Report 2010 - Turku Centre for Biotechnology

Transcription

TURUN BIOTEKNIIKAN KESKUS
to our 14
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ÅBO BIOTEKNIKCENTRUM
TURKU CENTRE FOR BIOTECHNOLOGY
TURKU CENTRE
FOR BIOTECHNOLOGY
REPORT 2010
TURUN BIOTEKNIIKAN KESKUS
Tykistökatu 6 B
P.O.BOX 123
FI 20521 Turku, Finland
Tel: +358 2 333 8603, Fax 358 2 333 8000
Annual Report 2010
Turku Centre for Biotechnology
Published by:
P.O. Box 123, FI-20521 Turku, Finland
Tel. int. +358-2-333 8603, fax int. +358-2-333 8000
http://www.btk.fi
Editorial Board
Riitta Lahesmaa (Chair)
Tero Aittokallio
Eleanor Coffey
Garry Corthals
Michael Courtney
Konstantin Denessiouk
Attila Gyenesei
John Eriksson
Jyrki Heino
Johanna Ivaska
Panu Jaakkola
Marko Kallio
Olli Kallioniemi
Päivi Koskinen
Tassos Papageorgiou
Lea Sistonen
Jukka Westermarck
Linnéa Linko
Juha Strandén
Mikael Wasberg
Photographs:
KUV@TEHDAS Roni Lehti, Photograph archives of the Centre for Biotechnology
Front cover image: Patrik Jones
Graphic Design: Anne Asplund, Finepress Oy
Printed by: Finepress Oy, Turku
ISSN 1237-5217
CONTENTS
Board of Trustees...................................................................... 2
Chairman’s Foreword................................................................. 4
From the Director....................................................................... 5
Year 2010 in a Nutshell.............................................................. 7
PhD and MSc Theses................................................................ 10
Funding..................................................................................... 11
Personnel 2010......................................................................... 12
The Finnish Microarray and Sequencing Centre......................... 15
Cell Imaging Core (CIC)............................................................. 18
The Proteomics Facility . ........................................................... 21
Protein Crystallography Core Facility.......................................... 23
Bioinformatics Core .................................................................. 24
Virus Vector Facility.................................................................... 27
Coordination of European Biobanking........................................ 28
Mechanisms and Biosensors of GTPases.................................. 30
Protein Kinase Regulation of Brain Development and Disease... 34
Translational Proteomics............................................................ 38
Cytoskeletal and Survival Signaling............................................ 41
Cell Adhesion and Cancer......................................................... 46
Hypoxia in Cell Survival.............................................................. 49
Kinetochore and Cancer Research Group.................................. 52
Canceromics Research Programme.......................................... 55
Signaling Pathways regulated by Oncogenic Pim Kinases......... 59
Molecular Systems Immunology and Stem Cell Biology............. 62
Protein Crystallography.............................................................. 68
Cell Fate
................................................................................ 72
Targeting Strategies for Gene Therapy....................................... 76
Regulation and Function of Heat Shock Transcription Factors... 78
Cancer Cell Signaling................................................................. 82
Structural Bioinformatics Group................................................. 85
Data Mining and Modeling Group.............................................. 87
Organisation of Neuronal Signaling Pathways............................ 91
Bioenergy Group....................................................................... 95
Computational Systems Biology................................................ 99
Publications 2010...................................................................... 99
PhD Defences........................................................................... 106
Life outside the Lab................................................................... 111
1
ORGANIZATION
Board of Trustees 1.1.2010-31.10.2010
Board of Trustees 1.11.2010 -
Chairman
HEINO Jyrki, Professor, University of Turku,
Department of Biochemistry and Food Chemistry,
Scientific Director, BioCity Turku
Chairman
HEINO Jyrki, Professor, University of Turku,
Department of Biochemistry and Food Chemistry,
Scientific Director, BioCity Turku
Vice-chairman
ERIKSSON John, Professor, Åbo Akademi University,
Department of Biology
Vice-chairman
ERIKSSON John, Professor, Åbo Akademi University,
Secretary
LAHESMAA Riitta, Professor, Director,
Secretary
LAHESMAA Riitta, Professor, Director,
Assistant Secretary
JAAKKOLA Minttu, Coordinator, Turku Centre for Biotechnology
and BioCity Turku (1.1.- 20.4.2010)
ALANKO Satu, Coordinator, Turku Centre for Biotechnology
and BioCity Turku (21.4.2010-)
Assistant Secretary
ALANKO Satu, Coordinator, Turku Centre for Biotechnology
and BioCity Turku
Members
ARO Eva-Mari, Academy Professor, the Academy of Finland,
University of Turku, Department of Biology
JALKANEN Sirpa, Professor, University of Turku,
MediCity Research Laboratory
JOHNSON Mark, Professor, Åbo Akademi University,
Department of Biochemistry and Pharmacy
LAHTI Reijo, Professor, University of Turku,
Department of Biochemistry and Food Chemistry
LASSILA Olli, Professor, University of Turku,
Department of Medical Microbiology
PIISPANEN Tero, Project Manager, Turku Science Park Ltd
PYRHÖNEN Seppo, Professor, University of Turku,
Department of Oncology
SAXÉN Henrik, Vice Rector ( 1.1.-3.2.2010)
SERE Kaisa, Vice Rector, Professor, Åbo Akademi University,
Department of Information Technology (4.2.-31.10.2010)
TÖRNQUIST Kid, Professor, Åbo Akademi University,
Vice-members
ARO Hannu, Professor, University of Turku,
Department of Surgery
HUPA Leena, Lecturer, Åbo Akademi University,
Åbo Akademi Process Chemistry
SALAKOSKI Tapio, Professor, University of Turku,
Department of Information Technology
SISTONEN Lea, Academy Professor, the Academy of Finland
SOUKKA Tero, Academy Research Fellow, Academy of Finland,
University of Turku, Department of Biotechnology
TOPPARI Jorma, Professor, University of Turku,
Department of Physiology
VUORELA Pia, Professor, Åbo Akademi University,
Department of Pharmaceutical Chemistry
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Members
ARO Eva-Mari, Professor, University of Turku,
JALKANEN Sirpa, Professor, University of Turku,
Department of Medical Microbiology and Immunology
JOHNSON Mark, Professor, Åbo Akademi University,
Department of Biosciences
POUTANEN Matti, Professor, University of Turku,
Institute of Biomedicine
SAVILAHTI Harri, Professor, Univer sity of Turku,
TERHO Perttu, Project Engineer, Turku Centre for Biotechnology
TÖRNQUIST Kid, Professor, Åbo Akademi University,
WILLFÖR Stefan, Professor, Åbo Akademi University,
Department of Chemical Engineering
Vice-members
FARDIM Pedro, Professor, Åbo Akademi University,
Department of Chemical Engineering
HÄNNINEN Pekka, Professor, University of Turku,
Institute of Biomedicine
JAAKKOLA Ulla-Marjut, Group Leader, Project Director,
LASSILA Olli, Professor, University of Turku,
Department of Medical Microbiology and Immunology
PETTERSSON Kim, Professor, University of Turku,
PRIMMER Craig, Professor, University of Turku,
SLOTTE J. Peter, Professor, Åbo Akademi University,
VUORELA Pia, Professor, Åbo Akademi University,
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CHAIRMAN’S FOREWORD
FROM THE DIRECTOR
Seventeen years ago, 1994, the Scientific Advisory Board of BioCity
decided to join all biotechnology and molecular biology employing
research groups under one single umbrella: BioCity Turku. To reflect
the success of BioCity concept professors Eero Vuorio and Pekka
Mäntsälä edited a book introducing all 40 research groups that were
actively working in this growing research field. The total number of
researcher and graduate students was estimated to be c. 400. The
forewords of the first BioCity Turku book ended: “It (the book) should
also serve as an invitation for more researchers and industries to join
BioCity Turku since the most exciting research still lies, unexplored,
ahead.”
