Y. E1AF expression is associated with extra-prostatic growth
and matrix metalloproteinase-7 expression in prostate cancer.
APMIS. 2009 Nov;117(11):791-6
Kurpios NA, Sabolic NA, Shepherd TG, Fidalgo GM, Hassell
JA. Function of PEA3 Ets transcription factors in mammary
gland development and oncogenesis. J Mammary Gland Biol
Neoplasia. 2003 Apr;8(2):177-90
Sloan KA, Marquez HA, Li J, Cao Y, Hinds A, O'Hara CJ,
Kathuria S, Ramirez MI, Williams MC, Kathuria H. Increased
PEA3/E1AF and decreased Net/Elk-3, both ETS proteins,
characterize human NSCLC progression and regulate
caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell
lines. Carcinogenesis. 2009 Aug;30(8):1433-42
Lavia P, Mileo AM, Giordano A, Paggi MG. Emerging roles of
DNA tumor viruses in cell proliferation: new insights into
genomic instability. Oncogene. 2003 Sep 29;22(42):6508-16
This article should be referenced as such:
Liu Y, Jiang H, Crawford HC, Hogan BL. Role for ETS domain
transcription factors Pea3/Erm in mouse lung development.
Dev Biol. 2003 Sep 1;261(1):10-24
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
K, Yoshida K,
activates the
increase the
cancer cells.
Miyata Y. ETV4 (ets variant 4). Atlas Genet Cytogenet Oncol
Haematol. 2011; 15(7):554-556.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
GPC5 (glypican 5)
Khin Thway, Joanna Selfe, Janet Shipley
Molecular Cytogenetics, Section of Molecular Carcinogenesis, the Institute of Cancer Research, 15 Cotswold
Road, Sutton, Surrey, SM2 5NG, United Kingdom (KT, JS, JS)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/GPC5ID45705ch13q31.html
DOI: 10.4267/2042/45993
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
HGNC (Hugo): GPC5
Location: 13q31.3
Local order: Centromere - MIR17HG - GPC5 - GPC6
- DCT - TGDS - GPR180 - SOX21 - telomere.
572 amino acids; 64 kDa protein (core protein). GPC5
is a heparan sulfate proteoglycan (HSPG), that is bound
to the cell surface by a glycosyl-phosphatidylinositol
(GPI) anchor.
GPC5 is expressed mainly in fetal tissues, including
brain, lung and liver. In the adult, expression is
primarily in brain tissue.
The gene spans 1.47 Mb of DNA, comprising 8 exons.
2.904 kb mRNA. 1718 bp open reading frame.
Attached to the cell membrane by a GPI anchor.
Schematic of glypican protein structure at the cell surface. The protein is held in the plasma membrane by a GPI anchor at the
carboxyl terminus. Numerous glycosoaminoglycan (GAG) attachment sites close to the membrane surface allow heparin and chondroitin
sulphate chains to be attached to the core protein (shown in green). The amino terminal end of the protein is a globular structure held
together by a conserved set of cysteine residues forming disulphide bridges. (Picture reproduced from Filmus and Selleck, 2001).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
GPC5 (glypican 5)
Thway K, et al.
well as gain of GPC5 copies in both alveolar and
embryonal rhabdomyosarcoma (Gordon et al., 2000).
GPC5 is overexpressed in the majority of
rhabdomyosarcomas compared with normal skeletal
muscle and has been shown to modulate responses to
FGF2 in rhabdomyosarcoma cells (Williamson et al.,
2007). GPC5 may also potentiate hedgehog signalling
in these cells as it can bind to both Hedgehog and the
Patched receptor (Li et al., 2010a). A recent genome
wide association study has linked polymorphisms in
GPC5 to risk of lung cancer in never-smokers (Li et al.,
2010b). The high-risk allele was coincident with lower
expression of GPC5, suggesting that the role of GPC5
is likely to be tumour type-specific in an analogous
manner to GPC3, the closest family member to GPC5.
The precise functions of GPC5 have yet to be fully
established. HSPGs are common constituents of cell
surfaces and the extracellular matrix (ECM), with
essential functions in cell growth and development
(Burgess and Macaig, 1989; Andres et al., 1992).
Glypicans appear to be expressed predominantly during
development, with expression levels changing in a
stage- and tissue-specific manner, suggesting their
involvement in morphogenesis (Sing and Filmus,
2002). As they can bind numerous ligands and be
associated with a variety of receptors, they act as coreceptors for a number of heparin-binding growth
factors, modulating their activity. The heparan sulfate
modifications of glypicans can mediate interactions
with growth factors or ECM proteins, but ligands and
ECM proteins can also bind through motifs in the core
proteins (Mythreye and Blobe, 2009). Glypicans can be
secreted from the cell surface, such soluble forms can
also bind growth factors. Evidence to date suggests that
glypicans can regulate Wnt, hedgehog, fibroblast
growth factor and bone morphogenetic protein
pathways. The effect on these pathways may be
stimulatory or inhibitory depending on cellular context
(Gallet et al., 2008; Capurro et al., 2008; Kreuger et al.,
2004; Yan and Lin, 2007; Grisaru et al., 2001; Yan et
al., 2010).
GPC5 expression has been shown in the developing
central nervous system, limbs and kidneys of mice, and
its expression in mammalian fetal tissues suggests roles
in growth and differentiation during development
(Veugelers et al., 1997; Saunders et al., 1997; Luxardi
et al., 2007). Its almost exclusive expression in adult
brain tissue suggests a possible role in controlling
neurotropic factors and maintaining neural function.
Developmental disorders
Studies on the role of GPC5 in disease are still
relatively limited. In humans, deletions of the 13q31-32
region are associated with the 13q deletion syndrome, a
developmental disorder with a wide phenotypic
spectrum including mental and growth retardation,
congenital defects and craniofacial dysmorphy, and
GPC5 is suggested as a candidate gene for digital
malformations in this syndrome (Quelin et al., 2009).
Correspondingly, GPC5 is also a candidate gene for
postaxial polydactyly type A2, which is associated with
duplication of 13q31-32 (van der Zwaag et al., 2010).
Multiple sclerosis
Several genome wide association studies have
identified GPC5 as having a potential role in Multiple
Sclerosis (MS) (Baranzini et al., 2009; Lorentzen et al.,
2010). Several different GPC5 polymorphisms were
also highlighted in an independent study designed to
determine which genes are associated with efficacy of
interferon beta therapy in MS (Byun et al., 2008), this
finding has subsequently been confirmed in a separate
study (Cenit et al., 2009). HSPGs are found in dense
networks in active MS plaques, where they may
sequester pro-inflammatory cytokines.
GPC5 is a member of the glypican family of HSPGs, of
which six members (GPC1, GPC2, GPC3, GPC4,
GPC5, GPC6) have been identified in mammals. GPC3
is the most homologous member to GPC5 in humans.
There is approximately 20-60% sequence homology
between family members, including conservation of a
pattern of 14 cysteine residues. Homolog glypican-like
genes are also present in Drosophila (dally and dallylike).
Burgess WH, Maciag T. The heparin-binding (fibroblast)
growth factor family of proteins. Annu Rev Biochem.
Implicated in
Andres JL, DeFalcis D, Noda M, Massagué J. Binding of two
growth factor families to separate domains of the proteoglycan
betaglycan. J Biol Chem. 1992 Mar 25;267(9):5927-30
Amplification of 13q31-32 has been shown in poor
prognosis liposarcomas, breast cancers and neurologic
tumours (Reardon et al., 2000; Ojopi et al., 2001;
Ullmann et al., 2001; Schmidt et al., 2005).
Amplification of 13q31-32 has also been shown in
approximately 20% of alveolar rhabdomyosarcoma, as
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Saunders S, Paine-Saunders S, Lander AD. Expression of the
cell surface proteoglycan glypican-5 is developmentally
regulated in kidney, limb, and brain. Dev Biol. 1997 Oct
Veugelers M, Vermeesch J, Reekmans G, Steinfeld R,
Marynen P, David G. Characterization of glypican-5 and
chromosomal localization of human GPC5, a new member of
the glypican gene family. Genomics. 1997 Feb 15;40(1):24-30
GPC5 (glypican 5)
Thway K, et al.
Gordon AT, Brinkschmidt C, Anderson J, Coleman N,
Dockhorn-Dworniczak B, Pritchard-Jones K, Shipley J. A novel
and consistent amplicon at 13q31 associated with alveolar
rhabdomyosarcoma. Genes Chromosomes Cancer. 2000
signaling and wingless
Filmus J, Selleck SB. Glypicans: proteoglycans with a surprise.
J Clin Invest. 2001 Aug;108(4):497-501
Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y,
Barkhof F, Radue EW, Lindberg RL, Uitdehaag BM, Johnson
MR, Angelakopoulou A, Hall L, Richardson JC, Prinjha RK,
Gass A, Geurts JJ, Kragt J, Sombekke M, Vrenken H, Qualley
P, Lincoln RR, Gomez R, Caillier SJ, George MF, Mousavi H,
Guerrero R, Okuda DT, Cree BA, Green AJ, Waubant E,
Goodin DS, Pelletier D, Matthews PM, Hauser SL, Kappos L,
Polman CH, Oksenberg JR. Genome-wide association
analysis of susceptibility and clinical phenotype in multiple
sclerosis. Hum Mol Genet. 2009 Feb 15;18(4):767-78
Grisaru S, Cano-Gauci D, Tee J, Filmus J, Rosenblum ND.
Glypican-3 modulates BMP- and FGF-mediated effects during
renal branching morphogenesis. Dev Biol. 2001 Mar
Cénit MD, Blanco-Kelly F, de las Heras V, Bartolomé M, de la
Concha EG, Urcelay E, Arroyo R, Martínez A. Glypican 5 is an
interferon-beta response gene: a replication study. Mult Scler.
2009 Aug;15(8):913-7
Ojopi EP, Rogatto SR, Caldeira JR, Barbiéri-Neto J, Squire JA.
amplifications in fibroadenomas of the breast. Genes
Chromosomes Cancer. 2001 Jan;30(1):25-31
Mythreye K, Blobe GC. Proteoglycan signaling co-receptors:
roles in cell adhesion, migration and invasion. Cell Signal.
2009 Nov;21(11):1548-58
Reardon DA, Jenkins JJ, Sublett JE, Burger PC, Kun LK.
Multiple genomic alterations including N-myc amplification in a
primary large cell medulloblastoma. Pediatr Neurosurg. 2000
Quélin C, Bendavid C, Dubourg C, de la Rochebrochard C,
Lucas J, Henry C, Jaillard S, Loget P, Loeuillet L, Lacombe D,
Rival JM, David V, Odent S, Pasquier L. Twelve new patients
with 13q deletion syndrome: genotype-phenotype analyses in
progress. Eur J Med Genet. 2009 Jan-Feb;52(1):41-6
Ullmann R, Petzmann S, Sharma A, Cagle PT, Popper HH.
Chromosomal aberrations in a series of large-cell
neuroendocrine carcinomas: unexpected divergence from
small-cell carcinoma of the lung. Hum Pathol. 2001
Li FE, Shi W, Capurro M, Filmus J.. Glypican-5 stimulates
rhabdomyosarcoma cell proliferation by activating hedgehog
signaling. Proceedings of the 101st Annual Meeting of the
American Association for Cancer Research; 2010 Apr 17-21;
Washington, DC. Philadelphia (PA): AACR; 2010a. Abstract
no. 3191.
Song HH, Filmus J. The role of glypicans in mammalian
Kreuger J, Perez L, Giraldez AJ, Cohen SM. Opposing
activities of Dally-like glypican at high and low levels of
Wingless morphogen activity. Dev Cell. 2004 Oct;7(4):503-12
Li Y, Sheu CC, Ye Y, de Andrade M, Wang L, Chang SC,
Aubry MC, Aakre JA, Allen MS, Chen F, Cunningham JM,
Deschamps C, Jiang R, Lin J, Marks RS, Pankratz VS, Su L, Li
Y, Sun Z, Tang H, Vasmatzis G, Harris CC, Spitz MR, Jen J,
Wang R, Zhang ZF, Christiani DC, Wu X, Yang P.. Genetic
variants and risk of lung cancer in never smokers: a genomewide association study. Lancet Oncol. 2010b Apr;11(4):321-30.
Epub 2010 Mar 19.
Schmidt H, Bartel F, Kappler M, Würl P, Lange H, Bache M,
Holzhausen HJ, Taubert H. Gains of 13q are correlated with a
poor prognosis in liposarcoma. Mod Pathol. 2005
Luxardi G, Galli A, Forlani S, Lawson K, Maina F, Dono R.
Glypicans are differentially expressed during patterning and
neurogenesis of early mouse brain. Biochem Biophys Res
Commun. 2007 Jan 5;352(1):55-60
Lorentzen AR, Melum E, Ellinghaus E, Smestad C, Mero IL,
Aarseth JH, Myhr KM, Celius EG, Lie BA, Karlsen TH, Franke
A, Harbo HF.. Association to the Glypican-5 gene in multiple
sclerosis. J Neuroimmunol. 2010 Sep 14;226(1-2):194-7. Epub
2010 Aug 6.
Williamson D, Selfe J, Gordon T, Lu YJ, Pritchard-Jones K,
Murai K, Jones P, Workman P, Shipley J. Role for amplification
and expression of glypican-5 in rhabdomyosarcoma. Cancer
Res. 2007 Jan 1;67(1):57-65
van der Zwaag PA, Dijkhuizen T, Gerssen-Schoorl KB, Colijn
AW, Broens PM, Flapper BC, van Ravenswaaij-Arts CM.. An
interstitial duplication of chromosome 13q31.3q32.1 further
delineates the critical region for postaxial polydactyly type A2.
Eur J Med Genet. 2010 Jan-Feb;53(1):45-9. Epub 2009 Nov
Yan D, Lin X. Drosophila glypican Dally-like acts in FGFreceiving cells to modulate FGF signaling during tracheal
morphogenesis. Dev Biol. 2007 Dec 1;312(1):203-16
Byun E, Caillier SJ, Montalban X, Villoslada P, Fernández O,
Brassat D, Comabella M, Wang J, Barcellos LF, Baranzini SE,
Oksenberg JR. Genome-wide pharmacogenomic analysis of
the response to interferon beta therapy in multiple sclerosis.
Arch Neurol. 2008 Mar;65(3):337-44
Yan D, Wu Y, Yang Y, Belenkaya TY, Tang X, Lin X.. The cellsurface proteins Dally-like and Ihog differentially regulate
Hedgehog signaling strength and range during development.
Development. 2010 Jun;137(12):2033-44.
Capurro MI, Xu P, Shi W, Li F, Jia A, Filmus J. Glypican-3
inhibits Hedgehog signaling during development by competing
with patched for Hedgehog binding. Dev Cell. 2008
This article should be referenced as such:
Thway K, Selfe J, Shipley J. GPC5 (glypican 5). Atlas Genet
Cytogenet Oncol Haematol. 2011; 15(7):557-559.
Gallet A, Staccini-Lavenant L, Thérond PP. Cellular trafficking
of the glypican Dally-like is required for full-strength Hedgehog
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Mini Review
GSDMA (gasdermin A)
Norihisa Saeki, Hiroki Sasaki
Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045,
Japan (NS, HS)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/GSDMAID45650ch17q21.html
DOI: 10.4267/2042/45994
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Other names: FLJ39120; GSDM; GSDM1;
Location: 17q21.1
Local order: Telomeric to ORMDL3 and GSDMB
genes; centromeric to PSMD3 gene.
GSDMA is the first member of Gasdermin family
genes which, with Gadermin-related genes, DFNA5
and DFNB59, form Gasdermin superfamily.
Genomic organization of the GSDMA gene.
GSDMA is involved in TGF-beta signaling which regulates
apoptosis induction in pit cells of the gastric epithelium.
Signaling from TGF-beta receptor up-regulates LMO1, a
transcription factor. LMO1 binds to the promoter of GSDMA
gene and enhances its expression, that results in the apoptosis
induction in the pit cells.
12 exons, spans approximately 13 kb of genomic DNA
in the centromere-to-telomere orientation. The
translation initiation codon is located to exon 2, and the
stop codon to exon 12.
mRNA of approximately 1.5 kb.
The GSDMA gene encodes a 445 amino acid protein
with estimated molecular weight of 49377.95 Da. The
Gasdermin family proteins have 9 conserved motifs but
no known functional motif.
Not reported.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
GSDMA (gasdermin A)
Saeki N, Sasaki H
Esophageal cancer
GSDMA protein is expressed in pit cells of the gastric
epithelium, where it is involved in maintenance of
homeostasis by its apoptosis induction ability under
TGF-beta signaling. Its expression was also observed in
epithelial cells of the esophagus, skin and mammary
GSDMA gene is frequently silenced in esophageal
squamous cell carcinoma (41 in 42 cases examined).
Saeki N, Kuwahara Y, Sasaki H, Satoh H, Shiroishi T.
Gasdermin (Gsdm) localizing to mouse Chromosome 11 is
predominantly expressed in upper gastrointestinal tract but
significantly suppressed in human gastric cancer cells. Mamm
Genome. 2000 Sep;11(9):718-24
Lunny DP, Weed E, Nolan PM, Marquardt A, Augustin M,
Porter RM. Mutations in gasdermin 3 cause aberrant
differentiation of the hair follicle and sebaceous gland. J Invest
Dermatol. 2005 Mar;124(3):615-21
Apoptosis induction, but detail is unknown.
Human genome possesses its three paralogues,
GSDMB, GSDMC and GSDMD. Both N- and Cterminal amino acids are conserved among them.
Saeki N, Kim DH, Usui T, Aoyagi K, Tatsuta T, Aoki K,
Yanagihara K, Tamura M, Mizushima H, Sakamoto H, Ogawa
K, Ohki M, Shiroishi T, Yoshida T, Sasaki H. GASDERMIN,
suppressed frequently in gastric cancer, is a target of LMO1 in
TGF-beta-dependent apoptotic signalling. Oncogene. 2007 Oct
Tamura M, Tanaka S, Fujii T, Aoki A, Komiyama H, Ezawa K,
Sumiyama K, Sagai T, Shiroishi T. Members of a novel gene
family, Gsdm, are expressed exclusively in the epithelium of
the skin and gastrointestinal tract in a highly tissue-specific
manner. Genomics. 2007 May;89(5):618-29
Not reported.
Not reported.
Saeki N, Usui T, Aoyagi K, Kim DH, Sato M, Mabuchi T,
Yanagihara K, Ogawa K, Sakamoto H, Yoshida T, Sasaki H.
Distinctive expression and function of four GSDM family genes
(GSDMA-D) in normal and malignant upper gastrointestinal
Implicated in
Gastric cancer
GSDMA gene is frequently silenced in gastric
adenocarcinoma (16 in 18 cases examined including
both diffuse and intestinal types), whose relation to
prognosis is unknown.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
This article should be referenced as such:
Saeki N, Sasaki H. GSDMA (gasdermin A). Atlas Genet
Cytogenet Oncol Haematol. 2011; 15(7):560-561.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
IGF2BP1 (insulin-like growth factor 2 mRNA
binding protein 1)
Theoni Trangas, Panayotis Ioannidis
Department of Biological Applications and Technologies University of Ioannina, Ioannina, Greece (TT),
National Reference Center for Mycobacteria, Sotiria Hospital, Athens, Greece (PI)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/IGF2BP1ID40969ch17q21.html
DOI: 10.4267/2042/45995
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
upstream (promoter) region contains binding sites for
the following transcription factors: delta CREB, CREB,
NF-kappaB1, NF-kappaB, AP-1, HNF4 alpha2,
FOXO1a, MZF-1, Max and c-Myc. Beta-catenin/TCF4
binding and activation of transcription has been
experimentally confirmed (Gu et al., 2008).
Other names: CRD-BP; CRDBP; IMP-1; IMP1;
HGNC (Hugo): IGF2BP1
Location: 17q21.32
Local order: The IGF2BP1 gene is located on the plus
strand on chromosome 17, at 17q21.32. This gene starts
at 47074774 and ends at 47133507 bp from pter,
encompasses 58734 bp and lies 5' of the gene
beta-1,4-N-acetylgalactosaminyl transferase 2.
The IGF2BP1 gene encodes a member of the IGF-II
mRNA-binding protein (IMP) family (RRM
IMP/VICKZ family).
Two protein coding transcripts exist resulting from
alternative splicing:
Transcript variant 1 (NM_006546). The length of this
transcript is 8769 nt and encompasses all 15 exons
(exon 1: 509 bp, exon 2: 60 bp, exon 3: 48 bp, exon 4:
51 bp, exon 5: 63 bp, exon 6: 281 bp, exon 7: 134 bp,
exon 8: 122 bp, exon 9: 135 bp, exon 10: 122 bp, exon
11: 119 bp, exon 12: 74 bp, exon 13: 131 bp, exon14:
113 bp, exon 15: 6973 bp).
Several alternative 3' ends (polyadenylation sites) exist
at exon 15 3'-UTR (marked by flags in the figure
above). Translation starts at +335 and ends at +2068.
Transcript variant 2 (NM_001160423.1). It
encompasses 8352 bp and lacks two consecutive inframe exons (6 and 7).
Other spliced variants have been reported without
corresponding protein product recorded.
There are 4 probable alternative promoters driving
transcription of IGF2BP1 and two of them have been
experimentally confirmed (Gu et al., 2008). The
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)
Trangas T, Ioannidis P
(spermatogonia), in semen (Hammer et al., 2005) and
in intestinal crypts (Nielsen et al., 1999; Dimitriadis et
al., 2007). It is expressed de novo in kidney, prostate,
trachea, testis, ovarian and lung cancer, melanoma,
mesenchymal and brain tumors. At protein level, it is
expressed in testicular, lung and colon cancer.