The present, international, Scientific Advisory Board of BioCity Turku
evaluated the applicant research programmes in October, 2010.
The total number of research groups in the applications was 120
and the number of researchers and graduate students was c. 1000.
Thus, the BioCity concept does indeed have the keys to growth and
success. The corner stone of BioCity Turku is close collaboration
between two Universities, the University of Turku and the Åbo
Akademi University, which share the common campus. The most
important strategic decision has been the establishment of highlevel, common research infrastructure. From the very beginning, the
core facilities in the Turku Centre for Biotechnology have been critical
for the development of life science and molecular medicine research
in the Turku campus area. They provide modern research services
and allow the access to the latest technologies for all scientists
working in Turku. The Turku Centre for Biotechnology has also
played a crucial role in making the Turku campus attractive for new
researchers and research groups. Happily many of the new group
leaders have moved from abroad. For comparison to year 1994 only
one out of forty group leaders was not originally from Finland.
In Finland the new Biocenter Finland -process has expanded the role
of many core facilities from a local to a national service provider. In
Turku most core facilities have already for a long time served a wide
scientific community in Finland and also abroad. Turku Centre for
Biotechnology has therefore been in many ways a forerunner in the
creation of the national infrastructure networks. Biocenter Finland
has significantly helped in the modernization of research equipment
and technologies. Its present funding will end on 2012 and after that
the continuation of this critical process is still uncertain. An equally
demanding future challenge is to link the Finnish infrastructure and
the largest core facilities to the emerging European infrastructure
networks. The present ESFRI (European Strategy Forum on Research
Infrastructures) process is preparing
ground for the forthcoming networks
that in the future will strengthen the
European Research Area. It is essential
for the development of life sciences in
Finland that also Finnish researchers
participate in this process. Turku
scientists have been especially active
in the Euro-bioimaging project.
Turku Centre of Biotechnology (CBT) continued further
developing its strengths in research and core competence in
research infrastructure in molecular biosciences. The Centre
provided state-of the-art core facilities, education and training
for altogether 80 BioCity Turku research groups and six research
programs featuring altogether seven Academy of Finland Centers
of Excellence.
Jyrki Heino, M.D., Ph.D.,
Professor of Biochemistry,
Scientific Director of the BioCity Turku and
Chairman of the Board of the Turku Centre for
Biotechnology
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Research was focused on cell signalling, regulation of gene and
protein expression, and systems biology. In 2010 a total of 63
papers were published, including top ranked journals. Altogether
14 Ph.D. students presented their dissertations in 2010, which
is a record of our Centre. Two new international group leaders
started research groups at the Centre, of whom Daniel Abankwa
was awarded the prestigious Marie Curie grant and Patrik Jones,
who joined us in 2009, received the distinguished ERC young
investigator’s award.
We have made significant investments in developing the stateof-the-art platforms in genomics and functional genomics,
proteomics, cell imaging and bioinformatics. The animal core
facility takes up a sizeable portion of basic resources in serving
researchers and Turku Centre for disease modelling.
A joint organization of the Finnish biocenters, Biocenter Finland,
was estabished in 2006 to facilitate national collaboration and
to coordinate development of research infrastructres in Finland.
Special funding from the Ministry of Education for 2010-2012
provides an excellent opportunity to significantly improve
research infrastucture and improve interactions between the
biocenters. Several of our group leaders are actively engaged
in these Biocenter Finland infrastructure networks. Hence, in
addition to serving local needs, CBT now further develops and
provides national services in several areas within the Biocenter
Finland infrastucture network. Bioimaging and systems biology
infrastructures are at the core of the research strategy of both our
universities and central infrastructures in the research strategy of
Biocity Turku. As seen from this report significant progress has
been made already during the first year of these Biocenter Finland
networks.
University of Turku and Åbo Akademi University along with
all the universites in Finland started with new judicial status
in the beginning of 2010 with increased independence and
responsibility. This should provide a substantial opportunity to
execute strategic decisions to improve our resources in research
and education in selected areas. The change has come with lots
of new administrative challenges as structures, processes and
tools have been re-established with a unforeseen speed. The
sooner these obstacles are met the better so that our reserachers
and administrative personnel can concentrate on achieving our
main goals in research, education and devoloping cutting-edge
research infrastructure.
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I wish to congratulate our scientists for their first-rate
accomplishments and express my deepest appreciation and
gratitude to the our administrative and technical staff for their
continuing commitment to making the Centre a great place to
work!