The IGF2BP1 protein translated from the transcript
variant 1 consists of 577 aa (63,48 kD) and has 2 highly
conserved RRM motifs belonging to the RNA
recognition motif (RRM) superfamily and 4 KH
domains (NP_006537.3). The third and fourth KH
domains constitute both the protein dimerization motif
and the RNA binding domain. The four KH domains
promote granule formation and stress granule targeting
(Stöhr et al., 2006). Two nuclear export signals (NES)
exist within the second and fourth KH domains
(Nielsen et al., 2003). The KH domains have been
implicated in the suppression of HIV-1 infectivity
(Zhou et al., 2008). Phosphorylation sites are marked
(Bennetzen et al., 2010; Dephoure et al., 2008).
Phosphorylation of Tyrosine 396 prevents RNA
binding and translation inhibition of beta-actin mRNA
(Hüttelmaier et al., 2005).
The IGF2BP1 protein translated from transcript 2
variant is predicted to consist of 438 aa (48.597 kD)
and contain 2 RRM and 3 KH domains
IGF2BP1 has been detected in the nucleus, cytoplasm,
cytoplasmic mRNPs, granules (Nielsen et al., 2002;
Nielsen et al., 2003). In stress granules IGF2BP1 co
localizes with G3BP1 and TIAL1 (Stöhr et al., 2006). It
has also been detected in lamellipodia (Yaniv et al.,
2003), growth cones and the leading edge of
developing axons (Eom et al., 2003).
mRNA translation: IGF2BP1 regulates translation by
binding the 5'-UTR of the mRNA of certain genes,
including insulin-like growth factor 2 (Nielsen et al.,
1999), and beta actin (Hüttelmaier et al., 2005). It has
been identified in a HCV IRES-mediated translation
complex along with EIF3C and RPS3, enhancing
translation of the Hepatitis C virus (HCV) RNAreplicon via the internal ribosome entry site (IRES),
without affecting 5'cap-dependent translation (Weinlich
et al., 2009). IGF2BP1 binds the adenine-rich
autoregulatory sequence (ARS) of the 5'-UTR of the
PABPC1 mRNA in collaboration with CSDE1 and
PABPC1 proteins and causes translational repression
(Patel and Bag, 2006; Patel et al., 2005).
IGF2BP1 is widely expressed in fetal tissues (liver,
lung, kidney, thymus, etc), placenta and CD34+ cord
blood cells (Nielsen et al., 1999; Ioannidis et al., 2001;
Ioannidis et al., 2005). Postnatally it is expressed in
ovary (oocytes and granulosa cells), in testis
IGF2BP1 protein translated from transcript 1 variant.
IGF2BP1 protein translated from transcript 2 variant.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)
Trangas T, Ioannidis P
mRNA stabilization: IGF2BP1 binds to the coding
region mRNA stability determinant (CRD) of c-myc
mRNA and protects it from endonucleolytic cleavage
(Doyle et al.,1998; Lemm and Ross, 2002). It protects
MDR-1 mRNAs from endonucleolytic cleavage by
binding to a coding region element (Sparanese and Lee,
2007). Also binds to the coding region of betaTrCP1
mRNA and stabilizes it by disrupting miRNAdependent interaction with AGO2 (Noubissi et al.,
2006; Elcheva et al., 2009). Binds and stabilizes GLI1
mRNA causing an elevation of GLI1 expression and
transcriptional activity (Noubissi et al., 2009).
IGF2BP1 binds to multiple elements in the 3'-UTR of
the CD44 mRNAs and stabilizes this mRNA (Vikesaa
et al., 2006). Binds to the 3'-UTR of Micropthalmia
associated transcription factor mRNA and prevents the
binding of miR-340 to its target sites, resulting in
stabilization of the transcript, elevated expression and
activity of this transcription factor (Goswami et al.,
mRNA transportation: IGF2BP1 binds to the fourth
and fifth exons of the oncofetal H19 RNA (Runge et
al., 2000) and with ELAVL4 and G3BP to 3'-UTR of
the neuron-specific TAU mRNA (Atlas et al., 2004;
Atlas et al., 2007) and regulates their localization. In
collaboration with IGF2BP2, IGF2BP1 binds to the
conserved 54-nucleotide element in the 3'-UTR of the
beta actin mRNA, known as the 'zip code'. IGF2BP1
promotes the localization of the beta-actin mRNA to
dendrites (Eom et al., 2003). IGF2BP1 may act as a
regulator of mRNA transport to activated synapses in
response to synaptic activity.
Protein binding: IGF2BP1 interacts through the third
and fourth KH domains with PABPC1 in a RNAindependent manner (Patel and Bag, 2006) and can
form homo- and heterodimers with IGF2BP2 or
IGF2BP3 (Nielsen et al., 2004). It interacts with fragile
X metal retardation protein isoform 18 (Rackham and
Brown, 2004). It interacts with DHX9, ELAVL2,
IGF2BP2, IGF2BP3, ILF2 and YBX1 (Weindensdorfer
et al., 2009). IGF2BP1 was identified in a mRNP
granule complex, with hnRNP A1, hnRNP A2/B1,
hnRNP D, hnRNP L, hnRNP Q, hnRNP R, hnRNP U,
YB1/major core protein, interleukin enhancer-binding
factor 2 and 3, PABP1, PABP2, PABP4, nucleolin,
RNA helicase A, a series of 40 S ribosomal proteins,
and the nuclear cap-binding protein CBP80 (Jønson et
al., 2007). IGF2BP1 associates with HIV-1 particles. It
interacts (via KH3 and KH4 domains) with HIV-1
GAG protein and diminishes viral RNA packaging,
thwarts GAG processing to the cellular membranes,
and impedes HIV-1 assembly (Zhou et al., 2008).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
The identity of human IGF2BP1 over an aligned region
in UniGene is as follows:
- Pan troglodytes: 99.83%
- Canis lupas familiaris: 90.93%
- Bos taurus: 91.05%
- Mus musculus: 89.43%
- Rattus norvegicus: 89.43%
Implicated in
Lung cancer
IGF2BP1 is expressed in lung cancer and its expression
correlates with adverse histological and clinical
features and is an indicator of poor prognosis.
Suppression of its expression with siRNA suppresses
growth of NSCLC cells in vitro (Ioannidis et al., 2004;
Kato et al., 2007).
Ovarian cancer
Increased expression of IGF2BP1 mRNA is associated
with an advanced clinical stage and poor prognosis in
patients with ovarian cancer (Köbel et al., 2007).
Testicular cancer
Detected in testicular carcinomas even in early stage
carcinoma in situ (Hammer et al., 2005).
IGF2BP1 is highly expressed in primary human
malignant melanomas and melanoma cell line (Elcheva
et al., 2008).
Breast cancer
The IGF2BP1 gene is amplified in breast cancer (Doyle
et al., 2000). Significant associations are detected
between IGF2BP1 expression and the absence of
estrogen receptors. IGF2BP1 collaborates with c-myc
amplification to render tumours more aggressive
(Ioannidis et al., 2003). Tissue specific induced
expression in transgenic mice promotes tumor
formation (Tessier et al., 2004).
Colon cancer
IGF2BP1 is scarce or absent from normal colon but is
over expressed in colorectal cancer. IGF2BP1 positive
tumours associate with metastasis/recurrence and
shorter survival (Ross et al., 2001; Dimitriadis et al.,
IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)
Trangas T, Ioannidis P
Yaniv K, Fainsod A, Kalcheim C, Yisraeli JK. The RNA-binding
protein Vg1 RBP is required for cell migration during early
neural development. Development. 2003 Dec;130(23):5649-61
Hepatocellular carcinoma
IGF2BP1 is detected as an autoantigen
hepatocellular carcinoma (Himoto et al., 2005).
Atlas R, Behar L, Elliott E, Ginzburg I. The insulin-like growth
factor mRNA binding-protein IMP-1 and the Ras-regulatory
protein G3BP associate with tau mRNA and HuD protein in
differentiated P19 neuronal cells. J Neurochem. 2004
The oncogenic action of IGF2BP1 is effected through
the stabilization of the mRNA of oncogenes such as cmyc, betaTrCP1, Gli and upregulation of their
expression. IGF2BP1 expression may promote
metastasis by shuttling requisite RNAs to the
lamellipodia of migrating cells (Vikesaa et al., 2006;
Vainer et al., 2008).
Ioannidis P, Kottaridi C, Dimitriadis E, Courtis N, Mahaira L,
Talieri M, Giannopoulos A, Iliadis K, Papaioannou D, Nasioulas
G, Trangas T. Expression of the RNA-binding protein CRD-BP
in brain and non-small cell lung tumors. Cancer Lett. 2004 Jun
Nielsen J, Kristensen MA, Willemoës M, Nielsen FC,
Christiansen J. Sequential dimerization of human zipcodebinding protein IMP1 on RNA: a cooperative mechanism
providing RNP stability. Nucleic Acids Res. 2004;32(14):436876
Rackham O, Brown CM. Visualization of RNA-protein
interactions in living cells: FMRP and IMP1 interact on mRNAs.
EMBO J. 2004 Aug 18;23(16):3346-55
Doyle GA, Betz NA, Leeds PF, Fleisig AJ, Prokipcak RD, Ross
J. The c-myc coding region determinant-binding protein: a
member of a family of KH domain RNA-binding proteins.
Nucleic Acids Res. 1998 Nov 15;26(22):5036-44
Tessier CR, Doyle GA, Clark BA, Pitot HC, Ross J. Mammary
tumor induction in transgenic mice expressing an RNA-binding
protein. Cancer Res. 2004 Jan 1;64(1):209-14
Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH,
Wewer UM, Nielsen FC. A family of insulin-like growth factor II
mRNA-binding proteins represses translation in late
development. Mol Cell Biol. 1999 Feb;19(2):1262-70
Hammer NA, Hansen TO, Byskov AG, Rajpert-De Meyts E,
Grøndahl ML, Bredkjaer HE, Wewer UM, Christiansen J,
Nielsen FC. Expression of IGF-II mRNA-binding proteins
(IMPs) in gonads and testicular cancer. Reproduction. 2005
Doyle GA, Bourdeau-Heller JM, Coulthard S, Meisner LF, Ross
J. Amplification in human breast cancer of a gene encoding a
c-myc mRNA-binding protein. Cancer Res. 2000 Jun
Himoto T, Kuriyama S, Zhang JY, Chan EK, Nishioka M, Tan
EM. Significance of autoantibodies against insulin-like growth
factor II mRNA-binding proteins in patients with hepatocellular
carcinoma. Int J Oncol. 2005 Feb;26(2):311-7
Runge S, Nielsen FC, Nielsen J, Lykke-Andersen J, Wewer
UM, Christiansen J. H19 RNA binds four molecules of insulinlike growth factor II mRNA-binding protein. J Biol Chem. 2000
Sep 22;275(38):29562-9
Hüttelmaier S, Zenklusen D, Lederer M, Dictenberg J, Lorenz
M, Meng X, Bassell GJ, Condeelis J, Singer RH. Spatial
regulation of beta-actin translation by Src-dependent
phosphorylation of ZBP1. Nature. 2005 Nov 24;438(7067):5125
Ioannidis P, Trangas T, Dimitriadis E, Samiotaki M,
Kyriazoglou I, Tsiapalis CM, Kittas C, Agnantis N, Nielsen FC,
Nielsen J, Christiansen J, Pandis N. C-MYC and IGF-II mRNAbinding protein (CRD-BP/IMP-1) in benign and malignant
mesenchymal tumors. Int J Cancer. 2001 Nov;94(4):480-4
Ioannidis P, Mahaira LG, Perez SA, Gritzapis AD, Sotiropoulou
PA, Kavalakis GJ, Antsaklis AI, Baxevanis CN, Papamichail M.
CRD-BP/IMP1 expression characterizes cord blood CD34+
stem cells and affects c-myc and IGF-II expression in MCF-7
cancer cells. J Biol Chem. 2005 May 20;280(20):20086-93
Ross J, Lemm I, Berberet B. Overexpression of an mRNAbinding protein in human colorectal cancer. Oncogene. 2001
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Lemm I, Ross J. Regulation of c-myc mRNA decay by
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Patel GP, Ma S, Bag J. The autoregulatory translational control
element of poly(A)-binding protein mRNA forms a heteromeric
Nielsen FC, Nielsen J, Kristensen MA, Koch G, Christiansen J.
Cytoplasmic trafficking of IGF-II mRNA-binding protein by
conserved KH domains. J Cell Sci. 2002 May 15;115(Pt
Noubissi FK, Elcheva I, Bhatia N, Shakoori A, Ougolkov A, Liu
J, Minamoto T, Ross J, Fuchs SY, Spiegelman VS. CRD-BP
mediates stabilization of betaTrCP1 and c-myc mRNA in
response to beta-catenin signalling. Nature. 2006 Jun
Eom T, Antar LN, Singer RH, Bassell GJ. Localization of a
beta-actin messenger ribonucleoprotein complex with zipcodebinding protein modulates the density of dendritic filopodia and
filopodial synapses. J Neurosci. 2003 Nov 12;23(32):10433-44
Patel GP, Bag J. IMP1 interacts with poly(A)-binding protein
(PABP) and the autoregulatory translational control element of
PABP-mRNA through the KH III-IV domain. FEBS J. 2006
Ioannidis P, Mahaira L, Papadopoulou A, Teixeira MR, Heim S,
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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Trangas T, Ioannidis P. IGF2BP1 (insulin-like growth factor 2
mRNA binding protein 1). Atlas Genet Cytogenet Oncol
Haematol. 2011; 15(7):562-566.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Mini Review
MTA3 (metastasis associated 1 family, member 3)
Ansgar Brüning, Ioannis Mylonas
University Hospital Munich, Department of Obstetrics/Gynaecology, Molecular Biology Laboratory,
Marchioninistrasse 15, 81377 Munchen, Germany (AB, IM)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/MTA3ID41445ch2p21.html
DOI: 10.4267/2042/45996
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
The human MTA3 gene is composed of 14 exons. The
MTA3 promoter sequence contains SP1, AP1, and
oestrogen receptor binding sites (ER half sites).
Other names: KIAA1266
HGNC (Hugo): MTA3
Location: 2p21
Two open reading frames of 1785 bp (isoform 1; 594
AA; MTA3L) and 1548 bp (isoform 2; 515 AA;
MTA3S, MTA3) were identified and predicted to be
transcribed. The smaller isoform (MTA3S = MTA3)
appears to be the most abundantly expressed isoform at
the RNA and protein level.
The human MTA3 gene was identified through
sequence homologies to other members of the MTA
gene family (human MTA1, human MTA2, murine
PGO.9606.51655; PGO.9606.72237.
Genomic organization of the human MTA3 gene. The intron/exon structure of MTA3 with start (ATG) and stop (TAA) codons indicated.
All 14 exons are depicted; the intron sequences shortened for better graphical visualization.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
MTA3 (metastasis associated 1 family, member 3)
Brüning A, Mylonas I
Domain structure of the MTA3 protein. BAH (bromo-adjacent homology) domain: putative protein-protein interaction domain, involved in
gene silencing; ELM (Egl-27 and MTA1 homology) domain: unknown function; SANT (SWI3, ADA2, N-CoR and TFIIIB B) domain:
putative DNA binding domain; ZnF (GATA-type zinc finger) domain: direct DNA binding domain.
of divers signalling pathways, including the Wnt
signalling pathway. Secretion of Wnt factors and their
binding by mammary epithelial cells is necessary for
correct gland development and its deregulation has
been described to be involved in tumorigenesis. MTA3
has been shown to inhibit Wnt4 expression by its
transcriptional repression function, causing reduced
Wnt4 secretion and subsequent lower beta-catenin
levels. Therefore, based on the observations made with
transgenic mouse models, expression of MTA3 in
mammary epithelial cells has been associated with the
inhibition of ductal branching in virgin and pregnant
murine mammary glands.
Epithelial cancer
Deregulation of MTA3 expression in epithelial breast
cancer, endometrial cancer, and ovarian cancer is
associated with cancer progression by promoting the
epithelial-mesenchymal transition (EMT). It is
principally believed that reduced expression of MTA3
allows higher expression levels of SNAIL and SLUG,
two repressors of metastasis-associated cell adhesion
proteins such as E-cadherin and occludin.
Haemangiogenesis and lymphomagenesis
A high expression level of MTA3 was found in
germinal centre B lymphocytes, suggesting an
involvement in B cell maturation by direct interaction
with BCL6. BCL6 (B-cell lymphoma-6) is a
transcriptional repressor that is co-expressed with
MTA3 in the germinal centre, where normal B cells
proliferate and undergo maturation. BCL6 functions as
a transcriptional repressor and suppresses, in
cooperation with MTA3, the expression of PRDM1 (Pr
domain-containing protein 1), a master regulator of
plasma cell differentiation. Overexpression of BCL6 is
often observed in lymphomas, especially in large B-cell
lymphomas. Thus, the cooperative action of BCL6
together with MTA3 is believed to block differentiation
Placenta development
A high expression level of MTA3 in trophoblast cells
and trophoblast tumour cells suggests
MTA3 functions as a transcriptional repressor by
interacting with histone deacetylases and nucleosome
remodelling complexes such as Mi-2/NuRD.
MTA3 expression has been found in normal human
breast, ovarian, and endometrial epithelial cells, in
malignant breast, ovarian, and endometrial cancer cells
and cancer cell lines, in trophoblast cells and chorionic
cancer cell lines, in germinal centre B cells, and in B
cell-derived lymphomas. A tissue distribution analysis
of MTA3 expression in mice revealed an even more
widespread distribution of MTA3 in the developing
embryo and in adult tissues (heart, brain, spleen, lung,
liver and kidney). In humans, MTA3 expression
appears to be absent from fibroblasts.
MTA3 exhibits primarily a nuclear localisation,
although additional cytoplasmic localisation has been
In epithelial cells, MTA3 maintains the expression of
E-cadherin through the suppression of the E-cadherin
inhibitor SNAIL. Expression of MTA3 is regulated by
oestrogens via direct binding of the oestrogen receptor
to the MTA3 promoter and is thus involved in the
generation and maintenance of oestrogen-dependent
epithelia such as the breast ductal epithelium and the
ovarian surface epithelium.
Mammary gland development
Animal experiments revealed involvement of MTA3
expression in mammary gland morphogenesis mediated
by the suppression of the Wnt4 signalling pathway and
upregulation of epithelial cell adhesion proteins such as
Normal mammary gland development, as confirmed
and studied by several knock out and knock in mouse
models, relies on the concerted and correct integration
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
MTA3 (metastasis associated 1 family, member 3)
Brüning A, Mylonas I
The MTA3 regulation network.
A. Breast ductal epithelia cells; epithelial cancer cells.
B. Germinal center B lymphocytes; B cell-derived lymphomas. The regulation of MTA3 expression and its target genes by transcriptional
activators (green) and transcriptional repressors (red) is shown. ER: oestrogen receptor.
Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, Boss
JM, Wade PA. MTA3 and the Mi-2/NuRD complex regulate cell
fate during B lymphocyte differentiation. Cell. 2004 Oct
involvement of MTA3 in placenta development and
homeostasis. However, the exact role of MTA3
expression for placenta development and the
downstream targets of MTA3 in trophoblast cells are
unknown and have to be elucidated.
Fujita N, Kajita M, Taysavang P, Wade PA. Hormonal
regulation of metastasis-associated protein 3 transcription in
breast cancer cells. Mol Endocrinol. 2004 Dec;18(12):2937-49
Mishra SK, Talukder AH, Gururaj AE, Yang Z, Singh RR, et al.
Upstream determinants of estrogen receptor-alpha regulation
of metastatic tumor antigen 3 pathway. J Biol Chem. 2004 Jul
MTA3 exhibits a high homology to human MTA1,
MTA2, and murine MTA3.
Implicated in
Zhang H, Singh RR, Talukder AH, Kumar R. Metastatic tumor
antigen 3 is a direct corepressor of the Wnt4 pathway. Genes
Dev. 2006 Nov 1;20(21):2943-8
Endometrial cancer
MTA3 expression is significantly reduced in
endometrioid adenocarcinomas of poor differentiation,
although not associated with patients' survival.
Zhang H, Stephens LC, Kumar R. Metastasis tumor antigen
family proteins during breast cancer progression and
metastasis in a reliable mouse model for human breast cancer.
Clin Cancer Res. 2006 Mar 1;12(5):1479-86
Jaye DL, Iqbal J, Fujita N, Geigerman CM, Li S, et al. The
BCL6-associated transcriptional co-repressor, MTA3, is
selectively expressed by germinal centre B cells and
lymphomas of putative germinal centre derivation. J Pathol.
2007 Sep;213(1):106-15
Ovarian cancer
MTA3 expression is reduced in ovarian cancer with
poor differentiation, although not at significant levels.
Brüning A, Makovitzky J, Gingelmaier A, Friese K, Mylonas I.
The metastasis-associated genes MTA1 and MTA3 are
abundantly expressed in human placenta and chorionic
carcinoma cells. Histochem Cell Biol. 2009 Jul;132(1):33-8
Breast cancer
Although extensively studied on breast cancer cells and
tissues, revealing a close correlation of MTA3
expression with oestrogen receptor expression, no
studies have yet shown a direct association of MTA3
expression with clinicopathological parameters in
breast cancer.
Li X, Jia S, Wang S, Wang Y, Meng A. Mta3-NuRD complex is
a master regulator for initiation of primitive hematopoiesis in
vertebrate embryos. Blood. 2009 Dec 24;114(27):5464-72
Brüning A, Jückstock J, Blankenstein T, Makovitzky J, Kunze
S, Mylonas I. The metastasis-associated gene MTA3 is
downregulated in advanced endometrioid adenocarcinomas.
Histol Histopathol. 2010 Nov;25(11):1447-56
This article should be referenced as such:
Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade
PA. MTA3, a Mi-2/NuRD complex subunit, regulates an
invasive growth pathway in breast cancer. Cell. 2003 Apr
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
NMT1 (N-myristoyltransferase 1)
Ponniah Selvakumar, Sujeet Kumar, Jonathan R Dimmock, Rajendra K Sharma
Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan,
Saskatoon, SK S7N OW8, Canada (PS, SK, RKS); Cancer Research Unit, Saskatchewan Cancer Agency, 20
Campus Drive, Saskatoon, SK S7N 4H4, Canada (PS, SK, RKS); Drug Design and Discovery Research
Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9,
Canada (JRD)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/NMT1ID43604ch17q21.html
DOI: 10.4267/2042/45997
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
It is a monomer and does not require any cofactor or
post-translational modifications. The enzyme follows
an ordered Bi Bi reaction mechanism in which the apoenzyme binds myristoyl-CoA to form a NMT1myristoyl-CoA binary complex which subsequently
binds to protein/peptide substrates. The catalytic
conversion (N-myristoylation) is via a direct
nucleophilic addition-elimination reaction. The
sequential release of CoA and myristoyl-peptide
follows the formation of an enzyme-product complex
from the enzyme-substrate complex (Farazi et al.,
2001; Wright et al., 2009). N-myristoyltransferases 1
have a common preference for myristoyl-CoA but have
divergent peptide substrate specificities and the enzyme
is highly selective for myristoyl-CoA in vitro and in
vivo (Farazi et al., 2001). The protein belongs to
GNAT superfamily of enzymes and consists of a
saddle-shaped beta-sheet flanked by a helices. There is
a pseudo two fold symmetry with regions
corresponding to N- and C-terminal portions of the
enzyme. The N-terminal half forms the myristoyl-CoA
binding site whereas the C-terminal half forms the
major portion of the peptide binding site (Farazi et al.,
2001; Wright et al., 2009). A large number of crystal
structures of NMT1 from yeast and human isoforms are
available in apo and complex form. Comparative
analysis of the various NMTs has shown that the
peptide binding pocket is more divergent than the
myristoyl-CoA-binding site (Farazi et al., 2001; Wright
et al., 2009). Further, the phospho-proteome analysis
studies have shown that the human isoform is
phosphorylated in vivo at position 47 (Beausoleil et al.,
2004; Beausoleil et al., 2006; Olsen et al., 2006;
Other names: NMT
HGNC (Hugo): NMT1
Location: 17q21.31
The gene located on the forward strand and spans a size
of 47705 bases. It starts at 43138680 and ends at
43186384 bp from pter. The total number of exons is
Alternate splicing.
No known pseudogenes.
N-myristoyltransferase 1 (NMT 1: EC is a
key cellular enzyme which carries out lipid
modification by facilitating the attachment of myristate
to the N-terminal glycine of several protein molecules.
The enzyme's function is indispensible for the growth
and development of many eukaryotic organisms and
several rotaviruses (Duronio et al., 1989; Duronio et al.,
1991; Maurer-Stroh and Eisenhower, 2004; Yang et al.,
2005; Wright et al., 2009). The best studied homologue
of NMT1 is from the S. cerevisiae (Farazi et al., 2001).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
NMT1 (N-myristoyltransferase 1)
Selvakumar P, et al.
Dephoure et al., 2008; Mayya et al., 2009). However
the biological significance of this observation is not yet
general consesus motif of GXXXS/T (where X is any
amino acid) (Boutin, 1997; Resh, 1999; Farazi et al.,
2001; Wright et al., 2009; Hannoush and Sun, 2010).
Various regular endogenous, physiological enzymes
and proteins such as protein kinase A, protein kinase G,
NADH-cytochrome b5 reductase, nitric oxide synthase,
recoverin, most of the G protein a subunit are the
substrates of myristoylation among higher eukaryotes.
A detailed list of the substrate proteins is available in a
number of reviews elsewhere (Boutin, 1997; Resh,
1999; Maurer-Stroh et al., 2004; Selvakumar et al.,
2007). Myristoylation increases protein lipophilicity
and is important for the full expression of biological
functions of proteins. It controls the functioning of
proteins by targeting them to specific localization,
promoting specific protein-protein and protein-lipid
interactions and ligand-induced conformational
changes (Resh, 1999; Farazi et al., 2001; Wright et al.,
The enzyme is ubiquitous in expression and often exists
as isozymes in vivo, varying in either apparent
molecular weight and/or subcellular distribution
(Selvakumar et al., 2007; Wright et al., 2009). In
humans NMT1 is processed to exist as four distinct
isoforms ranging from 49 to 68 kDa in size (Giang and
Cravatt, 1998). The longer isoform of 496 amino acids
represents the full-length protein whereas the shorter
isoform represents a translation product of 416 amino
acids that initiates with a methionine at amino acid
position 81 in the full-length cDNA (Giang and
Cravatt, 1998; Farazi et al., 2001). The shorter isoform
of NMT1 may arise from an alternative splice variant
or through initiation of translation at an internal
Implicated in
NMT1 is a cytoplasmic enzyme because of Nmyristoylation being a co-translational protein
modification. Recently, it has been reported that the
extended N-terminal domain of the longer isoform of
NMT1 is involved in targeting the enzyme to the
ribosome but it is not required for activity in vitro
(Glover et al., 1997). Targeting to the ribosome appears
to be consistent with its role as a co-translational
protein modifier. In previous studies it has been
observed that NMT1 activity from various cell lines
and tissues is associated with membranous and
particulate fraction (Magnuson et al., 1995; Boutin,
1997). However, the enzyme activity in particulate
fractions in earlier studies could represent an
association with ribosomes, rather than an authentic
membrane association.
Various cancers
Altered NMT expression is observed in many types of
cancer tissues including those of colon, breast,
gallbladder and brain (Selvakumar et al., 2007; Wright
et al., 2009). A quantitative RT-PCR investigation of
hNMT-1 expression during the progression of different
human cancers shows that hNMT-1 is upregulated in
breast, colon, lung and on average by 3.7 (p=0.032),
3.1 (p=0.001), 2.3 (p=0.003) and 1.8 (p=0.012) fold,
respectively (Chen et al., 2009). These findings are
explained by the hypothesis that many of the various
proteins/oncoproteins (src, ras etc.) which are
overexpressed and activated, during tumorigenesis
require myristoylation for their proper function
(Boutin, 1997; Resh, 1999; Wright et al., 2009). The
elevated NMT activity accounts for the functioning of
overexpressed oncoproteins and NMT thus plays a role
in cancer progression. The NMT substrate src has
elevated activity in human cancers and this contributes
to its pathogenicity (Frame, 2002). Inhibiting NMT1
functions has also been shown to reduce proliferation
and induce apoptosis in human and murine melanoma
cell lines and also to block tumor growth in vivo
(Bhandarkar et al., 2008). The siRNA mediated NMT1
knockdown shows that silencing NMT1 inhibits cell
replication associated with loss of c-Src activation and
its target FAK as well as reduction of various protein
kinase regulated pathways (Ducker et al., 2005). The
knockdown of either of the isozymes, NMT1 or NMT2
results in apoptosis with NMT2 having a more
pronounced effect than NMT1. However, in a mouse
model the intratumoral injection mainly of NMT1
siRNA has been shown to be responsible for inhibition
of tumor growth (Ducker et al., 2005). It has been
concluded that among the two isoforms of NMT
catalyses the covalent
attachment of myristate, a 14 carbon saturated fatty
acid, via amide bond to the N-terminal glycine residue
of several proteins (Wright et al., 2009; Hannoush and
Sun, 2010). This lipidic modification is an irreversible
process, however not without exceptions (Hannoush
and Sun, 2010). Intially this process was thought to be
co-translational in which the addition of myristate on
the N-terminal glycine takes place after initial amino
acid residues (within 100) have been synthesized by the
ribosome (Wilcox et al., 1987). The process follows
after the removal of the initiator methionine by a
methionine aminopeptidase to expose an available Nterminal glycine. However, now it has been shown to
occur post-translationally as well when an internal
glycine within a polypeptide chain is exposed
following a proteolytic cleavage (Zha et al., 2000;
Utsumi et al., 2003; Martin et al., 2008). The
Availability of exposed N-terminal glycine is an
absolute requirement and the modification occurs on a
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
NMT1 (N-myristoyltransferase 1)
Selvakumar P, et al.
cancer patients have offered an advantage for early
detection of colorectal cancer using NMT as a blood
based marker (Shrivastav et al., 2007; Kumar et al.,
2011). The immunohistochemical analysis shows weak
to negative staining for NMT in peripheral blood
mononuclear cells (PBMC) of controls, whereas strong
positivity is observed in the PBMC of colon cancer
patients (Shrivastav et al., 2007; Kumar et al., 2011). In
addition, NMT is confined mostly in the nuclei of the
bone marrow (BM) mononuclear cells of the colon
cancer patients, whereas in the control bone marrow
specimens it remained cytoplasmic. The strikingly
different NMT expression and its altered localization
offers the basis of a potential adjunct investigative tool
for screening or diagnosis of patients at risk for, or
suspected of having, colon cancer (Shrivastav et al.,
2007; Kumar et al., 2011). It has been observed that in
colon cancer cell lines, an elevated expression of NMT
correlates with high levels of c-Src levels (Rajala et al.,
2000a). Further it has been observed that the levels of
the myristoylated tyrosine kinases, pp60c-src and pp60cyes
are several fold higher in colonic preneoplastic
lesions and neoplasms compared with normal colon
cells (Bolen et al., 1987; Weber et al., 1992; Termuhlen
et al., 1993). Differential expression of pp60c-src has
been observed in colonic tumor-derived cell lines
(Bolen et al., 1987; Weber et al., 1992) and colonic
polyps prone to developing cancer (Cartwright et al.,
1990). In the intestinal crypt cells, higher levels of
cytoskeletal-associated pp60c-src protein tyrosine kinase
activity have been observed along with higher
expression of pp60c-yes in the normal intestinal
epithelium (Zhao et al., 1990; Cartwright et al., 1993).
Studies have revealed that pp60c-src is overexpressed in
human colon carcinoma and it has enhanced kinase
activity in progressive stages and metastases of human
colorectal cancer (Bolen et al., 1987; Termuhlen et al.,
1993). Furthermore, it has been shown that src kinase
activity is positively regulated by myristoylation and
the non-myristoylated c-Src exhibited has reduced
kinase activity (Patwardhan and Resh, 2010). The
blockages of pp60c-src N-myristoylation in colonic cell
lines have been reported to result in depressed colony
formation and reduced proliferation (Shoji et al., 1990).
(NMT1 and NMT2), both have only partially
overlapping functions and that NMT1 is critical for
tumor cell proliferation further suggesting that isoformspecific inhibitors might be developed as potential anticancer agents (Ducker et al., 2005). It is now apparent
that NMT represents both a valuable clinical marker
and therapeutic target for cancer (Boutin, 1997; Ducker
et al., 2005; Selvakumar et al., 2007; Wright et al.,
2009). A several fold increase in NMT activity in
polyps and stage B1 tumors compared to normal
colonic mucosa have been proposed to be used as a
diagnostic/prognostic tool for early detection of
colorectal cancer (Raju et al., 1997; Shrivastav et al.,
2007; Kumar et al., 2011).
Colorectal cancer
Colorectal cancer is associated with significantly high
mortality and is one of the most common forms of
malignancy world wide (Segal and Saltz, 2009). In the
western world, it accounts for the second most common
cause of cancer associated deaths (Midgley and Kerr,
2001; Tol and Punt, 2010) and is the fourth most
common cause of malignancy in the United States
(Wolpin et al., 2007; Wolpin and Mayer, 2008). A
majority of colon cancer develop from the precancerous polyps on the lining of the colon which grow
over the years to becomes cancerous in nature (Midgley
and Kerr, 1999). With the increasing armentarium
towards colon cancer (Midgley and Kerr, 1999;
Midgley and Kerr, 2001; Wolpin et al., 2007; Wolpin
and Mayer, 2008; Segal and Saltz, 2009; Tol and Punt,
2010), it is one of the most curable forms of cancer if
detected early. However, due to the lack of early
symptoms, the majority of the patients have an
advanced disease at presentation (Midgley et al., 2001;
Segal and Saltz, 2009). Studies have shown that NMT
represents both a valuable marker for clinical diagnosis
and as a therapeutic target for colon cancer (Magnuson
et al., 1995; Raju et al., 1997; Shrivastav et al., 2007;
Kumar et al., 2011).
A direct relationship has been reported for NMT
expression and activity and colon cancer progression
(Magnuson et al., 1995; Raju et al., 1997). NMT
activity and expression has been shown to be
upregulated during the progression of colorectal cancer
(Magnuson et al., 1995; Raju et al., 1997) and NMT
thus has been proposed as a potential chemotherapeutic
target (Felsted et al., 1995). A significantly higher
NMT activity in rat colonic tumors and a several fold
increase in NMT activity in polyps and stage B1
tumors compared to normal colonic mucosa have
indicated that NMT could be used as a
diagnostic/prognostic tool for colorectal cancer
(Magnuson et al., 1995; Raju et al., 1997; Shrivastav et
al., 2007). Altered expression and localization of NMT
in the peripheral blood and bone marrow of colon
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Gallbladder cancer
Gallbladder cancer, also known as carcinoma of the
gallbladder, is extremely rare affecting the gall bladder
(the organ behind the liver which stores bile
produced by the liver). Gallbladder is a non-essential
organ and can be removed without significant
consequences. However, since gallbladder cancer is
very uncommon and many of its symptoms are similar
to those of more common ailments (jaundice, pain, and
fever), cancer of the gallbladder is usually not found
until it is at an advanced stage and cannot be surgically
NMT1 (N-myristoyltransferase 1)
Selvakumar P, et al.
results in opportunistic infections or malignancies
leading to the death of individuals in most of the cases.
The pathogenic states linked to undesired
myristoylation activity includes the myristoylation of
viral proteins for their proper maturation and infectivity
(Boutin, 1997; Maurer-Stroh and Eisenhower, 2004;
Wright et al., 2009). Many of the viral genes are
homologues of the tyrosine kinases and require Nmyristoylation for the infectivity of viral particles. In
the case of HIV infections, viral proteins Gag and Nef
require myristoylation by the host cell NMT to carry
out their function properly. Gag is the precursor
polyprotein for structural components of the viral
capsid and requires myristoylation for intracellular
localization and its targeting to the lipid rafts in the
plasma membrane during virus assembly (Zhou et al.,
1994; Resh, 2004; Wright et al., 2009). Nef on the
other hand comprises many virulence factors to modify
the cellular environment of infected cells to facilitate
viral replication and evade detection by cells of the
immune system (Collins et al., 1998). It has been
reported that NMT1 myristoylates Gag in vivo and
inhibiting NMT1 negatively affects HIV production
(Takamune et al., 2008).
Gallbladder cancer tends to spread to the liver or small
intestine and also spreads to lymph nodes through the
lymphatic system in the region of the liver resulting in
involvement of other lymph nodes and organs. The
treatments available are not particularly effective,
unless the tumor is very small and found in which case
the gallbladder is removed for other reasons. A study of
documented gallbladder carcinoma cases has been
evaluated for NMT and p53 expression by
immunohistochemistry in both in situ and in invasive
tumor components (Rajala et al., 2000b). Moderate to
strong cytoplasmic positivity for NMT with increased
intensity in the invasive component was observed in
60% of the cases. A mild to moderate cytoplasmic
staining was revealed in the in situ component in 67%
of the cases studied. It has been concluded that
increased NMT expression in gall bladder tumors is
associated with poor clinical outcomes as evidenced by
their mean survival times (Rajala et al., 2000b).
Breast cancer
Breast cancer originates from the breast tissue, most
commonly from the inner lining of milk ducts (ductal
carcinoma) or the lobules (lobular carcinoma) that
supply the ducts with milk. It is the fifth most common
cause of cancer death and comprises 10.4% of all
cancer incidences among women worldwide, and is the
most common type of non-skin cancer in women.
It has been observed that in the mammary epithelial
cells, the proliferative capacity correlates with NMT
activity (Clegg et al., 1999). A study of the NMT
profiles in tumourigenic or metastatic breast cancer cell
lines have displayed reduced NMT activity and western
blot analysis shows that NMT1 is phosphorylated in
these breast cancer cells (Shrivastav et al., 2009).
Furthermore, patients' breast cancer tissue array
revealed strong positivity and high intensity for NMT
in malignant breast tissues compared with normal
breast cells. In the grade I, II, and III infiltrating ductal
carcinoma breast tissues, a gradation in the NMT
staining was observed (Shrivastav et al., 2009). It has
been concluded that NMT may prove to be an
additional diagnostic biomarker for breast cancer.
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
PAEP (progestagen-associated endometrial
Hannu Koistinen, Markku Seppälä
Department of Clinical Chemistry, Helsinki University Central Hospital and University of Helsinki,
Helsinki, Finland (HK, MS)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/PAEPID46067ch9q34.html
DOI: 10.4267/2042/45998
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PAEP mRNA (NM_001018049) has 857 bp. Several
alternatively spliced mRNA forms have been
described, but for most of these evidence for the
corresponding protein lacks. Alternative Splicing and
Transcript Diversity database (ASTD) reports 16
different transcripts.
Other names: GD; GdA; GdF; GdS; MGC138509;
MGC142288; PAEG; PEP; PP14
Location: 9q34.3
Local order: Several other lipocalin genes have been
mapped on the same chromosomal region. From
centromere to telomere (GeneLoc database): lipocalin 1
(tear prealbumin, LCN1) - ENSG00000221613 odorant binding protein 2A (OBP2A) - progestagenassociated
ENSG00000236543 - glycosyltransferase 6 domain
containing 1 (GLT6D1) - lipocalin 9 (LCN9).
Not known.
Some of the localization studies have employed
antibodies, the specificity of which is questionable.
Some of the biological studies have utilized short
peptides derived from PAEP sequence. It is unclear
whether such peptides are present in vivo.
modulating/dictating the activity of PAEP. In the
literature, PAEP is widely referred to as PP14 and
Many other lipocalin genes have similar exon/intron
Maps to chromosome 9: 138453602-138458801 on
forward (plus) strand (5200 bases). Gene consists of 7
exons. Promoter region contains, by sequence
similarity, 2 forward and two reverse Sp1-like binding
sites, four putative glucocorticoid/progesterone
response elements (PREs), cAMP responsive element
(CRE) and activator protein-1 (AP-1) element.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
PAEP (180 amino acids, of which 18 corresponds to
signal sequence) is a 28 kDa secreted glycoprotein,
belonging to the kernel lipocalin family. Most family
members share three conserved sequence motifs.
Although sequence similarity between the family
members is low, their three dimensional structures are
PAEP (progestagen-associated endometrial protein)
Koistinen H, Seppälä M
Chromosomal location and gene structure of PAEP. Promoter region shows some of the potential regulatory elements. After translationinitiating codon (ATG) exons of the major transcript are shown in black. Some splicing variants contain also parts outside of these exons.
PRE: glucocorticoid/progesterone response element; CRE: cAMP responsive element; Sp1: Sp1 transcription factor binding site; AP-1:
activator protein-1 element.
seminal vesicles. PAEP is also expressed in other
epithelial cells of reproductive tissues, such as fallopian
tubes, ovary and the breast. In addition, other secretory
epithelia, such as eccrine sweat glands and the
bronchus epithelium express PAEP. It is also expressed
in differentiated areas of breast cancer, ovarian tumors,
endometrial adenocarcinoma, and synovial sarcoma. In
addition to epithelial tissues, PAEP has been found in
megakaryocytes and erythroid precursor cells.
Experimental evidence suggests that PAEP expression
is regulated by progesterone/progestins, relaxin, and
histone deacetylase inhibitors.
Lipocalins are small extracellular proteins, many of
which bind small hydrophobic molecules, such as
retinol and steroids. There is no evidence that PAEP
exhibits similar binding properties. PAEP is a
glycoprotein with three potential glycosylation sites.
Two of them are glycosylated. Many differentially
glycosylated forms have been characterized in these
sites. Glycosylation modulates/dictates the biological
activity of PAEP. Some of the alternatively spliced
mRNAs lack the sequences encoding glycosylation
sites and/or the lipocalin signature sequence.
The expression of PAEP is highly regulated in a
spatiotemporal fashion. In the female, PAEP is mainly
expressed in secretory/decidualized endometrial glands
after progesterone exposure. In secretory endometrium,
expression becomes detectable four days after
ovulation and reaches maximum at the end of the
menstrual cycle unless pregnancy ensues. PAEP is one
of the major proteins in endometrial secretions. In the
male, the highest expression has been reported in
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
PAEP is mostly found in exocrine epithelial cells, from
which it is secreted into the gland lumen. In breast
cancer, PAEP has been found also in paranuclear
vacuoles of lobular carcinoma cells.
PAEP/PP14/glycodelin regulates the functions of
spermatozoa during fertilization in a glycosylation
dependent manner.