Riitta
Riitta Lahesmaa, M.D., Ph.D.,
Professor Director Turku Centre
for Biotechnology University of Turku
and Åbo Akademi University
YEAR 2010 IN A NUTSHELL
RESEARCH AND EDUCATION 2010
• 64 scientific papers were published
(p. 101)
• 14 new Ph.D.´s graduated
• CBT was awarded a substantial 1,5 million € funding through Biocenter Finland
• The Academy of Finland granted a a new postdoctoral fellowship to Dr. Sanna Edelman
• Two new international group leaders, Drs. Daniel Abankwa and David Hawkins were recruited
• For undergraduate training, CBT organized lecture
courses and practical demonstrations including a
laboratory course on “Functional Genomics” for Health Bioscience and Biology students (4 study points) and on “Medical Biotechnology” for Medical students
(5 study points)
• 9 M.Sc. theses were completed
DEVELOPMENT OF INFRASTRUCTURE, RESEARCH
SERVICES AND CORE FACILITIES 2010
Finnish Microarray and Sequencing Centre 2010
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The Centre got substantial competitive funding through Biocenter Finland to develop and provide national services in the area of gene expression, regulation of gene
expression and epigenetics
Dr. David Hawkins, Ph.D. was recruited as a group leader to establish epigenomics with the Centre’s scientists
Prof. Jorma Palvimo and Dr. Sami Väisänen joined as
affiliated group leaders to facilitate and develop ChIP-seq platforms
Prof. Harri Lähdesmäki and Dr. Matti Nykter joined as
affiliated group leaders to strengthen development and implementation of NGS analysis methods
The Centre changed its name from the Finnish DNA
Microarray Centre to the Finnish Microarray and
Sequencing Centre to reflect its activities in nextgeneration sequencing services/platform.
Next-generation sequencing instrument: ABI SOLiD 3 Plus was upgraded to version 4 in April.
FMSC’s website was renovated to improve the visibility of the centre’s services
Several events were organized in collaboration with vari-
ous instrument manufacturers throughout the year to spread information on available and emerging
technologies and the related FMSC’s services.
FMSC personnel gave talks in many scientific events and organized training courses to educate researchers on various topics.
Major efforts were carried out in further developing the centre’s project consultation services to help customers design their experiments. Also the centre’s bioinformatics team continued developing bioinformatics data analysis services.
Several high impact papers were published with
contribution from the FMSC
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Proteomics and Mass spectrometry Laboratory 2010
Bioinformatics Unit 2010
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• High-throughput screening of natural molecules was established in conjunction with Prof. Pia Vuorela at Åbo Akademi University
• Increased collaboration between our unit and CSC in high power computing and cloud computing
• Participated in projects involving analysis of protein-protein and protein-ligand interactions, computer-aided prediction and intelligent molecular modeling and design; computer-
based ligand docking and analysis; effects of molecular recognition and mutations on protein function
• Training of Ph.D. students in Bioinformatics and
Computational Biology within the National Graduate School of Informational and Structural Biology.
Contribution to courses organized by CBT and
Åbo Akademi University
• Plans made to increase high-capacity storage
infrastructure for archiving services to support Structural Bioinformatics, Structural Biology, Translational Area, Drug Discovery, Chemical Informatics and Bioimaging
• The High-throughput Bioinformatics Group (HTB) also
organized a Chipster course in collaboration with CSC during May, 2010.
• The HTB group purchased and installed a computer
cluster for next-generation sequencing (NGS) services. The group has been setting up bioinformatics pipelines for various NGS applications.
New facility Website (including new Project,
Pricing and Sample submission forms)
Received large 3 year funding through Biocenter Finland.
The LTQ OrbiTrap Velos /ETD and nanoLC system was installed in September.
Several new software purchases and developments to enable quantitative MS analysis.
Approximately 3500 hours of MS service operation.
New methods published in 2010 for quantitative
proteomics and phosphorylation analysis.
Several Nordic Quantitative Proteomics courses in
“MS-based phosphoprotein analysis” and “Design and Analysis of Quantitative Proteomics Experiments”, held.
Additional courses in “Imaging Mass Spectrometry” at Novartis (Basel) and our annual (4th) Summer School in “Mass Spectrometry in Biotechnology and Medicine” in Dubrovnik.
Three international meetings were organised, of which one locally, and 10 local seminars were held in proteomics (2 Frontiers of Science).
Dr. Petri Kouvonen defended in October his Ph.D. on “Simplified sample handling in mass spectrometry based protein research - focus on protein phosphorylation”. in the Facility.
Dr. Susumu Imanishi, recruited in November to bolster PTM and MS analytical capacity.
Several Masters students completed (Olli Kannaste, Veronika Suni, Ahmed Bulbul) and started (Firouz Saedi, Noora Jaakola). Two new Ph.D. students started
(Olli Kannaste, Veronika Suni, Ahmed Bulbul).
Cell Imaging Core 2010
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June 15: Turku Bioimaging Open Day. The seminar was also published online as webinar, web participants from Helsinki and Kuopio.
November 25: Installation of the new BD FACS Aria II cell sorter
December 9: Received Academy of Finland Infrastructure Grant FIRI2010 over 1.5 M€ for a new cutting edge
confocal microscope to study key molecular interactions in cancer
Turku Bioimaging is one of the first test sites that define access criteria for nodes of Euro-BioImaging, an
infrastructure umbrella organisation from the EU
Other demos during the year: Volocity Image analysis software, EvosFL microscope, Guava Flow Cytometer, Lambert Instrument FLIM-microscope
Viral Vector Facility 2010
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Ketlin Adel was recruited to produce viral vectors as part of the Biocenter Finland funded service
The Virus Vector Facility added Lenti vector production to its service repertoire
New and competitive pricing was introduced adhering to Biocenter Finland guidelines
Protein Crystallography Facility 2010
Continuation of participation in several courses (Medical
Biochemistry, TERBIO, Protein Crystallography and Structural
Genomics’, ‘How to solve a protein structure’) with lectures and
demonstrations in the X-ray facility.
• New web site launched. New links were added to
provide quick access to crystallographic theory,
techniques, crystallization, software, news and events.