PAEP (progestagen-associated endometrial protein)
Koistinen H, Seppälä M
Swiss model-deduced tertiary structure of the PAEP monomer. The S-S bridge is shown as cylinder and side chain nitrogen atoms of
asparagines of potential glycosylation sites are shown as balls. Below are representative examples of the major complex-type glycans
present at the N-glycosylation sites Asn 28 and Asn 63 of amniotic fluid glycodelin-isoform (glycodelin-A) and seminal plasma glycodelinisoform (glycodelin-S). Some of the characteristic epitopes are marked by broken line.
The various glycoforms of PAEP have different,
sometimes even opposite, biological actions at different
phases of the fertilization process. Seminal fluid
glycodelin-S binds to the sperm head and inhibits
premature capacitation. In the female reproductive
tract, spermatozoa come into contact with various
PAEP glycoforms, that modulate sperm function, e.g.,
by preventing premature, progesterone-induced
acrosome reaction (glycodelin-F). Glycodelin-A
inhibits binding of spermatozoa to the zona pellucida,
whereas another glycoform (glycodelin-C) stimulates
the same. All these actions are glycosylationdependent.
PAEP also regulates immune cell functions, which too
are, at least in part, regulated by glycosylation.
Different PAEP glycoforms contain diverse bi-, tri-,
and tetra-antennary complex-type glycans with varying
levels of fucose and sialic acid substitution.
Glycodelin-A and -F are the most heavily sialylated
and inhibit cell proliferation, induce cell death, and
suppress interleukin-2 secretion of Jurkat cells and
peripheral blood mononuclear cells. No such
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
immunosuppressive effect has been observed for
glycodelin-C and -S carrying less or no sialic acids, or
for desialylated glycodelin-A and -F. By its
immunosuppressive properties one of the PAEP
glycoforms (glycodelin-A) may contribute to
immunotolerance at the fetomaternal interface and
prevent rejection of the fetal semi-allograft.
inappropriate invasion of extravillous cytotrophoblasts
by suppressing activity of some key metalloproteinases.
In breast and endometrial cancer cell lines, PAEP has
been found to revert the malignant phenotype in vitro
by inducing morphological differentiation and specific
gene expression changes. In a preclinical mouse model,
transgenic PAEP expression in breast cancer cells has
reduced tumor growth.
Most lipocalins do not share high sequence similarity,
but they are likely to be homologous.
Functional PAEP gene has been found in higher
primates. Beta-lactoglobulins represent orthologs of
PAEP (progestagen-associated endometrial protein)
Koistinen H, Seppälä M
PAEP, but they are likely to be functionally different
from human PAEP, not least because of their
differences in glycosylation. No convincing evidence
of a PAEP ortholog in mouse or rat has been reported.
In sporadic breast cancer, PAEP is associated with low
proliferation rate and well-differentiated tumors,
whereas in familial "non BRCA1/BRCA2" patients,
PAEP expression is associated with a less favorable
phenotype and increased risk of metastases.
Reproductive failure
NCBI SNP database reports 128 PAEP SNPs (Homo
sapiens, 13 September 2010). Also HinfI restriction
enzyme polymorphism has been reported in Finnish
population with 5% frequency for allele A1 and 95%
frequency for allele A2. No disease associations for
mutations have been described.
During the period of endometrial receptivity for
implantation, reduced PAEP secretion/serum levels
have been observed in reproductive failure, e.g. in
unexplained infertility or recurrent early pregnancy
Unexplained infertility or recurrent miscarriage may
Implicated in
Ovarian carcinoma
PAEP is expressed in both normal and malignant
ovarian tissue. PAEP has been localized to the
cytoplasm of tumor cells and its staining is more
frequent in well-differentiated than in poorly
differentiated carcinomas. Nuclear progesterone
receptors (PRA and PRB) are often coexpressed with
cytoplasmic PAEP.
In 2002, ovarian cancer was the 6th most common
cancer in women, and 7th most common cause of
cancer death. Most malignant neoplasms of the ovary
originate from the coelomic epithelium.
In ovarian serous carcinoma, PAEP expression is
associated with a more favorable prognosis, even in
patients with the same tumor grade and clinical stage.
Polycystic ovary syndrome (PCOS)
Pregnant women with PCOS who subsequently
miscarry show subnormal rise of PAEP serum
concentration during the first trimester.
PCOS is a common endocrine disorder in fertile-aged
women. It is associated with ovulatory disturbance,
insulin resistance and androgen excess, and is a
frequent cause of menstrual disorders and infertility in
Joshi SG, Smith RA, Stokes DK. A progestagen-dependent
endometrial protein in human amniotic fluid. J Reprod Fertil.
1980 Nov;60(2):317-21
Breast cancer
Julkunen M, Koistinen R, Sjöberg J, Rutanen EM, Wahlström
T, Seppälä M. Secretory endometrium synthesizes placental
protein 14. Endocrinology. 1986 May;118(5):1782-6
In breast cancer tissue, PAEP staining has been found
in both estrogen and progesterone receptor negative
and positive cancers. PAEP is also present in normal
breast tissue. Transfection of PAEP in MCF-7 breast
cancer cells reverted the malignant phenotype of the
cells by inducing morphological differentiation and
specific gene expression changes. Furthermore, these
cells showed reduced tumor growth in a preclinical
xenograft tumor mouse model.
Breast cancer is the most common cancer among
women worldwide. Although the prognosis has
improved following improved diagnosis and therapies,
breast cancer remains an important cause of death
among women. Most of the neoplasms of the breast
originate from the ductal epithelium, while a minority
originates from the lobular epithelium. Family history
of breast cancer is associated with a 2-3-fold higher
risk of the disease.
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This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Koistinen H, Seppälä M. PAEP (progestagen-associated
endometrial protein). Atlas Genet Cytogenet Oncol Haematol.
2011; 15(7):576-581.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
SHBG (sex hormone-binding globulin)
Nicoletta Fortunati, Maria Graziella Catalano
Lab Endocrinologia Oncologica, Dip Oncologia, AOU San Giovanni Battista & Dip Fisiopatologia Clinica,
Universita di Torino, Via Genova 3, 10126 Torino, Italy (NF, MGC)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/SHBGID42286ch17p13.html
DOI: 10.4267/2042/45983
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Two major SHBG transcripts are known, each
originating from a different promoter. The variant 1,
which has also been referred to as SHBG-L, encodes
the longest protein (isoform 1), while the variant 2 uses
an alternate in-frame splice site in the 3' coding region
compared to variant 1. These two transcripts differ in
their 5' sequence and in the absence of exon 7 in the
latter one.
Other names: ABP; MGC126834; MGC138391; SBP;
Location: 17p13.1
This gene encodes a steroid binding protein that was
first described as a plasma protein secreted by the liver;
lately, it was recognized to be produced also by testis
germ cells; the protein is now thought to participate in
the regulation of steroid responses at cell level. The
encoded protein in biological fluids is a dimer formed
from identical or nearly identical monomers; in each
monomer one steroid binding pocket has been
recognized. SHBG binds androgen and estradiol with
different affinity. Alternate promoters and several
spliced transcripts were reported.
402 amino acids; 43779 Da each subunit: homodimer.
SHBG is a homodimer; each monomer is constituted of
402 aa, molecular weight 43,7 kDa. The protein
consists of a signal peptide (1-29 aa) and 2 laminin Glike domains (domain 1: 45-217 aa; domain 2: 224-390
aa). Each SHBG monomer has an O-linked
oligosaccharide at Thr(36) and up to two N-linked
oligosaccharides at Asn(380) and Asn(396).
The human SHBG gene is located on the short arm of
chromosome 17 (17pter-p12) and consists of eight
Schematic representation of SHBG gene. Exons are represented by the blue boxes.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
SHBG (sex hormone-binding globulin)
Fortunati N, Catalano MG
Linear structure of SHBG protein. Location of glycosylation sites is shown by red lines.
subsequently a specific intracellular pathway leading to
cross-talk with the estradiol-activated pathway, finally
inhibiting several effects of estradiol in breast cancer
cells, e.g. cell proliferation.
The Asp327Asn polymorphism of SHBG gene is
related to breast cancer risk. Cui et al. observed a
polymorphism with reduced breast cancer risk and
Becchis et al. reported a significantly higher frequency
of the polymorphism in postmenopausal patients with
ER-positive breast cancer than in ER-negative; more
recently Costantino and co-workers suggested a
protective role of this polymorphism since mutated
SHBG is more effective than wild type protein in
inhibiting estradiol-induced cell proliferation and antiapoptosis, and this is due to the fact that D327N SHBG
binds to MCF-7 cells to a greater extent than does wild
type protein.
SHBG is secreted by liver into the blood stream and it
is synthesized by testis germ cells; it also recognizes a
specific binding site located on membranes of sex
steroid target cells (e.g. breast, prostate).
SHBG binds and carries sex steroids, regulating their
biological active fraction; it also regulates sex steroid
effects in target cells by direct action.
Protein S, Gas6, laminin, agrin.
GAC-AAC; Asp-Asn327; reported in estrogendependent breast cancer.
(TAAAA)n promoter, n=6-11; n>8; reported in:
polycystic ovary syndrome; CAD in postmenopausal
women; reduced bone mineral density in men;
metabolic syndrome.
Prostate cancer
Patients with prostate cancer showed lower SHBG
levels than benign prostate hypertrophy patients and
Alternative splicing of SHBG gene is more pronounced
in LNCaP and MCF-7 cancer cell lines; at least six
independent transcripts each, resulting from alternative
splicing of exons 4, 5, 6, and/or 7 were described.
SHBG might be a significant multivariate predictor of
lymph node invasion in patients with prostate cancer.
The use of preoperative serum SHBG could help to
identify patients at risk of lymph node invasion.
Implicated in
Breast cancer
Human serum sex hormone-binding globulin (SHBG)
regulates the bioavailable fraction of circulating
estradiol that is known to be a critical factor in breast
cancer. In a case-controlled study within the European
Prospective Investigation into Cancer and Nutrition
(EPIC), SHBG levels in postmenopausal women who
developed breast cancer were confirmed to be
significantly lower compared with controls, while no
significant difference was observed in premenopausal
SHBG has a direct effect in breast cancer cells; it
interacts with membranes of these cells, initiates
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Type 2 diabetes mellitus
Epidemiological studies consistently show that
circulating SHBG levels are lower in type 2 diabetes
patients than in non-diabetic individuals.
Low circulating levels of SHBG are a strong predictor
of the risk of type 2 diabetes in women and men.
Carriers of a variant allele of the SHBG singlenucleotide polymorphism (SNP) rs6259 and carriers of
SHBG (sex hormone-binding globulin)
Fortunati N, Catalano MG
translocation breakpoints in a female patient with
hypomelanosis of Ito and choroid plexus papilloma. Eur J Hum
Genet. 1997 Mar-Apr;5(2):61-8
a rs6257 variant were associated with a risk of type 2
diabetes following their associated sex hormonebinding globulin levels.
Becchis M, Frairia R, Ferrera P, Fazzari A, Ondei S, Alfarano
A, Coluccia C, Biglia N, Sismondi P, Fortunati N. The
additionally glycosylated variant of human sex hormonebinding globulin (SHBG) is linked to estrogen-dependence of
breast cancer. Breast Cancer Res Treat. 1999 Mar;54(2):101-7
Insulin resistance and polycystic ovary
syndrome (PCOS)
SHBG concentrations are inversely associated with
insulin resistance, and in turn, with the risk of type 2
Women with polycystic ovary syndrome (PCOS)
present low SHBG levels that are negatively correlated
with body mass index and waist to hip ratio, and are,
furthermore, associated with insulin resistance.
Grishkovskaya I, Avvakumov GV, Sklenar G, Dales D,
Hammond GL, Muller YA. Crystal structure of human sex
hormone-binding globulin: steroid transport by a laminin G-like
domain. EMBO J. 2000 Feb 15;19(4):504-12
Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B,
Hammond GL. Human sex hormone-binding globulin variants
associated with hyperandrogenism and ovarian dysfunction. J
Clin Invest. 2002 Apr;109(7):973-81
Selva DM, Hogeveen KN, Seguchi K, Tekpetey F, Hammond
GL. A human sex hormone-binding globulin isoform
accumulates in the acrosome during spermatogenesis. J Biol
Chem. 2002 Nov 22;277(47):45291-8
An X;17 translocation breakpoint was characterized in
a 5-year-old female with hypomelanosis of Ito (HI)
who exhibits characteristic hypopigmented lesions,
psychomotor retardation, and choroid plexus
papilloma. A chromosome-17-specific DNA fragment
was isolated and used to identify cosmid clones
crossing the translocation from chromosome 17p13.
Exon trapping identified two known genes from
chromosome 17: FMR1L2 (the fragile X mental
retardation syndrome like protein 2) and SHBG (human
sex hormone-binding globulin). Mapping the FMR1L2
and SHBG genes showed that neither gene was
disrupted by the translocation.
Xita N, Tsatsoulis A, Chatzikyriakidou A, Georgiou I.
Association of the (TAAAA)n repeat polymorphism in the sex
hormone-binding globulin (SHBG) gene with polycystic ovary
syndrome and relation to SHBG serum levels. J Clin
Endocrinol Metab. 2003 Dec;88(12):5976-80
Catalano MG, Frairia R, Boccuzzi G, Fortunati N. Sex
hormone-binding globulin antagonizes the anti-apoptotic effect
of estradiol in breast cancer cells. Mol Cell Endocrinol. 2005
Jan 31;230(1-2):31-7
Cui Y, Shu XO, Cai Q, Jin F, Cheng JR, Cai H, Gao YT, Zheng
W. Association of breast cancer risk with a common functional
polymorphism (Asp327Asn) in the sex hormone-binding
globulin gene. Cancer Epidemiol Biomarkers Prev. 2005
Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C,
Secreto G, Amiano P, Bingham S, Boeing H, Bueno de
Mesquita HB, Chang-Claude J, Clavel-Chapelon F, Fournier A,
van Gils CH, Gonzalez CA, Gurrea AB, Critselis E, Khaw KT,
Krogh V, Lahmann PH, Nagel G, Olsen A, Onland-Moret NC,
Overvad K, Palli D, Panico S, Peeters P, Quirós JR, Roddam
A, Thiebaut A, Tjønneland A, Chirlaque MD, Trichopoulou A,
Trichopoulos D, Tumino R, Vineis P, Norat T, Ferrari P,
Slimani N, Riboli E. Serum sex steroids in premenopausal
women and breast cancer risk within the European Prospective
Investigation into Cancer and Nutrition (EPIC). J Natl Cancer
Inst. 2005 May 18;97(10):755-65
Siiteri PK, Murai JT, Hammond GL, Nisker JA, Raymoure WJ,
Kuhn RW. The serum transport of steroid hormones. Recent
Prog Horm Res. 1982;38:457-510
Westphal U. Steroid-protein interactions II. Monogr Endocrinol.
Porto CS, Musto NA, Bardin CW, Gunsalus GL. Binding of an
extracellular steroid-binding globulin to membranes and
soluble receptors from human breast cancer cells (MCF-7
cells). Endocrinology. 1992 May;130(5):2931-6
Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C,
Dossus L, Lukanova A, Bingham S, Khaw KT, Allen NE,
Bueno-de-Mesquita HB, van Gils CH, Grobbee D, Boeing H,
Lahmann PH, Nagel G, Chang-Claude J, Clavel-Chapelon F,
Fournier A, Thiébaut A, González CA, Quirós JR, Tormo MJ,
Ardanaz E, Amiano P, Krogh V, Palli D, Panico S, Tumino R,
Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D,
Ferrari P, Norat T, Saracci R, Riboli E. Postmenopausal serum
androgens, oestrogens and breast cancer risk: the European
prospective investigation into cancer and nutrition. Endocr
Relat Cancer. 2005 Dec;12(4):1071-82
Fortunati N, Fissore F, Fazzari A, Berta L, Benedusi-Pagliano
E, Frairia R. Biological relevance of the interaction between
sex steroid binding protein and its specific receptor of MCF-7
cells: effect on the estradiol-induced cell proliferation. J Steroid
Biochem Mol Biol. 1993 May;45(5):435-44
Fortunati N, Fissore F, Fazzari A, Becchis M, Comba A,
Catalano MG, Berta L, Frairia R. Sex steroid binding protein
exerts a negative control on estradiol action in MCF-7 cells
(human breast cancer) through cyclic adenosine 3',5'monophosphate and protein kinase A. Endocrinology. 1996
Eriksson AL, Lorentzon M, Mellström D, Vandenput L,
Swanson C, Andersson N, Hammond GL, Jakobsson J, Rane
A, Orwoll ES, Ljunggren O, Johnell O, Labrie F, Windahl SH,
Ohlsson C. SHBG gene promoter polymorphisms in men are
associated with serum sex hormone-binding globulin,
androgen and androgen metabolite levels, and hip bone
mineral density. J
Clin Endocrinol Metab. 2006
Joseph DR. Sequence and functional relationships between
androgen-binding protein/sex hormone-binding globulin and its
homologs protein S, Gas6, laminin, and agrin. Steroids. 1997
Zajac V, Kirchhoff T, Levy ER, Horsley SW, Miller A, SteichenGersdorf E, Monaco AP. Characterisation of X;17(q12;p13)
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
SHBG (sex hormone-binding globulin)
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Alevizaki M, Saltiki K, Xita N, Cimponeriu A, Stamatelopoulos
K, Mantzou E, Doukas C, Georgiou I. The importance of the
(TAAAA)n alleles at the SHBG gene promoter for the severity
of coronary artery disease in postmenopausal women.
Menopause. 2008 May-Jun;15(3):461-8
novel ligands and function. Mol Cell Endocrinol. 2010 Mar
Fortunati N, Catalano MG, Boccuzzi G, Frairia R. Sex
Hormone-Binding Globulin (SHBG), estradiol and breast
cancer. Mol Cell Endocrinol. 2010 Mar 5;316(1):86-92
Costantino L, Catalano MG, Frairia R, Carmazzi CM, Barbero
M, Coluccia C, Donadio M, Genta F, Drogo M, Boccuzzi G,
Fortunati N. Molecular mechanisms of the D327N SHBG
protective role on breast cancer development after estrogen
exposure. Breast Cancer Res Treat. 2009 Apr;114(3):449-56
Grosman H, Fabre B, Mesch V, Lopez MA, Schreier L, Mazza
O, Berg G. Lipoproteins, sex hormones and inflammatory
markers in association with prostate cancer. Aging Male. 2010
Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N,
Buring JE, Gaziano JM, Liu S. Sex hormone-binding globulin
and risk of type 2 diabetes in women and men. N Engl J Med.
2009 Sep 17;361(12):1152-63
Pugeat M, Nader N, Hogeveen K, Raverot G, Déchaud H,
Grenot C. Sex hormone-binding globulin gene expression in
the liver: drugs and the metabolic syndrome. Mol Cell
Endocrinol. 2010 Mar 5;316(1):53-9
Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn
SM. Human sex hormone-binding globulin gene expressionmultiple promoters and complex alternative splicing. BMC Mol
Biol. 2009 May 5;10:37
Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA.
Interactions of sex hormone-binding globulin with target cells.
Mol Cell Endocrinol. 2010 Mar 5;316(1):79-85
Xita N, Milionis HJ, Galidi A, Lazaros L, Katsoulis K, Elisaf MS,
Georgiou I, Tsatsoulis A. The (TAAAA)n polymorphism of the
SHBG gene in men with the metabolic syndrome. Exp Clin
Endocrinol Diabetes. 2011 Feb;119(2):126-8
Salonia A, Briganti A, Gallina A, Karakiewicz P, Shariat S,
Freschi M, Zanni G, Capitanio U, Bosi E, Rigatti P, Montorsi F.
Sex hormone-binding globulin: a novel marker for nodal
metastases prediction in prostate cancer patients undergoing
extended pelvic lymph node dissection. Urology. 2009
This article should be referenced as such:
Fortunati N, Catalano MG. SHBG (sex hormone-binding
globulin). Atlas Genet Cytogenet Oncol Haematol. 2011;
Avvakumov GV, Cherkasov A, Muller YA, Hammond GL.
Structural analyses of sex hormone-binding globulin reveal
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Mini Review
SLC39A6 (solute carrier family 39 (zinc
transporter), member 6)
Shin Hamada, Kennichi Satoh, Tooru Shimosegawa
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai city, Miyagi, Japan
(SH, KS, TS)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC39A6ID44189ch18q12.html
DOI: 10.4267/2042/45984
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
prostate, placenta, kidney, pituitary and corpus
callosum (Taylor et al., 2003). Elevated expressions in
malignancy of epithelial origin, such as pancreatic
cancer are reported (Unno et al., 2009). Its expression
is also reported in the second heart field progenitors,
which contribute to the cardiac outflow tract formation
(Barth et al., 2010).
Other names: LIV-1; ZIP6
HGNC (Hugo): SLC39A6
Location: 18q12.2
Located at cell membrane.
SLC39A6 gene contains ten exons. The length of this
gene is 20864 bases. This gene encodes two transcript
variants. Isoform 1 utilizes all of ten exons, while
isoform 2 lacks exon 2 and 10. Consequently, isoform
2 gives rise to shorter protein than isoform 1.
According to the structural similarity, may act as a zinc
influx transporter. Accelerates nuclear translocation of
the transcriptional factor Snail, the inducer of
epithelial-mesenchymal transition (EMT), as a
downstream target of STAT3 pathway in the zebrafish
gastrula organizer (Yamashita et al., 2004). SLC39A6
is induced by histone deacetylase inhibitors' treatment
in cancer cells, and involved in the apoptosis induction
by histone deacetylase inhibitors (Ma et al., 2009).