• New projects at various stages were initiated in
collaboration with other groups in Finland and abroad.
• All major crystallographic programs were kept
upgraded to latest versions. New computers and 3D-
monitors were purchased.
• Several docking calculations and ab initio structure
predictions were carried out for the needs of various
projects.
Quality Assurance Unit 2010
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Organized courses for the university on (1) quality
assurance and metrology and (2) how to assure the
reliability of your laboratory test results
Individual training for graduate and post-graduate students
Carried out GLP inspections for the Central Animal
Laboratory
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PhD and MSc Theses
2010
PhD Theses (p. 99)
Name
Supervisor
Ahlfors Helena
Lahesmaa Riitta
Ahlskog Johanna
Sistonen Lea Blomster Henri
Sistonen Lea
Filén Sanna
Lahesmaa Riitta
Kouvonen Petri
Corthals Garry Kukkonen-Macchi Anu Kallio Marko
Pallari Hanna-Mari
Eriksson John
Peuhu Emilia
Eriksson John
Sandqvist Anton
Sistonen Lea
Tahvanainen Johanna Lahesmaa Riitta
Tiikkainen Pekka
Kallioniemi Olli
Toivonen Raine
Savontaus Mikko
Tuomi Saara
Ivaska Johanna
Vuoriluoto Karoliina
Ivaska Johanna
Site besides CBT
UTU/Department of Medical Biochemistry and Genetics
ÅA/Department of Biosciences
UTU/Department of Pharmacology, Drug Development and Therapeutics
MSc Theses Name
Supervisor
Deshpande Prasannakumar Coffey Eleanor
Eerola Sini
Koskinen Päivi
Högnäs Gunilla
Ivaska Johanna
Kannaste Olli
Corthals Garry
Laiterä Tiina
Westermarck Jukka
Md Bulbul Ahmed
Corthals Garry
Piilonen Katri
Jaakkola Panu Suni Veronika
Corthals Garry
Virtakoivu Reetta
Ivaska Johanna
Site besides CBT
University of Skovde, Sweden
UTU/Department of Biology
University of Skovde, Sweden
UTU/Health biosciences
UTU/Department of
Information Technology
UTU/Department of Biochemistry
From left to right, front row: Juha Strandén, Terhi Jokilehto, Marjo Hakkarainen,
Elina Arojoki, Perttu Terho, Markku Saari, Virpi Korpiranta, Eva Hirvensalo,
second row: Mårten Hedman, Sirkku Grönroos, Petri Kouvonen, Päivi Junni,
Riitta Lahesmaa, Susanna Pyökäri, Aila Jasmavaara, Anne Rokka,
third row: Mikael Wasberg, Satu Alanko, Pasi Viljakainen, Hannele Vuori,
Sarita Heinonen.
FUNDING
Sources of funding received
by Centre for Biotechnology in 2010 (9.8 Million €)
Academy of
Finland 14%
Biocenter Finland 15%
EU
16%
Services
6%
Others
8%
Universities 41%
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PERSONNEL 2010
Administration
LAHESMAA Riitta, Director, Professor,
Group Leader
ALANKO Satu, Coordinator
GRÖNROOS Sirkku,
Senior Administrative Assistant
HIRVENSALO Eva, Clerical Official
JASMAVAARA Aila, Clerical Official
JOKILEHTO Terhi, Coordinator
PLOSILA Riina, Coordinator
BioCity Turku
HEINO Jyrki, Biocity Turku Scientific
Director, Professor
HEINO Ilona, Student
ALANKO Satu, Coordinator
JAAKKOLA Minttu, Coordinator
Technical Staff
ANDERSEN Raija, Laboratory Technician
HEDMAN Mårten, Systems Manager
KORPIRANTA Virpi,
Instrument Maintenance
STRANDÉN Juha, Laboratory Engineer
VAHAKOSKI Petri, Systems Manager
VILJAKAINEN Pasi, Senior Technician
VUORI Hannele, Instrument Maintenance
WASBERG Mikael, Laboratory Manager
Mechanisms and Biosensors of
GTPases
ABANKWA Daniel, Group Leader
GUZMAN Camilo, Postdoctoral Fellow
IFTIKHAR Zuhair, Scientific Programmer
NAJUMUDEEN Arafath Kaja,
Graduate Student
SOLMAN Maja, Graduate Student
Data Mining and Modeling
AITTOKALLIO Tero, Group Leader,
Adjunct Professor
NEVALAINEN Olli, Group Leader,
Professor
ELO Laura, Postdoctoral Fellow
ERONEN Ville-Pekka,
Undergraduate Student
GAO Bin, Graduate Student
HEISKANEN Marja, Graduate Student
HIISSA Jukka, Graduate Student
JÄRVINEN Aki, Undergraduate Student
KOSKINEN Ville, Graduate Student
LAAJALA Essi, Undergraduate Student
LAAJALA Teemu Daniel,
LINDEN Rolf, Graduate Student
NATRI Lari, Undergraduate Student
OKSER Sebastian, Graduate Student
PIIPPO Mirva, Undergraduate Student
SALMELA Pekka, Undergraduate Student
SALMI Jussi, Postdoctoral Fellow
SUOMI Tomi, Graduate Student
TUIKKALA Johannes, Graduate Student
VÄHÄMAA Heidi, Graduate Student
Protein Kinase Function
in Brain Development and Disease
COFFEY, Eleanor, Group Leader,
Academy of Finland Research Fellow
ADEL Ketlin, Laboratory Technician
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DESHPANDE Prasannakumar,
Graduate Student
HEIKELÄ, Hanna, Undergraduate Student
KOMULAINEN, Emilia, Graduate Student
MOHAMMAD Hasan, Graduate Student
MYSORE, Raghavendra,
Graduate Student
PADZIK, Artur, Graduate Student
PYÖKÄRI Susanna, Laboratory Technician
SUN Lihua, Graduate Student
TUITTILA Minna, Postdoctoral Researcher
ZDROJEWSKA, Justyna,
Graduate student
Proteomics and Mass Spectrometry
CORTHALS Garry, Group Leader,
Head of Proteomics
ANDERSÉN Raija, Laboratory Technician
HAKANEN Emmi, Undergraduate Student
HEINONEN Arttu, Project Engineer
IHERMANN Anneliis,
IMAMURA Motonori,
JAAKKOLA Noora,
KANNASTE Olli, Undergraduate Student
KAUNISMAA Katri,
KOUVONEN Petri, Researcher
MD BULBUL Ahmed,
NEES Susanne, Coordinator
RALPH Eliza, Systems Administrator
ROKKA Anne, Postdoctoral Fellow
SAEIDI Firouz, Undergraduate Student
SUNI Veronika, Graduate Student
VEHMAS Anni, Undergraduate Student
VIRTANEN Fanni, Student
YADAV Avinash, Undergraduate Student
Organisation of Neuronal
Signaling Pathways
COURTNEY Michael, Professor,
Group Leader
HO Franz, Postdoctoral Researcher
LI Lili, Graduate Student
LIU Xiaonan, Graduate Student
LOPEZ RODRIGUES Maykel,
Graduate Student
MARTINSSON Peter,
Postdoctoral Researcher
PEVGONEN Veera, Technicain
TUITTILA Minna, Postdoctoral Researcher
VERGUN Olga, Postdoctroal Researcher
WANG Xijun, Graduate Student
YADAV Leena, Graduate Student
Cytoskeletal and survival signaling
ERIKSSON John, Group Leader, Professor
ASAOKA Tomoko, Graduate Student
FERRARIS Saima, Graduate Student
HYDER Claire, Graduate Student
IMANISHI Susumu, Postdoctoral Fellow
KASTU Juha, Project Engineer
KAUNISTO Aura, Postdoctoral Fellow
KOCHIN Vitaly, Postdoctoral fellow
LAZARO, Glorianne, Exchange Student
LINDQVIST Julia, Graduate Student
LUNDGREN, Jolanta,
ISONIEMI Kimmo, Graduate Student
PALLARI Hanna-Mari, Postdoctoral Fellow
PAUL Preethy, Graduate Student
PEUHU Emilia, Postdoctoral Fellow
REMES Mika, Graduate Student
ROBERTS Maxwell,
SAARENTO Helena, Research Associate
SÖDERSTRÖM Thomas,
Postdoctoral fellow
TORVALDSON Elin, Graduate student
Cell Imaging Core
Abankwa Daniel, Group Leader,
Head of Cell Imaging Core
COFFEY Eleanor, Academy of Finland
Research Fellow,
Coordinator of the Cell Imaging Unit
ERIKSSON John, Group Leader,
Professor
KORHONEN Jari, Project Engineer
SANDHOLM Jouko, Research Engineer
SAARI Markku, Project Engineer
TERHO Perttu, Project Engineer
Cell Adhesion and Cancer
IVASKA Johanna, Group Leader,
Professor
ALANKO Jonna, Graduate Student
ARJONEN Antti, Graduate Student
DE FRANCESCHI Nicola,
Graduate student
HÖGNÄS Gunilla, Graduate Student
KAUKONEN Riina, Graduate Student
LAHTINEN Laura, Graduate Student
MAI Anja, Graduate student
MATTILA Elina, Postdoctoral Fellow
MUHARRAM Ghaffar,
Postdoctoral Fellow
POUWELS Jeroen, Postdoctoral Fellow
SIIVONEN Jenni, Laboratory Technician
TUOMI Saara, Postdoctoral Fellow
VELTEL Stefan, Postdoctoral Fellow
VIRTAKOIVU Reetta, Graduate Student
Hypoxia Group
JAAKKOLA Panu, Group Leader,
Adjunct Professor
BORBELY Gabor, Exchange Student
HEIKKINEN Pekka, Graduate Student
HÖGEL Heidi, Graduate Student
JOKILEHTO Terhi, Graduate Student
KALEVO-MATTILA Taina,
Laboratory Technician
NUUTILA Maiju, Undergraduate Student
RANTANEN Krista, Graduate Student
Kinetochore and Cancer
Research Group
KALLIO Marko, Group Leader, Chief
Research Scientist, Adjunct Professor
JAAKKOLA Kimmo, Postdoctoral Fellow
KUKKONEN-MACCHI Anu,
Graduate Student
LAINE Leena, Postdoctoral Fellow
MÄKI-JOUPPILA Jenni,
Graduate Student
NARVI Elli, Postdoctoral Fellow
OETKEN-LINDHOLM Christina,
Postdoctoral Fellow
SALMELA Anna-Leena,
Graduate Student
TOIVONEN Pauliina,
WINSEL Sebastian, Postdoctoral Fellow
VUORILUOTO Mariaana,
Graduate Student
Canceromics Research Programme
KALLIONIEMI Olli, Group Leader, Director
PLOSILA Riina, Coordinator
AAKULA Anna, Graduate Student
BUCHER Elmar, Graduate Student
BJÖRKMAN Mari Graduate Student
GUPTA Santosh, Graduate Student
KETOLA Kirsi, Graduate Student
KOHONEN Pekka, Graduate Student
POLLARI Sirkku, Graduate Student
VAINIO Paula, Graduate Student
Signaling Pathways Regulated
by Oncogenic Pim Kinases
KOSKINEN Päivi, Group Leader,
Adjunct Professor
EEROLA Sini, Undergraduate Student
EKMAN Heidi, Undergraduate Student
LAITERÄ Tiina, Undergraduate Student
RAINIO Eeva-Marja, Postdoctoral Fellow
SANDHOLM Jouko, Graduate Student
SANTIO Niina, Undergraduate Student
VAHAKOSKI Riitta, Graduate Student
Molecular Immunology Group
LAHESMAA Riitta, Director, Professor,
Group Leader
ALANEN Veera, Undergraduate Student
EDELMAN Sanna, Postdoctoral Fellow
ENGSTRÖM Emilia, Undergraduate
Student
FILEN Sanna, Graduate Student
HAKKARAINEN Marjo, Laboratory
Technician
HAHNE Lauri, Undergraduate Student
HEINONEN Mirkka, Graduate Student