Isoform 1; 3637 bases mRNA; 2265 bases of coding
region. Isoform 2; 1681 bases mRNA; 1299 bases of
coding region.
None reported.
Mus musculus Slc39a6; Rattus norvegicus Slc39a6;
Bos Taurus SLC39A6; Pan troglodytes SLC39A6.
SLC39A6 encodes the zinc transporter ZIP6. Isoform 1
consists of 755 amino acids; Isoform 2 consists of 433
amino acids. The molecular weight of ZIP6 is 85 kDa.
SLC39A6 is a multi-pass membrane protein and
showing the characteristics of zinc transporter (Taylor
and Nicholson, 2003).
No disease related mutations are reported.
Implicated in
Pancreatic cancer
SLC39A6 is highly expressed in pancreatic cancer cell
ZIP6 is highly expressed in normal breast tissue,
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
SLC39A6 (solute carrier family 39 (zinc transporter), member 6)
Hamada S, et al.
line and pancreatic cancer tissue. Knockdown of
SLC39A6 expression in the human pancreatic cancer
cell line Panc-1 resulted in the reduced tumorigenicity
in nude mice and acquisition of epithelial phenotype,
such as increased E-cadherin expression (Unno et al.,
Taylor KM, Nicholson RI. The LZT proteins; the LIV-1
subfamily of zinc transporters. Biochim Biophys Acta. 2003 Apr
Breast cancer
Kasper G, Weiser AA, Rump A, Sparbier K, Dahl E, Hartmann
A, Wild P, Schwidetzky U, Castaños-Vélez E, Lehmann K.
Expression levels of the putative zinc transporter LIV-1 are
associated with a better outcome of breast cancer patients. Int
J Cancer. 2005 Dec 20;117(6):961-73
Yamashita S, Miyagi C, Fukada T, Kagara N, Che YS, Hirano
T. Zinc transporter LIVI controls epithelial-mesenchymal
transition in zebrafish gastrula organizer. Nature. 2004 May
SLC39A6 regulates the expression level of E-cadherin,
a epithelial marker in human breast cancer cell line
MCF-7 (Shen et al., 2009). Higher expression of
SLC39A6 in breast cancer tissue correlates with the
better outcome of breast cancer patients (Kasper et al.,
SLC39A6 is induced upon the treatment of breast
cancer and cervical cancer cell lines by the histone
deacetylase inhibitor, TSA. Knockdown of SLC39A6
resulted in the decreased cell death of TSA-treated
cancer cells, which indicates the requirement of
SLC39A6 during the apoptosis induction (Ma et al.,
Zhao L, Chen W, Taylor KM, Cai B, Li X. LIV-1 suppression
inhibits HeLa cell invasion by targeting ERK1/2-Snail/Slug
pathway. Biochem Biophys Res Commun. 2007 Nov
Ma X, Ma Q, Liu J, Tian Y, Wang B, Taylor KM, Wu P, Wang
D, Xu G, Meng L, Wang S, Ma D, Zhou J. Identification of
LIV1, a putative zinc transporter gene responsible for HDACiinduced apoptosis, using a functional gene screen approach.
Mol Cancer Ther. 2009 Nov;8(11):3108-16
Shen H, Qin H, Guo J. Concordant correlation of LIV-1 and Ecadherin expression in human breast cancer cell MCF-7. Mol
Biol Rep. 2009 Apr;36(4):653-9
Cervical cancer
Unno J, Satoh K, Hirota M, Kanno A, Hamada S, Ito H,
Masamune A, Tsukamoto N, Motoi F, Egawa S, Unno M, Horii
A, Shimosegawa T. LIV-1 enhances the aggressive phenotype
through the induction of epithelial to mesenchymal transition in
human pancreatic carcinoma cells. Int J Oncol. 2009
SLC39A6 is involved in the cellular invasion of HeLa
cells by controlling the ERK-mediated Snail and Slug
expression (Zhao et al., 2007).
Barth JL, Clark CD, Fresco VM, Knoll EP, Lee B, Argraves
WS, Lee KH. Jarid2 is among a set of genes differentially
regulated by Nkx2.5 during outflow tract morphogenesis. Dev
Dyn. 2010 Jul;239(7):2024-33
Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI.
Structure-function analysis of LIV-1, the breast cancerassociated protein that belongs to a new subfamily of zinc
transporters. Biochem J. 2003 Oct 1;375(Pt 1):51-9
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
This article should be referenced as such:
Hamada S, Satoh K, Shimosegawa T. SLC39A6 (solute carrier
family 39 (zinc transporter), member 6). Atlas Genet Cytogenet
Oncol Haematol. 2011; 15(7):586-587.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
TRPV1 (transient receptor potential cation
channel, subfamily V, member 1)
Massimo Nabissi, Giorgio Santoni
School of Pharmacy, Section of Experimental Medicine, University of Camerino, 62032 Camerino (MC),
Italy (MN, GS)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/TRPV1ID50368ch17p13.html
DOI: 10.4267/2042/45985
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
including a coding region and a 5' and a 3' non-coding
Other names: DKFZp434K0220; VR1
HGNC (Hugo): TRPV1
Location: 17p13.2
Local order: Colocalized with another transient
receptor potential channel gene (TRPV3).
There are four transcript variants encoding the same
protein, but with different segments in the 5' UTR
(var.1, var.2, var.3, var.4) and one alternative splice
variant lacking exon 7 (TRPV1b). TRPV1 gene
transcription was demonstrated in different cells and
tissues, but no data are available on TRPV1 variant
expression profiles.
TRPV1 gene consists of 17 exons and 17 introns
Schematic representation of human TRPV1 gene and neighbouring family gene.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
TRPV1 (transient receptor potential cation channel, subfamily V, member 1)
Nabissi M, Santoni G
Genomic structure of human TRPV1. In gene the exon number and relative length in bp are shown. In cDNA, the coding region is
shown by open bars. The non-traslated regions are shown by black filled bars. The different 5' UTR TRPV1 splice variants with relative 5'
UTR length are described in table. The TRPV1 splice variant (TRPV1b) is described in table. Hyperlink to FASTA nucleotide sequences
of all TRPV1 cDNAs are inserted.
Schematic representation of TRPV1 protein. Double broken line is representative of cellular membrane, transmembrane domains are
numbered. Red spot indicates the position of the three ankyrin repeat domains and a representative image of the structural ankyrin
repeat unit containing two antiparallel helices and a beta-hairpin, with repeats that are stacked in a superhelical arrangement is shows in
black box (from NCBI Conserved Domains), N and C (-terminal domains). SP (signal peptide region), ANK (ankyrin regions, red box), TM
(trasmembrane domain, grey box), ED (extracellular domain, blue box), CD (cytoplasmatic domain, orange box), PFD (pore forming
domain, green box). An association domain (AD) in 685-713 region has been found necessary for self-association.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
TRPV1 (transient receptor potential cation channel, subfamily V, member 1)
Nabissi M, Santoni G
TRPV1 has also been found in different brain region,
such as in dopaminergic neurones of the substantia
nigra, hippocampal pyramidal neurones, hypothalamic
neurones, neurones in the locus coeruleus, and in
various layers of the cortex as in small to medium
diameter primary afferent fibres, In non-neuronal cells
TRPV1 has been found in keratinocytes, bladder
urothelium, smooth muscle, liver, polymorphonuclear
granulocytes, pancreatic beta-cells, endothelial cells,
lymphocytes, thymocytes and macrophages. Moreover
by expression profile studies more cells and tissues has
been analyzed for TRPV1 expression.
The canonical form comprises 839 aa (MW~96 kDa)
and is composed of six transmembrane spanning
domains and a pore forming region between
transmembrane domains 5 and 6. The N-terminal and
C-terminal tails are in cytoplasmatic side. Three N
terminal ankyrin (ANK) repeats are present in Nterminal tail. The variant form TRPV1b is identical to
TRPV1 except for the partial deletion of the third
ankyrin repeat domain and adjoining polypeptide
sequence. Aminoacid modifications has been found
(according to Swiss-Prot) in different residues (Table
1). The N-terminal intracellular domain appears to play
a pivotal role in intracellular activation of TRPV1, in
fact, by mutagenesis analysis a loss of sensitivity to
capsaicin has been found related to residue Tyr-511
(Gavva et al., 2004). Modification of a single Nterminal cysteine altered activation of TRPV1 by
pungent compounds ranging from onions to garlic
(Salazar et al., 2008). The N-terminal intracellular
domain also interacts with adjacent modulatory
proteins and with the C-terminal intracellular domain.
In the closed state, the N-terminal domain is likely
exposed to the binding of ATP and a C-terminal region
residues interact with PIP-2, facilitating channel
activation. In contrast, a desensitized state may be
promoted through the interaction of the N- and Cterminal domains through modulatory action involving
calcium-calmodulin interacting regions. Moreover, the
ankyrin repeat domains residing within the N-terminal
intracellular domain forming a region of three repeats
spanning amino acids participating in protein-protein
(subunit) interactions (Bork, 1993). The presence of
concave binding surfaces for ATP within the ANK
regions suggest a role of ANKs in modulating channel
activation and function (Lishko et al., 2007).
Residue modification
TRPV1 is expressed in discrete spots in the plasma
membrane and cytosol of different cell types (e.g.
urothelial cells). Moreover, dorsal root ganglion (DRG)
neurons express ectopic but functional TRPV1
channels in the endoplasmic reticulum (ER)
TRPV1 agonists. TRPV1 is a non-selective cation
channel, belonging to the superfamily of TRP channels.
TRPV1 agonists are of exogenous and endogenous
origins. Exogenous agonist are of natural, semisynthetic and synthetic origin. The natural compounds
include dietary derived compounds as: capsaicinoids,
capsinoids, piperine, allicin, alliin, eugenol and
gingerol or non dietary plant compounds as
resiniferatoxin, ∆9-tetrahydrocannabinol, cannabidiol
and venom from animal origins (Pertwee, 2005; Vriens
et al., 2009). Moreover, other environmental irritants as
well as noxious heat (> 43-45 °C) has been found to act
as TRPV1 agonist. The existence of endogenous
vanilloid agonists, a class of compounds referred to as
endovanilloids, as TRPV1 channels modulators as been
also investigated. TRPV1 has been found to be
Narachidonylethanolamine (AEA, anandamide), Narachidonoyldopamine
Noleoylethanolamine (OLEA), N-arachidonolylserine,
and various N-acyltaurines and N-acylsalsolinols.
Various lipids from the fatty acid pool have also been
identified as TRPV1 activators, as inflammatory
compounds such as bradykinin, products of the
lipoxygenases (12-HPETE and leukotriene B4, 5(S)HPETE (hydroperoxyeicosatetranoic acid) and/or
leukotriene B4) (Van Der Stelt and Di Marzo, 2004).
Also nerve growth factor (NGF), an inflammatory
mediator is known to activate/sensitize TRPV1 through
TrkA receptor,
phosphoinositide-3- kinase (PI3K) and mitogen
activated protein kinase (MAPK) signaling pathways
(Chuang et al., 2001).
Table 1. Aminoacid number and type of putative
modification in TRPV1 protein.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
TRPV1 (transient receptor potential cation channel, subfamily V, member 1)
phosphorylation of TRPV1 by PKC has been located at
Ser502 and Ser800 (Bhave et al., 2003).
IGF-I (insulin growth factor I). Insulin and IGF-I
increase translocation of TRPV1 to the plasma
membrane via activation of IGF receptors, which, in
turn, induced PI(3) kinase and PKC activation (Van
Buren et al., 2005).
CdK5 (cyclin-dependent kinase 5). CdK5 can directly
phosphorylate Thr407 in TRPV1, while inhibition of
CdK5 activity decreases TRPV1 function and Ca2+
influx (Pareek et al., 2007).
TRPV1 antagonists. Natural TRPV1 antagonists are
actually restricted to two plant derived compounds, the
thapsigargin that is the irritant principle of Thapsia
garganica L. and yohimbine, an indole alkaloid from
the tree Corynanthe yohimbe K. The endogenous
TRPV1 antagonists discovery up to now are
dynorphins, adenosine, various dietary omega-3 fatty
acids like eicosapentaenoic and linolenic acids, the
endogenous fatty acid amide hydrolase (FAAH) and
different polyamines as putrescine, spermidine, and
spermine permeate. The most active non-natural
compound that act as TRPV1 antagonist are
capsazepine and 5-iodoRTX.
Ligand-binding site. By comparative analysis of the
primary structure of theTRPV1 and by mutagenesis
studies has been revealed a critical role for Tyr511 and
Ser512 (between the second intracellular loop and
TM3), confirming that the vanilloid binding site is
located intracellulary, moreover a third critical residue
in the putative TM4 segment (Leu547) was indicated as
relevant in ligand-binding.
The effect of extracellular protons (as Ca2+), acts
primarily by increasing channel opening, rather than
interacting directly with the vanilloid binding site.
86% identity with Mus musculus TRPV1, 85% with
Rattus norvegicus TRPV1, 65% with human TRPV3.
Implicated in
Bone cancer
Bone cancer leads to osteoclast activation, which
promotes acidosis and consequently TRPV1 activation
in sensory fibers. The correlation between TRPV1
activation and bone cancer pain was demonstrated by
the evaluation of the RTX analgesic effects of
pharmacological blockade of TRPV1. So, TRPV1
activation plays a critical role in the generation of bone
cancer pain, and bone cancer increases TRPV1
expression within distinct subpopulation of DRG
neurons (Niiyama et al., 2007).
EGFR (epidermal growth factor receptor). TRPV1
has been found to down-regulate epidermal growth
factor receptor (EGFR) expression. Interaction of
TRPV1 terminal cytosolic domain with EGFR induces
EGFR ubiquitination and degradation. Moreover, by
transfection of TRPV1 in HEK293 cells a decreased
EGFR protein expression was observed (Bode et al.,
Fas/CD95. Activation of TRPV1 with capsaicin, in
low-grade urothelial cancer cells, induced a TRPV1dependent G0/G1 cell cycle arrest and apoptosis by
inducing transcription of pro-apoptotic genes
Fas/CD95, Bcl-2 and caspases, and by activation of the
DNA damage response pathway. Moreover, CPS
stimulation induced a TRPV1-dependent redistribution
and its clustering with Fas/CD95. In addition, an
involvement of capsaicin in activation of the ATM
kinase/p53 pathways was found (Amantini et al., 2009).
PKA (protein kinase A). TRPV1 are found
phosphorylated by PKA in the amino terminus Ser116
and Thr370 and involved in desensitisation while
phosphorylation of Ser116 by PKA inhibits
dephosphorylation of TRPV1 caused by capsaicin
exposure (Mohapatra and Nau, 2003).
PKC (protein kinase C). Several inflammatory
mediators, like ATP, bradykinin, prostaglandins and
trypsin or tryptase activated Gq coupled receptors and
induced PKC-dependent phosphorylation of TRPV1
(Moriyama et al., 2003).
PKC dependent phosphorylation of TRPV1 potentiates
capsaicin- or proton-evoked responses and reduces
temperature 'threshold' for TRPV1 activation. Direct
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Nabissi M, Santoni G
Skin cancer
TRPV1 is highly and specifically expressed in both
premalignant (leukoplasia) and low-grade papillary
skin carcinoma, whereas its expression is substantially
absent in invasive carcinoma. Recently, TRPV1 has
been found to exhibit tumor suppressive activity on
skin carcinogenesis in mice because of its ability to
down-regulate epidermal growth factor receptor
(EGFR) expression; conversely, loss of TRPV1
expression resulted in marked increase in papilloma
development. TRPV1 by interacting with EGFR
through its terminal cytosolic domain, facilitates Cblmediated EGFR ubiquitination and subsequently its
degradation via the lysosomal pathway. In addition,
ectopic TRPV1 expression in HEK293 cells resulted in
decreased EGFR protein expression, and higher EGFR
levels were observed in the skin of TRPV1 deficient
mice (TRPV1-/-) as compared to wild-type control
animals (Marincsák et al., 2009; Hwang et al., 2010).
Urothelial cancer
Changes in the TRPV1 expression occur during the
development of human urothelial cancer. Thus,
transitional cell carcinoma (TCC) show a progressive
decrease in TRPV1 expression as the tumor stage
increases. Treatment of low-grade RT4 urothelial
TRPV1 (transient receptor potential cation channel, subfamily V, member 1)
Nabissi M, Santoni G
However, resinferatoxin (RTX), a potent TRPV1
agonist, induced apoptosis by targeting mitochondrial
respiration, and decreased pancreatic cancer cell
growth in a TRPV1-independent manner (Hartel et al.,
cancer cells with a specific TRPV1 agonist, capsaicin
(CPS) induced a TRPV1-dependent G0/G1 cell cycle
arrest and apoptosis. These events were associated with
the transcription of pro-apoptotic genes including
Fas/CD95, Bcl-2 and caspases, and with the activation
of the DNA damage response pathway. Moreover,
stimulation of TRPV1 by CPS significantly increased
Fas/CD95 protein expression and more importantly
induced a TRPV1-dependent redistribution and
clustering of Fas/CD95 that co-localized with the
vanilloid receptor, suggesting that Fas/CD95 ligandindependent TRPV1-mediated Fas/CD95 clustering
results in death-inducing signaling complex formation
and triggering of apoptotic signaling through both the
extrinsic and intrinsic mitochondrial-dependent
pathways. Moreover, we found that CPS activates the
ATM kinase involved in p53 Ser15, Ser20 and Ser392
phosphorylation. ATM activation is involved in
Fas/CD95 up-regulation and co-clustering with TRPV1
as well as in urothelial cancer cell growth and
apoptosis. Finally, the role of TRPV1 mRNA downregulation as a negative prognostic factor in patients
with bladder cancer has been reported. By univariate
analysis, cumulative survival curves calculated
according to the Kaplan-Meier method for the canonic
prognostic parameters such as tumor grade and high
stage (pT4), lymph nodes and distant diagnosed
metastasis, reached significance. Notably, the reduction
of TRPV1 mRNA expression was associated with a
shorter survival of urothelial cancer patients (P=0.008).
On multivariate Cox regression analysis, TRPV1
mRNA expression retained its significance as an
independent risk factor, also in a subgroup of patients
without diagnosed metastasis (M0). These findings
may be particularly important in the stratification of
urothelial cancer patients with higher risk of tumor
progression for the choice of therapy options (Amantini
et al., 2009; Kalogris et al., 2010).
Cervical cancer
TRPV1 expression has been reported in human cervical
cancer cell lines and tissues, and the endocannabinod
anandamide (AEA) induced TRPV1-dependent tumor
cell apoptosis. In addition, TRPV1 stimulation
completely reverted the cannabidiol (CBD)-mediated
inhibitory effect on human cervical cancer cell invasion
by blocking CBD-induced increase of TIMP-1, a MMP
inhibitor both at mRNA and protein levels, and
ERK1/ERK2 and p38MAPK activation (Contassot et
al., 2004a; Contassot et al., 2004b).
Prostate cancer
A functional TRPV1 channel is expressed in human
prostate cancer cells (PC3 and LNCaP) and in prostate
hyperplasic tissue. Moreover, increased TRPV1 mRNA
and protein expression was found in human prostate
cancer tissues as compared to prostate hyperplastic and
healthy donors, and this increase correlated with degree
of malignancy. CPS induced a growth inhibition and
apoptosis of PC3 prostate cancer cells, but in TRPV1independent manner, through ROS generation,
dissipation and caspase-3 activation. Moreover, CPS or
the specific antagonist capsazepin inhibited tumor
growth in vivo, in a xenograft human prostate PC3
cancer model. By contrast, in androgen-responsive
LNCaP prostate cancer cells, CPS was found to
stimulate TRPV1-dependent cell proliferation. CPS
effects were attributable to decreased ceramide levels
and to activation of Akt/PKB and ERK pathways, and
were associated with increased androgen receptor
expression (Sanchez et al., 2005).
TRPV1 mRNA and protein expression was evidenced
in normal astrocytes and glioma cells and tissues. Its
expression inversely correlated with glioma grading,
with a marked loss of TRPV1 expression in the
majority of grade IV glioblastoma tissues. TRPV1
activation by CPS induced apoptosis of U373MG
glioma cells, and involved rise of Ca2+ influx,
p38MAPK activation, mitochondrial permeability
transmembrane pore opening and transmembrane
potential dissipation, and caspase-3 activation
(Amantini et al., 2007).
TRPV1 expression has been also demonstrated on the
plasma membrane of rat pheochromocytoma-derived
PC12 cell line. PC12 stimulation by CPS resulted in
TRPV1-dependent nitric oxide synthase (iNOS)
expression. CPS exposure triggered Ca2+ influx, which
in turn enhanced mitochondrial Ca2+ accumulation and
promoted NO generation, events that have been
associated with tumor progression (Qiao et al., 2004).
Pancreatic cancer
Human pancreatic cancer, significantly expressed
increased levels of TRPV1 mRNA and protein.
Hepatocarcinoma patients show high TRPV1
expression that is associated with increased disease-free
survival (Miao et al., 2008).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
TRPV1 (transient receptor potential cation channel, subfamily V, member 1)
expressing afferent nerve fibers (Blumensohn et al.,
Digestive tract diseases
TRPV1 sensitive sensory nerves are densely distributed
in the gastrointestinal system, and one of the important
roles of these nerves is the preservation of the tissues
integrity from the exposed to aggressive compounds,
such as protons and activated enzymes. Moreover,
activation of TRPV1 either by endogenous or by
exogenous agonists exerts hypotensive effects or
protective effects against gastrointestinal injury.