HEINONEN Sarita, Laboratory Technician
KALLIONPÄÄ Henna, Graduate Student
KYLÄNIEMI Minna, Graduate Student
LAAJALA Essi, Undergraduate Student
LUND Riikka, Senior Scientist
LÖNNBERG Tapio, Graduate Student
MOULDER Robert, Senior Scientist
NÄRVÄ, Elisa, Graduate Student
OIKARI Lotta, Undergraduate Student
PIETILÄ Elina, Laboratory Technician
PURSIHEIMO Juha-Pekka,
Senior Scientist
RAHKONEN Nelly, Graduate Student
RAJAVUORI Anna, Student
RASOOL Omid, Adjunct Professor,
Senior Scientist
SALO Verna, Undergraduate Student
SARAPULOV Alexey, Graduate Student
SOMANI Juhi, Undergraduate Student
SPARVERO Louis,
Senior Research Fellow
TAHVANAINEN Johanna,
Postdoctoral Fellow
TRIPATHI Subhash, Graduate Student
TUOMELA Soile, Graduate Student
VALTONEN Joona,
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Quality Assurance Unit
LINKO Linnéa, Adjunct
Professor
Protein Crystallography
PAPAGEORGIOU Tassos,
Group Leader, Adjunct Professor
DHAVALA Prathusha, Graduate Student
HAIKARAINEN Teemu, Graduate Student
KINARET Pia, Undergraduate Student
MATTSSON Jesse, Graduate Student
MOHAMMADI Omid, Graduate Student
MULETA Abdi, Undergraduate Student
SUBEDI Bishwa, Undergraduate Student
WECKSTRÖM Kristian, Senior Scientist
Bioinformatics Unit
DENESSIOUK Konstantin,
Group Leader (Structural Bioinformatics)
GYENESEI Attila, Senior Scientist
(High-throughput Bioinformatics)
CHOUHAN Bhanupratap Singh,
Graduate Student
JUNTTILA Sini, Graduate Student
LAIHO Asta, Project Engineer
KYTÖMÄKI Leena,
Cell fate
SAHLGREN Cecilia, Group Leader,
Academy of Finland Research Fellow
ANTFOLK Daniel, Undergraduate Student
ANTILA Christian, Undergraduate Student
BATE-EYA Laurel Tabe,
Graduate Student
HIETAMÄKI Marika, Graduate Student
GRANQVIST Cecilia,
LANDOR Sebastian, Graduate Student
MAMAEVA Veronika, Postdoctoral Fellow
NIEMI Rasmus, Undergraduate Student
SAARENTO, Helena,
Targeting Strategies for
Gene Therapy
SAVONTAUS Mikko, Group Leader,
Adjunct Professor
EEROLA Kim, Graduate Student
MATTILA Minttu, Undergraduate Student
TOIVONEN Raine, Graduate Student
Transcriptional Regulation of
Heat Shock
SISTONEN Lea, Group Leader, Professor
AHLSKOG Johanna, Postdoctoral Fellow
ANCKAR Julius, Postdoctoral Fellow
BERGMAN Heidi,
BJÖRK Johanna, Graduate Student
BLOM Malin, Undergraduate Student
BLOMSTER Henri, Postdoctoral Fellow
BUDZYNSKI Marek, Graduate Student
CHITIKOVA Zhanna, Graduate Student
ELSING Alexandra, Graduate Student
HENRIKSSON Eva, Postdoctoral Fellow
HYRY Annukka, Undergraduate Student
JOUTSEN Jenny, Graduate Student
PUUSTINEN Mikael,
RAUTOMA Karoliina,
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SAARENTO Helena, Research Associate
SANDQVIST Anton, Postdoctoral Fellow
VARTIAINEN Aki,
VASARA Jenni, Undergraduate Student
VIHERVAARA Anniina,
Graduate Student
ÅKERFELT Malin, Postdoctoral Fellow
The Finnish Microarray and
Sequencing Centre
Full-time personnel:
GYENESEI Attila, Senior Scientist
HAWKINS David, Group Leader
JUNNI Päivi, Laboratory Technician
JUNTTILA Sini, Project Engineer
KYTÖMÄKI Leena, Biotechnology Engineer
LAIHO Asta, Project Engineer
LUND Riikka, Senior Scientist
NURMI Miina, Laboratory Technician
PURSIHEIMO Juha-Pekka,
Senior Scientist
RISSANEN Oso, Laboratory Technician
VENHO Reija, Laboratory Technician
VIRTANEN Eveliina, Project Engineer
Part-time personnel:
ALA-KULJU Ritva,
ISOJÄRVI Janne, Undergraduate Student
SIPILÄ Anna, Undergraduate Student
SUNDSTRÖM Robin,
TAMMINEN Seppo,
Cancer Cell Signaling
WESTERMARCK Jukka, Group Leader,
Professor
CÕME Christophe, Postdoctoral Fellow
CVRLJEVIC Anna, Postdoctoral Fellow
HALONEN Tuuli, Graduate Student
KALEVO-MATTILA Taina,
KAUKO Otto, Graduate Student
KAUR Amanpreet, Graduate Student
LAINE Anni, Graduate Student
MANNERMAA Leni, Scientist
NIEMELÄ Minna, Graduate Student
OKKERI Juha, Postdoctoral fellow
POKHAREL Yuba, Postdoctoral fellow
VENTELÄ Sami, Postdoctoral Fellow
Coordination of European
Biobanking
VUORIO Eero, Professor, Director,
Biocenter Finland
SALMINEN-MANKONEN Heli,
Adjunct professor, Project manager
GRÖNROOS Sirkku, Project assistant
THE FINNISH MICROARRAY AND
SEQUENCING CENTRE
http://fmsc.btk.fi
Scientists in charge:
Attila Gyenesei, Ph.D., Senior Scientist
– FMSC services and daily issues, bioinformatics
Juha-Pekka Pursiheimo, Ph.D., Senior Scientist – SOLID NGS
Riikka Lund, Ph.D., Senior Scientist – Epigenetics
David Hawkins, Ph.D., Group Leader
– Epigenetics and emerging technologies
Contact information:
Turku Centre for Biotechnology, BioCity,
Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland.
Tel. +358-2-333 8634, Fax +358-2-333 8000.
Email: [email protected]
http://fmsc.btk.fi
Personnel:
Ritva Ala-Kulju, Päivi Junni, Sini Junttila, Leena Kytömäki,
Asta Laiho, Oso Rissanen, Reija Venho, Eveliina Virtanen,
Seppo Tamminen
Steering Committee:
Prof. Olli Carpén, Chair (University of Turku), Prof. Eva-Mari Aro
(University of Turku), Prof. Klaus Elenius (University of Turku), Prof.
Riitta Lahesmaa (University of Turku), Prof. Tarja Laitinen (University
of Turku), Prof. Harri Lähdesmäki (University of Turku, Aalto
University), Prof. Craig Primmer (University of Turku), Prof. Harri
Savilahti (University of Turku), Prof. Lea Sistonen (Åbo Akademi
University), Prof. Stina Syrjänen (University of Turku)
General description:
The Finnish Microarray and Sequencing Centre (FMSC), an
internationally recognised Functional Genomics Core Facility
belongs to the Turku Centre for Biotechnology. As a national core
facility, we provide state-of-the-art research technologies and
services in the areas of genomics, epigenomics, transcriptomics and
bioinformatics for the Finnish as well as the international scientific
community. Our services include next-generation sequencing and
microarray based services mainly facusing on gene expression and
regulation as well as epigenetics, Real-Time PCR and traditional
DNA sequencing. Our service covers all steps from experimental
planning and design to sample processing and bioinformatics data
analysis. The Centre also regularly organizes courses, symposia
and training for its users.
FMSC hosts a high-throughput next-generation sequencing
(NGS) instrument SOLiDTM 4 from Life Technologies. The system
supports a wide range of genetics applications covering genomics,
transcriptomics and epigenomics and it is distinguished by its
unmatched accuracy and capability of generating more than 100
gigabases of mappable sequence data per run. The combination
of increased throughput, shorter run times, and improved data
analysis make the SOLiD technology an ideal choice for research
applications in any genetics project. The system enables for
example distinguishing strand specific expression patterns,
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discoverage of novel stranscripts and splice variation without the
bias of microarrays, detecting SNPs at low coverage with a low
false positive rate, global assessment of DNA-protein binding
interactions and charaterization of structural rearrangements
including balanced translocations.
Our Centre also provides services on commercial microarray
platforms for genome-wide RNA expression profiling, SNP
genotyping and comparative genomic hybridization needs. These
platforms include Affymetrix GeneChip©, Illumina Sentrix Bead
Array© and Agilent DNA technology services for all of which we have
been granted the Certified Service Provider status. All platforms
have dedicated scanners and software for array data analysis.
Diverse aspects of the microarray techniques are continuously
developed and tested.
The Microarray and Sequencing Centre also offers a number of
other genomic analysis technologies for gene expression, SNP
and genotyping studies including a sequencing facility and realtime PCR service. Services include BioRad Experion and Agilent
Bioanalyzer runs for verifying the RNA quality.
Bioinformatics data analysis and data mining are included in the
data analysis service that is provided for microarray and nextgeneration sequencing customers. The data handling is done by
our bioinformaticians, using both commercial and R/Bioconductor
software tools.
and its regulation. Publications and unpublished data by Helicos
scientists and their collaborators indicated this to be a method
of choice for single molecule sequencing applied to digital gene
expression and ChIP sequencing. Biocity Turku decided to test this
technology - as BF funding was not available, strategic funding
was reserved by our university for purchase. The instrument was
installed in March 2010 for evaluation. Methods and data analysis
pipelines were set up and tested for Digital Gene Expression (DGE),
RNA-Seq and ChIP-Seq analysis. These have provided invaluable
data not possible to generate through the other platforms available.
During the summer 2010 the company went through reorganization
and changed their business strategy. Thus, Heliscope instrument
was not purchased, however, the collaboration with the company
continues. The advantages of the Helicos technique include low
amount of starting material needed, short sample preparation time
(3h-3d) and amplification free sample processing for DGE and
ChIP-Seq applications.
Funding:
University of Turku
Biocenter Finland
Users:
Finnish Microarray and Sequencing Centre has national and
international customers from universities, biocenters and research
institutes in the field of biosciences.
Seminars and practical courses on microarrays, next-generation
sequencing and related bioinformatics are held frequently to
facilitate knowledge transfer within the field, often this is done in
collaboration with graduate schools.
Major achievements in 2010:
According to the division of tasks within the Biocenter Finland
Genome-wide Methods Network Turku node focuses on developing
technologies in the areas of gene expression. Accordingly, we have
focused on optimising methods to implement services for:
• Sequencing of immunoprecipitated DNA/RNA
(ChIP-seq, CLIP-seq, ChIP-chip)
• RNA sequencing
• Gene expression microarrays
Additionally, the Centre is focusing on developing advanced
techniques and optimizing reagents for studies on epigenetics and
chromatin structure exploiting both next generation and later nextnext generation platforms.
To achieve the goals the following was accomplished in 2010:
• SOLiD 3 was successfully installed, upgraded to SOLiD 3.5 and then to SOLiD 4; during the first quarter of the 2011 the instrument will be further upgraded to the latest version, 5500xl SOLiD.
• 84 service projects were carried out in 2010 including both microarray and NGS projects.
For the next-next generation sequencing, HeliScope Instrument
from Helicos BioSciences was tested. Based on our thorough
survey in 2009 Helicos Single Molecule Sequencing was identified
as one of the most promising emerging technologies and particularly
useful for studies in our focus area of expertise - gene expression
16
From left to right: Sini Junttila, Reija Venho, Leni Mannermaa, Eveliina Virtanen, Päivi
Junni, Attila Gyenesei, Asta Laiho, Sanna Vuorikoski and Juha-Pekka Pursiheimo.
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CELL IMAGING CORE (CIC)
http://www.btk.fi/cell-imaging/
Coordinator and Group Leader
Daniel Abankwa, Ph.D., PI, Turku Centre for Biotechnology,
BioCity, 5th floor, Tykistökatu 6B, FI-20521, Finland.
Tel. +358-2-3336969, Fax +358-2-3338000.