Therefore, TRPV1 is not only a prime target for the
pharmacological control of pain but also a useful target
for drug development to treat various gastrointestinal
diseases. The function of TRPV1 visceral sensitivity
and hypersensitivity tends to be well established. It was
shown the involvement of TRPV1 in the regulation of
gastrointestinal motility and absorption, visceral
sensation and visceral hypersensitivity (Holzer, 2010).
Cardiovascular diseases
TRPV1 is expressed in cardiac spinal sympathetic
sensory fibers. During cardiac ischemia these fibers are
essential for the sympathoexcitatory reflex, which is
associated with increased blood pressure and chest
pain. Acidosis TRPV1 activation and ischemia
provides the organism with a mechanism, which relays
painful information to the brain. Conversely, the
release substance P (SP), neurokinin A (NKA) and
CGRP by the nerve fiber itself has beneficial effects,
which helping to reduce the effects of ischemia and
acidosis. Some data indicated that spinal cord
stimulation (SCS) used to improve peripheral blood
flow in selected populations of patients with ischemia
is mediated via VR-1 containing sensory fibers.
Treatment of patients with the TRPV1 agonist RTX
result in a SCS-induced vasodilation indicating a
cardioprotective role for TRPV1 (Wu et al., 2006).
Respiratory system diseases
TRPV1 is expressed on vagal afferent C fibers in the
lungs and may be activated by intense heat, acidic
arachidonic acid, capsaicin and ROS.The role of
TRPV1 in respiratory system is correlated to date
indicating that acidic solutions as other TRPV1inducing stimuli lead to C-fiber-mediated respiratory
reflexes and activation of these fibers leads to
bronchoconstriction, mucus secretion, bradycardia and
hypotension, in addition to cough and airway irritation
(Taylor-Clark and Undem, 2006).
A fundamental role for insulin responsive TRPV1+ in
pancreatic sensory neurons in controlling islet
inflammation and insulin resistance function and
diabetes pathoetiology has been demonstrated. Infact,
eliminating these neurons in diabetes-prone NOD mice
prevents insulitis and diabetes. In type 2 diabetes
administration of capsaicin and RTX which desensitize
TRPV1 result in improved glucose tolerance through
enhancement of insulin secretion and decreased plasma
insulin levels. So ablation of TRPV1-expressing
neurons which innervate the pancreas through neonatal
capsaicin treatment prevents the insulitis and pancreatic
beta-cell destruction that normally occurs in these
animals (Gram et al., 2007; Razavi et al., 2006).
Bladder diseases
The role of TRPV1 in overactive (irritable) bladder
disease has been shown in TRPV1 knockout mice
where differences in their response to bladder injury
when compared to their wild-type counterparts. TRPV1
knockout mice didn't develop bladder overactivity
during acute bladder inflammation, suggesting a role
for TRPV1 in bladder inflammatory states. Moreover,
in patients diagnosed with neurogenic detrusor
overactivity (NDO), higher levels of TRPV1
immunoreactivity in the urothelium and in the number
of nerve fibers were found, compared to control
(Apostolidis et al., 2005).
TRPV1 is expressed on the "pruriceptor subpopulation"
of mechano insensitive fibers and the itch-selective
sensory afferents respond to capsaicin.
Itch sensation can be modulate by changing skin
temperature and pH, to common TRPV1 activator
stimuli. Therefore, TRPV1 may function as a 'central
integrator' molecule in the itch pathway (Yosipovitch et
al., 2005; Ghilardi et al., 2005).
Diseases of the basal ganglia
TRPV1 plays a role in dopaminergic mechanisms
associated with schizophrenia and Parkinson's disease.
Exposure of mesencephalic dopaminergic neurons to
the TRPV1 agonist capsaicin triggers cell death, while
exposure to TRPV1 antagonists prevents these effects.
In addition, schizophrenic patients tend to display
reduced pain sensitivity and a diminished skin flare
response to niacin, suggesting a defects in TRPV1-
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cation channel, subfamily V, member 1). Atlas Genet
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Nabissi M, Santoni G
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Mini Review
WRAP53 (WD repeat containing, antisense to
Marianne Farnebo
Karolinska Institutet, Cancer Center Karolinska (CCK) R8 :04, 17176 Stockholm, Sweden (MF)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/WRAP53ID50705ch17p13.html
DOI: 10.4267/2042/45986
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Other names: FLJ10385; TCAB1; WDR79
HGNC (Hugo): WRAP53
Location: 17p13.1
548 amino acids; 75 kDa protein; contains from N-term
to C-term, a proline-rich region (aa 8-57), a WD40
domain, 5 repeats (160-441), and a glycin-rich region
Widely expressed, overexpressed in cancer.
The WRAP53 gene encompasses 16 kb of DNA; 13
exons (three non-coding alternative start exons: exon
1alpha, 1beta and 1gamma. Exon 1alpha directly
overlaps the first exon of TP53 in an antisense fashion
by up to 227 base pairs (bp), depending on transcription
start site (TSS) usage. Exon 1gamma of WRAP53 is
located in the first intron of TP53 overlapping the
previously identified transcript Hp53int1 in an
antisense fashion.
Cytoplasm and nucleus (enriched in Cajal bodies).
Essential for Cajal body formation and maintenance.
Targets the SMN complex, scaRNAs and telomerase
enzyme (via TERC) to Cajal bodies. Inhibition of
WRAP53 triggers mitochondrial-dependent apoptosis
specifically in cancer cells.
At least 17 splice variants. 1.9 kb mRNA; 1647 bp
open reading frame.
Regulatory antisense RNA
Expression: widely expressed at low levels.
Localisation: cytoplasm and nucleus.
Function: regulates p53 mRNA levels by interacting
with the 5'UTR of p53 mRNA.
Homology: conserved in mouse.
Diseases implication currently not analysed.
Highly-conserved in mammals, the WD40 domain is
conserved from human to fly.
Single nucleotide polymorphisms (SNPs) in women
with breast cancer (see below).
Not known.
Not reported.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
WRAP53 (WD repeat containing, antisense to TP53)
Farnebo M
Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C,
Wiman KG, Farnebo M. Wrap53, a natural p53 antisense
transcript required for p53 induction upon DNA damage. Mol
Cell. 2009 Feb 27;33(4):462-71
Not reported.
Implicated in
Schildkraut JM, Goode EL, Clyde MA, Iversen ES, Moorman
PG, Berchuck A, Marks JR, Lissowska J, Brinton L, Peplonska
B, Cunningham JM, Vierkant RA, Rider DN, Chenevix-Trench
G, Webb PM, Beesley J, Chen X, Phelan C, Sutphen R,
Sellers TA, Pearce L, Wu AH, Van Den Berg D, Conti D, Elund
CK, Anderson R, Goodman MT, Lurie G, Carney ME,
Thompson PJ, Gayther SA, Ramus SJ, Jacobs I, Krüger Kjaer
S, Hogdall E, Blaakaer J, Hogdall C, Easton DF, Song H,
Pharoah PD, Whittemore AS, McGuire V, Quaye L, AntonCulver H, Ziogas A, Terry KL, Cramer DW, Hankinson SE,
Tworoger SS, Calingaert B, Chanock S, Sherman M, GarciaClosas M. Single nucleotide polymorphisms in the TP53 region
and susceptibility to invasive epithelial ovarian cancer. Cancer
Res. 2009 Mar 15;69(6):2349-57
Breast and ovarian cancer
Single nucleotide polymorphisms (SNPs) in WRAP53
were found to be overrepresented in women with breast
cancer, in particular estrogen receptor negative breast
cancer. The same SNPs were also associated with
aggressive ovarian cancer. The SNPs are located in the
coding region of WRAP53 and results in the amino
acid change R68G.
Spinal muscular atrophy (SMA)
Tycowski KT, Shu MD, Kukoyi A, Steitz JA. A conserved
WD40 protein binds the Cajal body localization signal of
scaRNP particles. Mol Cell. 2009 Apr 10;34(1):47-57
WRAP53 targets the SMN complex to Cajal Bodies.
WRAP53 and SMN association is disrupted in SMA
patients suggesting a role of WRAP53 in SMA
Spinal muscular atrophy (SMA) is a common
neurodegenerative disorder caused by reduced levels of
SMN due to mutations or deletions of the SMN1 gene.
SMA is the leading genetic cause of infant mortality
worldwide, affecting approximately 1 in 6000 infants.
Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM,
Veenstra TD, Terns MP, Artandi SE. A human telomerase
holoenzyme protein required for Cajal body localization and
telomere synthesis. Science. 2009 Jan 30;323(5914):644-8
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This article should be referenced as such:
Farnebo M. WRAP53 (WD repeat containing, antisense to
TP53). Atlas Genet Cytogenet Oncol Haematol. 2011;
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
YBX1 (Y box binding protein 1)
Valentina Evdokimova, Alexey Sorokin
Institute of Protein Research, Pushchino, Moscow Region 142290, Russian Federation (VE, AS)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/YBX1ID46554ch1p34.html
DOI: 10.4267/2042/45987
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
boxes located between -1855 and -422 nucleotides
(relative to the start of exon 1) and several GT and GC
boxes. The gene also contains a large and highly
conserved CpG island at the immediate 5' promoter
region which extends to the first exon encoding 5' UTR
of YBX1 mRNA. The region between nucleotides -119
to +127 was shown to be essential for transcriptional
activity in the reporter assays (Makino et al., 1996).
YBX1 is constitutively expressed in multiple human
tissues and its expression can be further induced by the
E-box-binding transcription factors such as c-myc
(Uramoto et al., 2002), Twist (Shiota et al., 2008) and
Math2 (Ohashi et al., 2009).
Other names: BP-8; CSDA2; CSDB; DBPB; MDRNF1; MGC104858; MGC110976; MGC117250;
NSEP-1; NSEP1; YB-1; YB1
HGNC (Hugo): YBX1
Location: 1p34.2
Local order: The human YBX1 gene maps on 1p34
between the PPIH and the LOC100287607 loci.
The human YBX1 gene consists of 8 exons and 7
introns spanning a 19.2-kb genomic region. Intron
number 1 is phase 1 (between 1st and 2nd base of
codon). Introns number 2 and 6 are phase 2 (between
2nd and 3rd base of codon). Introns number 3, 4, 5 are
phase 0 (between codons). According to the SNP
polymorphism has been reported for the codons 30
(rs11558135), 237 (rs3887881), 251 (rs55676223), and
261 (rs3887879). The YBX1 promoter region contains
no typical TATA or CCAAT box, but has multiple E-
The main processed mRNA is 1514 bp. It encompasses
exons 1-8. The 70-amino acid cold-shock domain
(CSD) is encoded separately by exons 2-5. Four
additional splice variants in human were predicted
(Ensembl), two of which (YBX1-004 and YBX1-201)
preserve exons 2 and 3 coding for core elements of the
CSD, the RNP1 and RNP2 motifs, respectively. An
alternative transcript for ctYB-1, the YBX1
homologous gene in C. tentans, has been reported
(Nashchekin et al., 2007).
Genomic organization of YBX1. Box = exon (blue = 5'UTR, yellow = CDS, light red = 3'UTR). Line = intron.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
YBX1 (Y box binding protein 1)
Evdokimova V, Sorokin A
gene ID
nuclease sensitive
element binding
protein 1 pseudogene
after E88 (97%)
Y box binding protein
1 pseudogene 1
1496 bp
Y box binding protein
1 pseudogene 2
2 exons,
1 intron,
after E88 (93%)
1553 bp
820 bp
Y box binding protein
1 pseudogene
The C-terminal region of YB-1 is responsible for
sequence-nonspecific binding to DNA and RNA and
mediation of protein-protein interactions (Wolffe,
1994; Sommerville and Ladomery, 1996). An inverted
CCAAT-box found in HLA class II gene promoters, a
so-called Y-box, was originally determined as the YB-1
binding motif (Didier et al., 1988). Later studies have
concluded that YB-1 rather recognizes the DNA
structure than a defined nucleotide sequence, making
prediction of its target genes not feasible with
conventional in silico analyses (Swamynathan et al.,
1998). YB-1 is also capable of unwinding DNA and
mismatches, thereby promoting strand exchange and
formation of perfectly matched duplex structures
(Skabkin et al., 2001; Gaudreault et al., 2004).
The YBX1 gene encodes the Y-box protein 1 (YB-1)
which consists of 324 amino acid residues and has the
isoelectric point 10.3. Theoretical MW is 35924,
however YB-1 is known to migrate as a ~45-50 kDa
protein in SDS-polyacrylamide gels due to its
anomalous electrophoretic mobility. YB-1 belongs to
the family of multifunctional DNA/RNA binding
proteins that are highly conserved throughout evolution
and found in eukaryotes, prokaryotes and archaea. The
most conserved region in YB-1 is the 80 amino acid
CSD which exhibits >40% identity and >60%
similarity to the major E. coli cold shock protein CspA
(Matsumoto and Wolffe, 1998; Sommerville, 1999).
The CSD possesses RNP1 and RNP2-like consensus
motifs and is represented by a five-stranded beta-barrel
structure which creates a surface rich in aromatic and
basic amino acids that may act as a large nucleic acidbinding site (Wolffe et al., 1992; Wolffe, 1994). The
CSD has a preference for binding single-stranded
pyrimidine-rich sequences. The N-terminal AP domain
of YB-1 is similar to that found in several other
transcription factors and may thus be important for its
transcriptional activity. This region is also essential for
interaction with p53 and modulation of p53-mediated
transcription (Okamoto et al., 2000), and for
association with actin microfilaments and mRNA
compartmentalization (Ruzanov et al., 1999).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
with YBX1
According to Human Protein Atlas, YB-1 is variably
expressed in most normal human tissues. Its expression
is elevated in multiple cancer types (Kohno et al.,
Mostly cytosolic. Shuttles between cytoplasm and
nucleus. Localized in cytoplasmic stress granules and
processing bodies containing untranslated mRNAs
(Kedersha and Anderson, 2007). Nuclear translocation
is induced in response to various stresses, including
adenoviral infection (Holm et al., 2002), hyperthermia
(Stein et al., 2001), DNA damage (Kohno et al., 2003)
and activation of
YBX1 (Y box binding protein 1)
Evdokimova V, Sorokin A
Structural and functional organization of YB-1. YB-1 is composed by three domains: N-terminal Ala/Pro rich (AP) domain, cold shock
domain (CSD) and the C-terminal domain (CTD) containing clusters of positively and negatively charged amino acids. Indicated are
some known molecular partners of YB-1 and sites of their interactions (from Sorokin et al., 2005). The arrow indicates proteasomal
cleavage sites.
PI3K-Akt signaling (Sutherland et al., 2005).
2003). Overall, YB-1 is considered as an important
regulator of growth- and stress-associated genes.
mRNA translation and stability. YB-1 (p50) is
known as a major structural component of messenger
ribonucleoprotein particles (mRNPs) which exerts
positive or negative effects on translation, depending
on the amount bound to mRNA (Evdokimova and
Ovchinnikov, 1999). YB-1 regulates translational
activity of many growth- and differentiation-associated
mRNAs, including Snail1, and selectively protects
capped mRNAs against degradation (Evdokimova et
al., 2001; Evdokimova et al., 2006; Evdokimova et al.,
2009). YB-1 appears to play a role in stabilization of
short-lived mRNAs, including IL-2 (Chen et al., 2000),
GM-CSF (Capowski et al., 2001) and VEGF (Coles et
al., 2004).
DNA repair and stress response. YB-1 is involved in
base excision and mismatch repair pathways via
interaction with multiple DNA repair proteins including
glycosylase NEIL2, DNA polymerase beta and delta,
DNA ligase III, APE1, MSH2, Ku80, WRN,
endonuclease III, etc (Marenstein et al., 2001;
Gaudreault et al., 2004; Das et al., 2007). YB-1 also
directly binds and promotes separation of DNA strands
that contain mismatches or are modified by cisplatin
(Ise et al., 1999; Skabkin et al., 2001; Gaudreault et al.,
2004). Various stresses, including DNA damage,
adenovirus infection and hyperthermia, induce nuclear
The diverse biological functions of YB-1 appear to
arise from its broad nucleic acid binding properties.
YB-1 has been implicated in pre-mRNA splicing,
transcriptional regulation, mRNA translation and
stability as well as in chromatin remodelling, DNA
repair and environmental stress responses (Kohno et
al., 2003; Matsumoto and Bay, 2005).
Splicing. YB-1 regulates splice site selection via direct
binding to splicing recognition motifs in pre-mRNA,
including A/C-rich exon enhancers (Stickeler et al.,
2001) or via interaction with splicing factors from the
SR family (Li et al., 2003; Raffetseder et al., 2003).
Transcription. YB-1 is capable of binding to
promoters of many genes, many of which lack the Ybox, and either activates or represses transcription.
Among the genes activated by YB-1 are thymidine
kinase, proliferating cell nuclear antigen (PCNA),
cyclin A and cyclin B1, DNA topoisomerase II alpha,
gelatinase A, matrix metalloproteinase 2, multidrug
resistance 1 (MDR1), EGFR and protein tyrosine
phosphatase 1B. Genes that are transcriptionally
repressed by YB-1 include MHC class II, collagen
alpha1, granulocyte-macrophage colony-stimulating
factor (GM-CSF), etc (reviewed in Ladomery and
Sommerville, 1995; Kohno et al., 2003; Kuwano et al.,
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
YBX1 (Y box binding protein 1)
Evdokimova V, Sorokin A
translocation of YB-1 (Ohga et al., 1996; Kohno et al.,
2003) and its proteasomal cleavage (Sorokin et al.,
2005). Accumulation of the full-length and/or truncated
YB-1 proteins in the nucleus is associated with
increased survival and multidrug resistance (Kohno et
al., 2003; Sorokin et al., 2005). YB-1 knock-out in
mice is lethal (Lu et al., 2005; Lu et al., 2006).
Fibroblasts derived from YB-1(-/-) embryos exhibit a
reduced ability to respond to oxidative, genotoxic and
oncogene-induced stresses, further implicating YB-1 in
stress responses and embryonic development.
Tumorigenesis. YB-1 is frequently overexpressed in
multiple human cancers (reviewed in Kohno et al.,
2003; Kuwano et al., 2003). In many cases, YB-1
levels are elevated in the nucleus, positively correlating
with multiple drug resistance and poor patient outcome
(Bargou et al., 1997; Janz et al., 2002). Ectopic
expression of YB-1 in breast cancer cells and mouse
models stimulated tumor growth (Bergmann et al.,
2005; Sutherland et al., 2005). Yet, the role of YB-1 in
tumorigenesis is controversial. YB-1 overexpression
blocked oncogenic transformation caused by PI3K or
Akt (Bader et al., 2003). These apparently
contradictory results were proposed to be due to
differential localization of YB-1; its interference with
oncogenic transformation is associated with cytosolic
localization and a consequent function in translational
control (Bader and Vogt, 2004; Bader and Vogt, 2005).
induced chromosomal instability and tumorigenesis
(Bergmann et al., 2005). YB-1 effects on tumorigenesis
are likely dependent on cellular signaling. It blocks
oncogenic transformation induced by Akt or PI3K but
not by Src, Jun or Qin oncoproteins (Bader et al.,
2003), and decreases proliferation of tumor cells with
activated MAPK-Ras signaling, while inducing their
metastatic ability (Evdokimova et al., 2009).
Nuclear YB-1 is considered as a marker of poor clinical
outcome. Patients with high YB-1 levels are likely to
benefit from dose-intensified chemotherapy regimens
(Gluz et al., 2009).
Prostate cancer
YB-1 is upregulated during prostate cancer tumor
progression and is reported to increase P-glycoprotein
activity (Giménez-Bonafé et al., 2004).
Lung cancer
Nuclear YB-1 is associated with poor survival and
expression of HER2/ErbB2 and HER3/ErbB3 in nonsmall cell lung cancer (Kashihara et al., 2009).
Patients with nuclear YB-1 expression and p53
mutations appear to have the worst prognosis (median
survival 3 months), while best outcome was found in
patients with no nuclear YB-1 and wild-type p53
(Gessner et al., 2004).
YB-1 is highly homologous to human DbpA (12p13;
expressed predominantly in heart and muscle) and
DbpC/contrin (17p11; expressed exclusively in germ
cells). They share greater than 90% identity within the
CSD and a high degree of similarity in the N- and Cterminal domains, including C-terminal clusters of
basic and acidic amino acids. Mouse orthologues are
YB-1 (encoded by Ybx1; 99% overall aminoacid
identity with human YB-1), MSY2 (Ybx2; ~93%
identity with contrin) and MSY4 (~86% identity with
Colon cancer
YB-1 expression levels are elevated in colorectal
carcinoma and positively correlate with DNA
topoisomerase II alpha and PCNA expression but not
with P-gp (Shibao et al., 1999). In colon cancer cells,
YB-1 accumulates in the nuclei in response to
vinblastin and is associated with development of
vinblastin resistance and elevated expression of P-gp
(Vaiman et al., 2007).
Ovarian cancer
Mutations in YBX1 are not reported.
YB-1 levels are elevated in the nuclei of cisplatinresistant cancer cell lines and cancer patients,
indicating that nuclear YB-1 may be associated with
acquired cisplatin resistance in ovarian cancers (Yahata
et al., 2002).
Co-expression of YB-1 and P-gp is indicative of
unfavourable prognosis in ovarian cancer (Huang et al.,
Implicated in
Breast cancer
Elevated expression and nuclear localization of YB-1 is
associated with increased proliferation, multidrug
resistance and tumor aggressiveness across all tumor
subtypes. Nuclear localization positively correlates
with increased expression of MDR1/P-gp and
HER2/ErbB2 (Bargou et al., 1997; Saji et al., 2003;
Fujii et al., 2008; Habibi et al., 2008). Enforced YB-1
expression in mammary glands of transgenic mice
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Haematopoietic malignancies
Large B-cell lymphoma, multiple myeloma.
YBX1 (Y box binding protein 1)
Evdokimova V, Sorokin A
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B-cell lymphoma (Xu et al., 2009). YB-1 is strongly
expressed in normal plasma cell precursor blasts as
well as in a multiple myeloma tumor specimens and
cell lines but not in normal bone marrow or plasma
cells. Its expression is associated with an immature
morphology, a highly proliferative phenotype and
doxorubicin resistance, indicating its involvement in
drug resistance and disease progression in multiple
myeloma (Chatterjee et al., 2008).
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anchorage-independent growth of breast cancer cells.
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PH. Akt-mediated YB-1 phosphorylation activates translation of
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YB-1 and MSY4 share essential functions during murine
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benefiting from rapidly cycled tandem high-dose adjuvant
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The increased expression of Y box-binding protein 1 in
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antagonizes apoptosis and enhances chemoresistance. Int J
Cancer. 2007 May 15;120(10):2110-8
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Gerecke C, Lorentz H, Royer HD, Bargou RC. The Y-box
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and mediates survival and drug resistance in multiple
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and estrogen receptor alpha depends upon nuclear localization
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predictor of relapse and disease-specific survival than estrogen
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Evdokimova V, Sorokin A. YBX1 (Y box binding protein 1).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7):598-604.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Mini Review
ZBTB33 (zinc finger and BTB domain containing
Michael R Dohn, Albert B Reynolds
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA (MRD, ABR)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/ZBTB33ID43785chXq24.html
DOI: 10.4267/2042/45988
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Kaiso was originally identified in a yeast two-hybrid
screen as a binding partner for the Armadillo repeat
domain protein p120-catenin (CTNND1) and has
subsequently been found to also interact with the p120catenin-related protein delta-catenin. The N-terminal
POZ/BTB domain mediates Kaiso interactions with NCoR, the CTC-binding factor (CTCF), and Znf131, as
well as Kaiso homodimerization.
DNA consists of three exons, the third of which
contains the coding region.
Kaiso is ubiquitously expressed.
In various mammalian cell lines Kaiso localizes nearly
exclusively to the nucleus, but in normal and tumor
tissues Kaiso is predominantly detected in the
cytoplasm. During mitosis a pool of Kaiso localizes to
microtubles and centrosomes.
Other names: ZNF-kaiso; ZNF348
HGNC (Hugo): ZBTB33
Location: Xq24
Transcription of this gene produces transcript variants 1
(5324 bp) and 2 (5225 bp) that encode the same
protein. Variant 2 lacks exon 2 in the 5' UTR.
Via its zinc finger domain, Kaiso binds DNA and
functions as both a repressor and activator of
transcription. Kaiso recognizes methylated CpG
dinucleotides as well as a sequence-specific site
(TCCTGCNA). While several genes are repressed by
Kaiso (including matrilysin, siamois, c-Fos, cyclin-D1,
c-Myc, Wnt11, MMP-7 and MTA2), rapsyn is the only
reported gene to be activated by Kaiso.
ZBTB33/Kaiso (hereafter Kaiso) is a member of the
BTB/POZ (Broad complex, Tramtrak, Bric à brac/Pox
virus and zinc finger)-zinc finger family of
transcription factors.
ZBTB33/Kaiso genomic sequence (7.64 Kb) is composed of three exons (green). The coding region (red) is within exon 3.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
ZBTB33 (zinc finger and BTB domain containing 33)
Dohn MR, Reynolds AB
ZBTB33/Kaiso contains an N-terminal POZ/BTB domain (green), two acidic regions (blue), and three C-terminal zinc finger domains
and non-canonical Wnt-signaling were thought to
contribute to this phenotype, but subsequent studies
determined that Kaiso's main role in early Xenopus
development is restricted to the maintenence of
transcriptional silencing. However, disruption of the
Kaiso gene in mice did not reveal any abnormalities in
development or gene expression.
Mus musculus - Zbtb33; Rattus norvegicus - Zbtb33;
Xenopus laevis - zbtb33; Danio rerio - zbtb33; Pan
troglodytes - ZBTB33; Bos Taurus - ZBTB33; Gallus
gallus - ZBTB33.
None reported.
Daniel JM, Reynolds AB. The catenin p120(ctn) interacts with
Kaiso, a novel BTB/POZ domain zinc finger transcription
factor. Mol Cell Biol. 1999 May;19(5):3614-23
Implicated in
Prokhortchouk A, Hendrich B, Jørgensen H, Ruzov A, Wilm M,
Georgiev G, Bird A, Prokhortchouk E. The p120 catenin
partner Kaiso is a DNA methylation-dependent transcriptional
repressor. Genes Dev. 2001 Jul 1;15(13):1613-8
Lung cancer
Immunohistochemical analysis of 294 cases of nonsmall cell lung cancer, including 50 cases of paired
lymph node metastases, revealed a correlation of
cytoplasmic Kaiso staining with poor prognosis, and
shRNA-mediated knockdown of Kaiso enhances
proliferative and invasive capabilities of several lung
cancer cell lines.
Daniel JM, Spring CM, Crawford HC, Reynolds AB, Baig A.
The p120(ctn)-binding partner Kaiso is a bi-modal DNA-binding
protein that recognizes both a sequence-specific consensus
and methylated CpG dinucleotides. Nucleic Acids Res. 2002
Jul 1;30(13):2911-9
Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J. N-CoR
mediates DNA methylation-dependent repression through a
methyl CpG binding protein Kaiso. Mol Cell. 2003
Colon cancer
Kaiso has been shown to repress expression of
methylated tumor suppressor genes, and depletion of
Kaiso sensitizes colon cancer cell lines to
chemotherapy. Moreover, Kaiso is upregulated in
intestinal tumors in mice, and a delayed onset of
intestinal tumorigenesis is observed when Kaiso-null
mice are crossed with the tumor-susceptible ApcMin/+
Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA,
Daniel JM, McCrea PD. Non-canonical Wnt signals are
modulated by the Kaiso transcriptional repressor and p120catenin. Nat Cell Biol. 2004 Dec;6(12):1212-20
Rodova M, Kelly KF, VanSaun M, Daniel JM, Werle MJ.
Regulation of the rapsyn promoter by kaiso and delta-catenin.
Mol Cell Biol. 2004 Aug;24(16):7188-96
Ruzov A, Dunican DS, Prokhortchouk A, Pennings S,
Stancheva I, Prokhortchouk E, Meehan RR. Kaiso is a
genome-wide repressor of transcription that is essential for
Gastric cancer
A study of the Helicobacter pylori-induced
inflammatory response, which, if persistent, increases
the risk for gastric adenocarcinoma, revealed that H.
pylori induces nuclear translocation of the Kaisobinding partner p120-catenin. Nuclear p120-catenin
then relieves Kaiso-mediated repression of MMP-7,
which is often overexpressed in premalignant and
malignant gastric lesions.
Defossez PA, Kelly KF, Filion GJ, Pérez-Torrado R, Magdinier
F, Menoni H, Nordgaard CL, Daniel JM, Gilson E. The human
enhancer blocker CTC-binding factor interacts with the
transcription factor Kaiso. J Biol Chem. 2005 Dec
Park JI, Kim SW, Lyons JP, Ji H, Nguyen TT, Cho K, Barton
MC, Deroo T, Vleminckx K, Moon RT, McCrea PD.
coordinately regulate canonical Wnt gene targets. Dev Cell.
2005 Jun;8(6):843-54
Vertebrate development
Soubry A, van Hengel J, Parthoens E, Colpaert C, Van Marck
E, Waltregny D, Reynolds AB, van Roy F. Expression and
nuclear location of the transcriptional repressor Kaiso is
regulated by the tumor microenvironment. Cancer Res. 2005
Mar 15;65(6):2224-33
Injection of Xenopus laevis embryos with morpholinos
targeting xKaiso leads to a developmental delay during
gastrulation. Initially, Kaiso's roles in both general
transcription repression and in regulation of canonical
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Spring CM, Kelly KF, O'Kelly I, Graham M, Crawford HC,
Daniel JM. The catenin p120ctn inhibits Kaiso-mediated
ZBTB33 (zinc finger and BTB domain containing 33)
Dohn MR, Reynolds AB
transcriptional repression of the beta-catenin/TCF target gene
matrilysin. Exp Cell Res. 2005 May 1;305(2):253-65
poor prognosis in non-small cell lung cancer. BMC Cancer.
2009 Jun 9;9:178
Prokhortchouk A, Sansom O, Selfridge J, Caballero IM,
Salozhin S, Aithozhina D, Cerchietti L, Meng FG, Augenlicht
LH, Mariadason JM, Hendrich B, Melnick A, Prokhortchouk E,
Clarke A, Bird A. Kaiso-deficient mice show resistance to
intestinal cancer. Mol Cell Biol. 2006 Jan;26(1):199-208
Ruzov A, Savitskaya E, Hackett JA, Reddington JP,
Prokhortchouk A, Madej MJ, Chekanov N, Li M, Dunican DS,
Prokhortchouk E, Pennings S, Meehan RR. The nonmethylated DNA-binding function of Kaiso is not required in
early Xenopus laevis development. Development. 2009
Daniel JM. Dancing in and out of the nucleus: p120(ctn) and
the transcription factor Kaiso. Biochim Biophys Acta. 2007
Donaldson NS, Nordgaard CL, Pierre CC, Kelly KF, Robinson
SC, Swystun L, Henriquez R, Graham M, Daniel JM. Kaiso
regulates Znf131-mediated transcriptional activation. Exp Cell
Res. 2010 Jun 10;316(10):1692-705
Lopes EC, Valls E, Figueroa ME, Mazur A, Meng FG, Chiosis
G, Laird PW, Schreiber-Agus N, Greally JM, Prokhortchouk E,
Melnick A. Kaiso contributes to DNA methylation-dependent
silencing of tumor suppressor genes in colon cancer cell lines.
Cancer Res. 2008 Sep 15;68(18):7258-63
Soubry A, Staes K, Parthoens E, Noppen S, Stove C, Bogaert
P, van Hengel J, van Roy F.. The transcriptional repressor
Kaiso localizes at the mitotic spindle and is a constituent of the
pericentriolar material. PLoS One. 2010 Feb 15;5(2):e9203.
Ogden SR, Wroblewski LE, Weydig C, Romero-Gallo J,
O'Brien DP, Israel DA, Krishna US, Fingleton B, Reynolds AB,
Wessler S, Peek RM Jr. p120 and Kaiso regulate Helicobacter
pylori-induced expression of matrix metalloproteinase-7. Mol
Biol Cell. 2008 Oct;19(10):4110-21
This article should be referenced as such:
Dohn MR, Reynolds AB. ZBTB33 (zinc finger and BTB domain
containing 33). Atlas Genet Cytogenet Oncol Haematol. 2011;
Dai SD, Wang Y, Miao Y, Zhao Y, Zhang Y, Jiang GY, Zhang
PX, Yang ZQ, Wang EH. Cytoplasmic Kaiso is associated with
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Leukaemia Section
Short Communication
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: December 2010
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0305p21q32ID2139.html
DOI: 10.4267/2042/45989
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
colony stimulating factor-1 (CSF1). Upon binding of
CSF1, CSF1R tyrosine phosphorylation is induced
leading to RAS/RAF/MAPK, PI3K/AKT/mTOR and
JAK/STAT (specifically STAT1, STAT3, and STAT5)
pathways activation. CSF1R activation by CSF1 results
in increased growth, proliferation and differentiation
(Fischer et al., 2008).
Clinics and pathology
MKPL-1 cell line, established from a 66-year-old male
patient with an acute megakaryoblastic leukemia (M7AML) and a karyotype apparently with -21,+3mar
(Takeuchi et al., 1992), re-analysed for tyrosine kinase
dysregulation (Gu et al., 2007).
Result of the chromosomal
Only one case to date.
Hybrid gene
Genes involved and proteins
Fusion of RBM6 exon 2 to CSF1R exon 12; the
reciprocal CSF1R-RBM6 was not detected.
From N-term to C-term, contains a BTB/POZ domain
(mediates homomeric dimerization) and decamer repeat
multimerization/selfassociation of the protein, RRM1 and RRM2 (RNA
recognition motif) domains, an octamer repeat, a C2H2
zinc finger, a nuclear localisation signal, and a G-patch
(made of highly conserved glycines; may have RNA
binding functions). RNA-binding protein. Binds
poly(G). Splicing factor (Heath et al., 2010).
Fusion protein
The RBM6-CSF1R fusion protein consists of the amino
terminal 36 amino acids of RBM6, fused to the carboxy
terminal 399 amino acids of CSF1R, including a
polymerisation domain of RBM6, and the tyrosine
kinase domain of CSF1R.
Constitutive tyrosine kinase activation.
Takeuchi S, Sugito S, Uemura Y, Miyagi T, Kubonishi I,
Taguchi H, Enzan H, Ohtsuki Y, Miyoshi I. Acute
megakaryoblastic leukemia: establishment of a new cell line
(MKPL-1) in vitro and in vivo. Leukemia. 1992 Jun;6(6):588-94
transmembrane domain, and a split tyrosine kinase
domain (intracellular), from N-term to C-term.
Transmembrane glycoprotein, receptor for the ligand
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Gu TL, Mercher T, Tyner JW, Goss VL, Walters DK, Cornejo
MG, Reeves C, Popova L, Lee K, Heinrich MC, Rush J,
Daibata M, Miyoshi I, Gilliland DG, Druker BJ, Polakiewicz RD.
A novel fusion of RBM6 to CSF1R in acute megakaryoblastic
leukemia. Blood. 2007 Jul 1;110(1):323-33
Huret JL
Fischer JA, Rossetti S, Sacchi N.. CSF1R (colony stimulating
factor 1 receptor, formerly McDonough feline sarcoma viral (vfms) oncogene homolog). Atlas Genet Cytogenet Oncol
nascent transcripts. Chromosome Res. 2010 Dec;18(8):85172. Epub 2010 Nov 18.
This article should be referenced as such:
Huret JL. t(3;5)(p21;q32). Atlas Genet Cytogenet Oncol
Haematol. 2011; 15(7):608-609.
Heath E, Sablitzky F, Morgan GT.. Subnuclear targeting of the
RNA-binding motif protein RBM6 to splicing speckles and
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Deep Insight Section
Role of HB-EGF in cancer
Rosalyn M Adam
Urological Diseases Research Center, Enders Research Building, Rm 1077, Children's Hospital Boston, 300
Longwood Avenue, Boston MA 02115, USA (RMA)
Published in Atlas Database: November 2010
Online updated version : http://AtlasGeneticsOncology.org/Deep/HB-EGFInCancerID20090.html
DOI: 10.4267/2042/45990
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
generate recognition motifs for interactors that mediate
downstream signaling cascades. Among the ERBB
proteins, ERBB2 is an orphan receptor with no known
ligand, whereas ERBB3 lacks functional intrinsic
tyrosine kinase activity. In addition, the EGF-like
growth factors show specificity in ERBB binding, with
some factors such as EGF, amphiregulin (AREG) and
TGFα selective for ERBB1 but others such as HB-EGF
and betacellulin (BTC) able to interact with ERBB1
and ERBB4. Consequently, as a result of differential
intrinsic receptor activity, ligand selectivity and
modulation of ligand availability by interactions with
heparin, a wide range of downstream responses can be
evoked following ligand-ERBB interaction (Citri and
Yarden, 2006).
Peptide growth factors regulate diverse processes from
cell survival and proliferation to migration and
programmed cell death. Due to their central role in
growth regulation, growth factors are major players in
the development and progression of cancer. Among this
broad class of molecules, those comprising the EGFlike family are amongst the best characterized. In this
Deep Insight, I will elaborate on the evidence
implicating one such protein, heparin-binding EGF-like
growth factor (HB-EGF), in tumor biology and how its
activity may be targeted for therapeutic gain.
HB-EGF: a member of the EGF-like
growth factor family
HB-EGF: structure, molecular
interactions and function
Heparin-binding EGF-like growth factor (HB-EGF) is a
member of the epidermal growth factor (EGF)-like
growth factor family of proteins that bind to and
activate the EGF receptor (EGFR) and its associated
receptors ERBB2, ERBB3 and ERBB4. The extended
family comprises 15 members, all of which conform
broadly to common structural framework centered
around 6 cysteine residues in the sequence: CX7CX45CX10-13CXCX8GXRC. Disulphide bond formation
between 3 pairs of cysteines gives rise to the
characteristic 3-looped EGF-like motif that mediates
high-affinity binding to receptors (reviewed in Wilson
et al., 2009).
The EGF-like growth factors achieve their effects
through interaction with one or more ErbB receptor
tyrosine kinases. The ERBB receptors are class I
transmembrane proteins that homo- or heterodimerize
following ligand binding and undergo autophosphorylation on defined tyrosine residues to
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
HB-EGF was originally identified as a secreted product
of macrophages that was purified on the basis of its
high affinity for heparin (Higashiyama et al., 1991).
The gene is encoded on the long arm of chromosome 5,
at 5q23, and gives rise to a 208 amino acid protein of
20-22 kDa in size. Determination of the primary
peptide sequence revealed the presence in HB-EGF of
an extended N-terminal domain that was absent in the
prototypical EGFR ligands EGF and transforming
growth factor-alpha (TGFα). Notably, the N-terminal
sequence in HB-EGF is enriched in basic amino acids
that are positively charged at physiological pH and
enable interaction with negatively charged heparin
sulphate proteoglycans both on the cell surface and in
the extracellular matrix.
HB-EGF is synthesized as a single pass membraneanchored precursor with a short cytoplasmic tail
(Figure 1).
Role of HB-EGF in cancer
Adam RM
Figure 1. Molecular structure of HB-EGF. The figure illustrates in schematic form the secondary structure of HB-EGF. The protein
possesses a short cytoplasmic region, a single transmembrane domain, and an ectodomain that harbors the 3-looped EGF-like motif
characteristic of this growth factor family. Vertical arrows indicate primary sites of ectodomain cleavage. Molecules that interact with HBEGF are indicated in blue.
Membrane-anchored proHB-EGF undergoes a number
of post-translational modifications ranging from Olinked glycosylation of the N-terminal ectodomain, Nterminal truncations, phosphorylation of the
cytoplasmic domain and regulated cleavage of the
entire ectodomain. The significance of these
modifications will be considered in subsequent
Among the EGFR ligands, proHB-EGF is notable for
the number of proteins and other molecules with which
it interacts, including transmembrane receptors,
adhesion molecules, and transcriptional regulators as
described below.
(i) Transmembrane receptors: the best-studied
functions of HB-EGF are as a ligand for the
EGFR/ErbB1 and the related receptor ErbB4. Highaffinity interactions with receptors are mediated via the
3-looped EGF-like motif and result in receptor
autophosphorylation and initiation of downstream
signaling cascades. Interestingly, the biological effects
evoked by HB-EGF binding to ErbB1 and ErbB4 are
distinct, with the former typically promoting
proliferation but the latter stimulating chemotaxis and
migration (Elenius et al., 1997). Interactions between
the membrane-anchored form of HB-EGF and ErbB
receptors expressed on adjacent cells also mediate both
cell survival (Singh et al., 2007) and intercellular
adhesion functions (Raab et al., 1996; Paria et al.,
1999). More recently, radioligand binding assays with
I-labeled HB-EGF using the breast cancer cell line
MDA-MB 453 revealed the existence of a novel
receptor that was subsequently identified as the
metalloendopeptidase N-arginine dibasic convertase
(NRDc). In that study, NRDc was found to enhance
HB-EGF stimulated migration of tumor cells in an
EGFR/Erb1-dependent manner (Nishi et al., 2001).
(ii) Heparan sulphate proteoglycans (HSPGs): HB-EGF
was purified from the conditioned medium of a
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(7)
macrophage-like cell line on the basis of its high
affinity for heparin (Higashiyama et al., 1991).
Interaction of HB-EGF with heparin, in the form of
HSPGs present on cell surfaces and in the extracellular
matrix is known to enhance ErbB receptor binding
affinity as well as bioactivity (Paria et al., 1999;
Higashiyama et al., 1993).
(iii) CD9 and integrins: CD9 is a member of the
tetraspanin family of transmembrane proteins that
interacts with membrane-anchored HB-EGF via its
heparin-binding domain (Sakuma et al., 1997) and
upregulates its ability to stimulate juxtacrine activation
of the EGFR expressed on adjacent cells (Higashiyama
et al., 1995). HB-EGF and CD9 were also found to be
co-expressed in gastric cancers (Murayama et al.,
2002), although the prognostic significance of these
observations has not been determined. CD9 and HBEGF were also demonstrated to exist in complex with
integrin α3β1 at sites of cell-cell junctions (Nakamura
et al., 1995) where the multiprotein complex
waspredicted to participate in cell-cell adhesion.
(iv) Cytoplasmic tail interactors: several binding
partners for the cytoplasmic domain of proHB-EGF
were identified using either yeast 2-hybrid or coimmunoprecipitation
cochaperone BAG-1 and the transcriptional repressors
PLZF and Bcl6. Interaction between BAG-1 and
proHB-EGF was found to augment the prosurvival
function of proHB-EGF (Lin et al., 2001). Conversely,
association between the C-terminal fragment of HBEGF that is liberated following ectodomain shedding,
with PLZF or Bcl6 leads to nuclear export or
degradation, respectively of the transcriptional
repressors and a resulting inhibition of repressive
activity (Nanba et al., 2003; Kinugasa et al., 2007;
Hirata et al., 2009). The relevance of these interactions
to cancer will be considered in more detail below.
Role of HB-EGF in cancer
Adam RM
Figure 2. Regulated processing and activity of HB-EGF. ProHB-EGF expressed on the plasma membrane undergoes ectodomain
cleavage mediated by enzymes of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) families (A).
Release of the mature, soluble protein facilitates both autocrine (B) and paracrine (C) activation of ERBB receptors expressed on the
same or adjacent cells, respectively. The membrane-anchored proHB-EGF can also activate ERBB receptors via juxtacrine signaling (D).
In addition to release of the ectodomain, regulated cleavage releases the Cterminal cytoplasmic fragment, HB-EGF-C (E), which can
translocate to the nucleus to effect either nuclear export (F) or degradation (G), respectively, of the transcriptional repressors PLZF or
revealed no differences in processing with wild type
MEFs (Weskamp et al., 2002) suggesting that there is
some redundancy among ADAM factors that cleave
proHB-EGF. Elegant studies using cells from mice
deficient in specific ADAM family members identified
ADAM-17/TACE as the primary mediator of HB-EGF
cleavage (Sahin et al., 2004). Importantly, ADAM-17
itself is upregulated in a range of tumor types (Tanaka
et al., 2005) and at least part of its association with
tumor progression is likely to reflect increased
processing of EGFR ligands including HB-EGF.
Ectodomain shedding of HB-EGF has also been
implicated in EGFR transactivation in tumor cells
downstream of multiple discrete agonists including Gprotein coupled receptor activators (Filardo et al., 2000;
Madarame et al., 2003; Schäfer et al., 2004a; Schäfer et
al., 2004b; Yano et al., 2004; Itoh et al., 2005), Ser/Thr
kinase activators (Ebi et al., 2010), ligands for gp130
cytokine receptors (Ogunwobi and Beales, 2008) and
others. EGFR transactivation by GPCR-dependent HBEGF cleavage has been discussed recently (reviewed in
Higashiyama et al., 2008) and will not be considered
further here.
Although much attention has focused on the fate of the
soluble HB-EGF that is liberated following precursor
cleavage, the C-terminal fragment of HB-EGF that
remains following ectodomain shedding has also been
shown to be functional, independently of proHB-EGF.
HB-EGF-C, comprising both the transmembrane and
cytoplasmic domains, was demonstrated to undergo
nuclear translocation following cleavage of the HB-
Regulated processing of proHBEGF
Like all ERBB ligands, HB-EGF is synthesized as a
membrane-anchored precursor that is trafficked to the
plasma membrane and subsequently processed to yield
the mature, soluble growth factors. Regulated
processing of the HB-EGF precursor represents a
critical control point in ligand function since it
represents the conversion from a membrane-anchored,
non-diffusible state to a diffusible protein that has a
greatly expanded sphere of influence on surrounding
cells and tissues (Figure 2).
In addition to normal post-translational maturation of
HB-EGF, regulation of precursor processing is highly
relevant to cancer, since many of the enzymes that
cleave HB-EGF and other EGFR ligands are
themselves upregulated in cancer versus normal cells
(Murphy, 2008). The signals and enzymes responsible
for liberation of the HB-EGF ectodomain will be
considered in the following sections.
Several metalloproteinases have been implicated in
ectodomain shedding of proHB-EGF including matrix
metalloproteinase-3 (MMP-3) (Suzuki et al., 1997),
MMP-7 (Yu et al., 2002), ADAM10 (Yan et al., 2002),
ADAM12 (Asakura et al., 2002) and TNFα-converting
enzyme (TACE)/ADAM17 (Sahin et al., 2004). In
forced expression experiments, ADAM9 was
demonstrated to promote both basal and TPAstimulated proHB-EGF processing (Izumi et al., 1998).
However, subsequent evaluation of ADAM9-/- MEFs
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Adam RM
EGF ectodomain (Nanba et al., 2003; Nanba et al.,
2004; Toki et al., 2005). Detection of the C-terminal
fragment of HB-EGF in nuclei was consistent with an
earlier report from our group identifying nuclear
localization of HB-EGF as a feature of aggressive
disease in bladder cancer (Adam et al., 2003). Nuclear
localization of HB-EGF-C was accompanied by nuclear
export of the promyelocytic leukemia zinc finger
(PLZF) protein, identified as an interactor for HB-EGFC by yeast 2-hybrid analysis (Nanba et al., 2003).
PLZF is a sequence-specific transcriptional repressor
and inhibitor of cell cycle transit that achieves its effect
by binding via its zinc finger domains to the promoters
of target genes such as cyclin A (Yeyati et al., 1999).
Export from the nucleus therefore prevents it from
exerting its inhibitory function, resulting in enhanced
movement through the cell cycle (Nanba et al., 2003).
Interestingly, Bcl6, another transcriptional repressor,
was also demonstrated to interact with HBEGF-C by a
similar mechanism. In contrast to PLZF, however,
binding to HB-EGF-C led to Bcl6 degradation and
attenuation of its negative regulatory activity (Kinugasa
et al., 2007; Hirata et al., 2009).
In light of the dual growth stimulatory effects of
proHB-EGF cleavage, resulting in liberation of the HBEGF ectodomain that can promote autocrine and
paracrine stimulation of tumor cells, and the HB-EGFC carboxyl terminal fragment, that induces cell cycle
transit, attempts have been made to target both
biological consequences pharmacologically to achieve
tumor cell inhibition (Shimura et al., 2008).
sufficiency in growth signals; (ii) limitless replicative
potential; (iii) resistance to growth inhibitory signals;
(iv) evasion of apoptosis; (v) ability to migrate, invade
and metastasize; and (vi) ability to evoke sustained
angiogenesis. Recently, it has been argued that the list
should be updated to include inflammation as an
additional hallmark of cancer (Colotta et al., 2009). In
the following sections, we will consider how HB-EGF
relates functionally these features.
Self-sufficiency in growth signals and limitless
replicative potential
As a ligand for members of the ErbB family of receptor
tyrosine kinases, it is well established that HB-EGF can
promote proliferation of a wide range of cells,
including tumor cells from diverse cancer types. HBEGF gene expression is a target of several oncogenes
including v-jun (Fu et al., 1999), Raf and Ras
(McCarthy et al., 1995), and can therefore mediate
growth-promoting effects subsequent to oncogenic
The growth promoting effects of HB-EGF are mediated
largely, although not exclusively, through binding to
ErbB receptors on the plasma membrane. HB-EGF
binding to EGFR/ErbB1 activates downstream
signaling that converges on the Raf/Ras/MEK/Erk and
phosphoinositide-3-kinase (PI3K)/Akt pathways to
promote survival and proliferation (reviewed in Yarden
and Sliwkowski, 2001). However, recent studies have
demonstrated receptor-independent activities for HBEGF-C, the C-terminal fragment of HB-EGF that
remains after ectodomain cleavage. In particular HBEGF-C has been shown to inhibit the transcriptionrepressing capabilities of PLZF and Bcl6 through either
nuclear export or degradation, respectively (Nanba et
al., 2003; Kinugasa et al., 2007). This resulted in
enhanced expression of cyclin A and cyclin D2,
together with increased cell cycle transit.
Resistance to growth inhibitory signals evasion of
HB-EGF has been implicated as a survival factor for
multiple cell types exposed to growth inhibitory
stimuli. One of the earliest demonstrations of HB-EGFmediated cell survival revealed that whereas proHBEGF could prevent TGFβ-induced apoptosis in
hepatoma cells in culture, this function could not be
replicated with soluble HB-EGF (Miyoshi et al., 1997).
That study provided the first demonstration of discrete
functions for the soluble and cell-associated forms of
HB-EGF, a concept that has been borne out in many
subsequent studies both in non-malignant and tumor
cells (Takemura et al., 1997; Singh et al., 2007; Ray et
al., 2009).
It is important to appreciate that HB-EGF expressed by
cells in the microenvironment has also been implicated
in tumor cell survival. Circulating cells such as T
lymphocytes and macrophages that infiltrate tumors
have been demonstrated to secrete HB-EGF that can act
on tumor cells as well as other components critical for
HB-EGF in cancer
HB-EGF expression is altered in a number of cancer
types including bladder (Adam et al., 2003; Kramer et
al., 2007), breast (Ito et al., 2001c; Yotsumoto et al.,
2010), colon (Ito et al., 2001a), hepatic (Inui et al.,
1994), ovarian (Miyamoto et al., 2004; Tanaka et al.,
2005), pancreatic (Kobrin et al., 1994; Ito et al., 2001b)
and prostate cancers (Freeman et al., 1998) as well as
gliomas (Mishima et al., 1998). In addition to
quantitative increases in its expression in tumor versus
non-tumor tissue, HB-EGF has also been found to
undergo qualitative changes including altered
subcellular localization, and cleavage to release N- and
C-terminal fragments that mediate oncogenic
behaviors. Notably, although HB-EGF in cancer is
typically expressed in epithelial cells, we and others
have reported robust HB-EGF expression in the stroma
(Freeman et al., 1998; Adam et al., 1999) and
endothelium (Nolan-Stevaux et al., 2010) in certain
organs that exerts profound paracrine effects on tumor
To understand the potential functions of HB-EGF in
cancer, it is instructive to consider the defining
characteristics of tumor cells In their seminal article
published 10 years ago Hanahan and Weinberg defined
six features or 'hallmarks' characteristic of tumor cells
(Hanahan and Weinberg, 2000). These are: (i) self
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Role of HB-EGF in cancer
Adam RM
neuroendocrine tumorigenesis (Nolan-Stevaux et al.,
2010). In that study the authors identified discrete roles
for HB-EGF expressed by tumor endothelial and
perivascular cells, and TGFα released by cancer cells
both of which act through the EGFR to promote
angiogenesis and tumor cell survival/growth,
Ability to migrate, invade and metastasize
To exit the primary tumor and disseminate to distant
sites in the body, tumor cells must acquire the ability to
migrate, intravasate, survive in the circulation,
extravasate and establish in the secondary site. HBEGF has been shown to promote prostate cancer cell
migration and invasion both directly and as an
intermediate in EGFR transactivation by G-protein
coupled receptor agonists (Madarame et al., 2003;
Schäfer et al., 2004a; Cáceres et al., 2008). HBEGF
was also found to participate in the epithelialmesenchymal transition (EMT) in gastric and ovarian
cancer cells (Yagi et al., 2008). Gastric cancer cells
exposed to the pathogen Helicobacter pylori, displayed
increased MMP-7- and gastrin-dependent HB-EGF
shedding and induction of EMT-associated genes.
Inhibition of either gastrin or MMP-7 in vitro, or
gastrin in vivo suppressed expression of HB-EGF and
EMT-associated genes (Yin et al., 2010). Treatment of
ovarian cancer cells with recombinant HB-EGF
reduced E-cadherin levels and upregulated expression
of Snail, a key regulator of the EMT. Conversely
RNAi-mediated silencing of Snail attenuated HB-EGF
expression and release of HB-EGF into the medium.
Together these findings led the authors to conclude that
HB-EGF could promote ovarian cancer metastasis
through induction of the EMT (Yagi et al., 2008).
Interestingly, Wang and colleagues demonstrated
opposing effects on E-cadherin expression in pancreatic
cells by retention of HB-EGF on the membrane. In
cells either expressing non-cleavable proHB-EGF or
treated with an inhibitor of HB-EGF ectodomain
shedding, E-cadherin levels were up-regulated as a
result of inhibition of ZEB1, a transcriptional repressor
for E-cadherin (Wang et al., 2007b). Increased Ecadherin not only attenuated cell motility, but also
sensitized cells to chemotherapy-induced apoptosis.
Regulation of neuroendocrine differentiation and
Although not strictly defined as 'hallmarks' of cancer,
HB-EGF is known to participate in two additional
processes linked to development and progression of
cancer, namely inflammation and neuroendocrine
differentiation. In intestinal cells exposed to cytokines
(Mehta and Besner, 2003) or intestinal tissue exposed
to ischemia/reperfusion injury (Rocourt et al., 2007)
HB-EGF was found to exert anti-inflammatory activity
in part through downregulation of NFκB and the
ensuing reduction in expression of pro-inflammatory
cytokines. In contrast, however, HB-EGF expression
by mesenchymal cells in the liver was upregulated in
tumor expansion such as endothelial cells and pericytes
(Blotnick et al., 1994; Peoples et al., 1995). The
cytokine CXCL12 was shown to promote HB-EGF
release from mononuclear phagocytes and subsequent
activation of the EGFR/ErbB1 and initiation of prosurvival signaling in tumor cells (Rigo et al., 2010).
This in turn stimulated release of the macrophage
mitogen GM-CSF to further promote HB-EGF in a
growth stimulatory loop.
Resistance to growth inhibition and evasion of
apoptosis are relevant not only to cancer initiation,
where cells lose responsiveness to normal cell death
signals, but also in the setting of cancer treatment
where tumor cells develop resistance to cytotoxic
agents. Several recent reports have identified HB-EGF
as a key mediator of treatment resistance and several
tumor types. Exposure of cancer cells to either
conventional chemotherapy or treatment with small
molecule inhibitors was found to upregulate HB-EGF
expression, release and activation of the EGFR, thereby
enhancing survival signaling (Johnson et al., 2005;
Yotsumoto et al., 2010). Both transcriptional and posttranscriptional mechanisms have been proposed to
account for increased HB-EGF levels, including AP1/NFkappaB-dependent transcription (Wang et al.,
2007a; Sorensen et al., 2006) and enhanced mRNA
stability contributing to upregulation of HB-EGF
protein expression.
Ability to evoke sustained angiogenesis
Decades of work by Judah Folkman and colleagues led
to the concept that tumor growth beyond a defined size
is an angiogenesis-dependent process (reviewed in
Bishop-Bailey, 2009) i.e. requiring the development of
a tumor blood supply. Using bladder cancer cells stably
expressing either soluble or membrane-anchored HBEGF, Ongusaha and colleagues demonstrated that HBEGF was a potent inducer of several oncogenic
behaviors including growth and migration in vitro as
well as xenograft growth and angiogenesis in vivo
(Ongusaha et al., 2004). Consistent with distinct
functions for soluble and membrane-anchored HBEGF,
expression of non-cleavable proHB-EGF was unable to
replicate the tumorigenic potential of either soluble or
wild type proHB-EGF. The HB-EGF sheddase
ADAM17 has also been implicated in pathological
neovascularization. Studies in which ADAM17 was
deleted conditionally in either endothelial cells or
pericytes using tissue-specific promoters to drive Cre
recombinase expression demonstrated that loss of
ADAM17 expression specifically in endothelial cells
attenuated growth of implanted tumor cells (Weskamp
et al., 2002). Significantly, effects of ADAM17
ablation could be restored by administration of
exogenous HB-EGF, consistent with a role for
ADAM17-dependent release of HBEGF in regulation
of angiogenesis. The proangiogenic function of HBEGF was verified in an independent study that
employed the RIP1-Tag2 mouse model of pancreatic
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Role of HB-EGF in cancer
Adam RM
migration and invasion in vitro and to diminish growth,
promote apoptosis and suppress angiogenesis in
xenografts in nude mice (Sanui et al., 2010; Miyamoto
et al., 2004; Martarelli et al., 2009). In addition,
enhanced antitumor activity of CRM197 has been
chemotherapeutic agents such as paclitaxel (Yagi et al.,
2009; Sanui et al., 2010). Although the results of
CRM197 combination chemotherapy are provocative, it
is important to note that exposure of cells to
chemotherapeutic agents has been shown to upregulate
HB-EGF levels that may in turn promote resistance to
chemotherapy (Wang et al., 2007a). However, by
careful attention to scheduling of drug administration,
chemotherapy-induced upregulation of HB-EGF could
be exploited to sensitize tumor cells to HB-EGFtargeted agents.
Based on its demonstrated bioactivity, CRM197 has
been administered to patients with advanced, treatmentrefractory malignant disease (Buzzi et al., 2004). One
potential limitation of this strategy is that many in the
general population are immunized against diphtheria
and therefore may have innate resistance to CRM197
delivered systemically. Nevertheless, objective antitumor activity was observed in a small proportion of
patients, with 3 responses and stable disease in a further
6 patients. Moreover, CRM197 demonstrated
reasonable bioavailability, and toxicity associated with
the treatment was deemed acceptable. Although the
effect of CRM197 in that study was modest, more
recent demonstrations of enhanced bioactivity in
combination with conventional chemotherapeutic
agents (Yagi et al., 2009; Sanui et al., 2010) suggests
CRM197 may still have utility as an anti-cancer agent.
As noted earlier, cleavage of membrane-anchored
proHB-EGF represents a major control point for
regulation of HB-EGF bioactivity. Consequently,
several groups have focused on this event as a means to
inhibit HB-EGF-dependent regulation of tumor cell
behavior. Fridman and colleagues described the
identification of selective inhibitors that could prevent
shedding of ERBB ligands in vitro and went on to
demonstrate potent anti-tumor effects in a range of
assays, including survival pathway activation and
growth and survival of xenografts (Fridman et al.,
2007). Although such inhibitors are inhibiting shedding
of multiple EGF-like ligands, in addition to HB-EGF,
these results suggest the potential for combined
inhibition of ligand shedding and ERBB receptor
activation with small molecule inhibitors. In addition to
pharmacological inhibition of MMP/ADAM activity
using KB-R7785 also suppressed generation and
nuclear translocation of the HB-EGF C-terminal
fragment (Shimura et al., 2008). This resulted in
growth arrest, induction of apoptosis and decreased
expression of proliferation-associated genes.
inflamed tissue and augmented by pro-inflammatory
stimuli (Sagmeister et al., 2008). Moreover, increased
HB-EGF expression contributed to enhanced DNA
synthesis and mitogenesis in premalignant hepatocytes
consistent with a facilitative role for HB-EGF in
In certain cancer types, such as prostate cancer the
presence of neuroendocrine differentiation is associated
with more aggressive tumors and worse patient
outcome (Slovin, 2006). Our group showed that HBEGF could drive the neuroendocrine phenotype in
prostate cancer cells in vitro and in vivo (Kim et al.,
2002; Adam et al., 2002). Notably, cells exposed to
HB-EGF continued to traverse the cell cycle in contrast
to previous reports showing inducers of NE
differentiation promoting cell cycle arrest (Cox et al.,
2000; Wang et al., 2004). Moreover, HB-EGF induced
downregulation of androgen receptor (AR) expression
in xenografts as well as AR expression and activity in
vitro (Adam et al., 2002). Subsequent analysis revealed
HB-EGF-mediated AR inhibition occurred through an
mTOR-dependent mechanism involving cap-dependent
mRNA translation (Cinar et al., 2005).
HB-EGF as a therapeutic target
In light of the involvement of HB-EGF in multiple
aspects of tumor development, progression and
metastasis, it is not surprising that attempts have been
made to target it for therapeutic benefit. Promising
targeting strategies include prevention of ligand
binding to the EGFR, inhibition of proHBEGF
cleavage and subsequent release of ectodomain and Cterminal fragments and exploitation of proHB-EGF as
the receptor for diphtheria toxin. In this section, we will
review the approaches used to inhibit HB-EGF and
their potential for clinical use.
In situations where HB-EGF is overexpressed in
tumors, some of its effects can obviously be blocked in
the presence of either function blocking anti-EGFR
antibodies or small molecule inhibitors of the intrinsic
kinase domain. However this topic has been covered in
many excellent reviews (Laskin and Sandler, 2004;
Jimeno and Hidalgo, 2005) and will not be considered
further here.
A number of studies have exploited the identity of
proHB-EGF as the receptor for diphtheria toxin (DT) in
human cells by treating cells, and in some cases
patients, with a non-toxic DT mutant termed CRM197.
CRM197 harbors a point mutation (G52E) in the DT A
chain that diminishes its ability to perform the ADPribosylation of elongation factor 2 and inhibition of
protein synthesis characteristic of wild type DT
(Mekada and Uchida, 1985). Although CRM197 lacks
the toxicity of DT, it nonetheless exerts potent growth
inhibitory effects through binding to the EGF-like
domain of cell surface and soluble HB-EGF (Mitamura
et al., 1995; Kageyama et al., 2007). In experimental
evaluation, CRM197 alone has been found to induce
apoptosis and inhibit oncogenic behaviors such as
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Role of HB-EGF in cancer
Adam RM
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HB-EGF plays multiple important roles in cancer, and
has been implicated in each of the hallmarks
characteristic of neoplastic disease. Recent work has
emphasized the potential for HB-EGF as a viable
therapeutic target for certain cancer types, through a
variety of strategies. Moreover, its unique identity
among ERBB ligands as a receptor for DT/CRM197
may provide novel avenues for rational targeting in the
context of cancer therapeutics. The future challenge
will be to realize this potential and to translate our
knowledge of this inimitable molecule into treatments
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Rigo A, Gottardi M, Zamò A, Mauri P, Bonifacio M, Krampera
M, Damiani E, Pizzolo G, Vinante F. Macrophages may
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Oncol Haematol. 2011; 15(7):610-619.
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Role of HB-EGF in cancer
Adam RM
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