E-mail: [email protected]
Technical Team/Technical Team leaders
Perttu Terho, M.Sc., Technical Engineer Flow Cytometry, E-mail:
[email protected], Markku Saari, M.Sc., Researcher Microscopy,
E-mail: [email protected], Jari Korhonen, M.Sc., Researcher Microscopy,
E-mail: [email protected], Jouko Sandholm, M.Sc., Senior
Researcher Microscopy, E-mail: [email protected]
Most of the instruments are provided in two facility areas of the
CBT, while others are housed nearby within Biocity. In mid 2011,
we will expand our instrumentation to feature a new confocal
microscope with fluorescence lifetime imaging and fluorescence
correlation spectroscopy capabilities. In addition, image treatment
workstations will become available, that run the locally developed
BioImageXD advanced image treatment software.
We organize local and national training programs, service existing
equipment, sustain research on new imaging techniques, and
implement the latest technological advances demanded by the
research community. A number of international leaders in the field of
microscopic imaging have visited Turku for scientific presentations
and lectures, such as Jennifer Lippincott-Schwartz (NIH, USA) and
Kota Miura (EMBL, Germany).
Steering Committee:
Prof. Olli Carpén, M.D., Ph.D., University of Turku, Prof. John Eriksson
(chairman), Ph.D., Åbo Akademi University, Prof. Jyrki Heino, M.D.,
Ph.D., University of Turku, Prof. Pekka Hänninen, Ph.D., University
of Turku, Prof. Sirpa Jalkanen, M.D., Ph.D., University of Turku, Prof.
Riitta Lahesmaa, M.D., Ph.D., University of Turku, Prof. Olli Lassila,
M.D., Ph.D., Prof. Matti Poutanen, Ph.D., University of Turku, Prof.
Lea Sistonen, Ph.D., Åbo Akademi University, Kid Törnquist, Ph.D.,
Åbo Akademi University
Core facility description:
The mission of Cell Imaging Core (CIC) is to provide state-of-theart cell imaging and flow cytometry technologies and to make
them available to scientists and students mainly coming from the
University of Turku, Åbo Akademi University and VTT Technical
Research Centre for Medical Biotechnology. Importantly, CIC is
open to both academic and industrial researchers.
One major goal of CIC is to enhance the research and teaching
environment locally, nationally and internationally. Therefore, CIC:
• provides technical training to local and visiting researchers and to industries
• offers consultation on experimental design and image analysis
• evaluates new methods and fluorescence tools and communicates acquired knowledge to users
• implements advances in hardware and software relevant for biomedical sciences
• provides ongoing education in theory and practice by organizing training courses and international workshops
Our staff include a coordinator and experienced application
specialists, who maintain the instruments, learn new technologies
and most importantly, provide personal training to users. Our
areas of technical expertise are STED-superresolution microscopy,
F-techniques (FRET, FRAP and FLIP-imaging), confocal microscopy
(including timelapse and spectral detection), high-content imaging,
widefield fast CCD imaging, laser microdissection, high throughput
cell sorting, flow cytometry FRET and advanced flow cytometry
software development. The STED-technique was developed by
Stefan Hell in the group of Prof. Pekka Hänninen in the mid 1990s in
Turku. Complementary to this superresolution technology, we have
two Atomic Force Microscopy (AFM) setups, which are coupled to
a Zeiss 510 and the Leica STED microscope
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From left to right: Daniel Abwanka, Perttu Terho, Markku Saari, Jari Korhonen.
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Current information on events, services and pricing can be found
on the facility webpages.
THE PROTEOMICS FACILITY
CIC has succeeded both as a service provider and as a point
of integration of emerging imaging technologies. Added value is
achieved by the first-class expertise in the fields of fluorescenceactivated cell sorting, fluorescence-based screening and robotic
instrumentation, high-content screening, in vivo animal imaging,
and viral gene transfer in the Turku scientific community.
http://www.btk.fi/proteomics
CIC is nationally and internationally networked (e.g. through the
Nordic Network on Imaging in Medicine and Biology). Importantly,
CIC is one of the major contributors to Turku Bioimaging, an
umbrella organization, which aims at organizing and supporting
bioimaging expertise in the Turku area. Through this activity,
Turku Bioimaging sites have become one of the first three test
sites for the Euro-BioImaging initiative. Euro-BioImaging aims at
providing access, service and training to state-of-the-art imaging
technologies in Europe. To this end a harmonized infrastructure
deployment is planned in the next few years, which is meant to
facilitate excellence in research.
Funding:
The Academy of Finland, University of Turku, Åbo Akademi
University, BioCity Turku Research Groups, Biocenter Finland,
Health and Welfare Ministry
Coordinator and Group Leader:
Garry Corthals, Ph.D. (2005). Address: Turku Centre for
Biotechnology, BioCity, Tykistökatu 6, P.O. Box 123, FI-20521
Turku, Finland. Tel. +358-2-333 8889, Fax +358-2-333 8000.
Personnel:
Senior scientists: Dr. Anne Rokka, Ph.D.; Petri Kouvonen, Ph.D.;
Susumu Imanishi, Ph.D.; Laboratory Engineer: Arttu Heinonen;
Technician: Raija Andersen; Bioinformatician: Eliza Ralph
Steering Committee:
Prof. Eva-Mari Aro (University of Turku), Dr. Eleanor Coffey (Åbo
Akademi University), Prof. John Eriksson (Åbo Akademi University), Prof. Jyrki Heino (University of Turku), Prof. Riitta Lahesmaa
(CBT), Prof. Matti Poutanen, Prof. Craig Primmer (University of
Turku), Prof. Jukka Westermarck (CBT) and Prof. Johanna Ivaska
(VTT & CBT)
General description:
The Turku Proteomics Facility is engaged in the development and
application of proteomics and mass spectral methods in key areas
of life science research. In doing so we have developed a wide
basis of operation and expertise in Quantitative proteomics, Posttranslational modification analysis, Imaging mass spectrometry, Biological mass spectrometry, Protein separation and Bioinformatics.
The Mission of the Facility is to advance MS methods and instrumentation to meet the needs in molecular biotechnology and medicine. Our goals are to identify new areas appropriate for MS in
biological sciences and to develop new approaches involving MS,
to apply cutting-edge MS to tackle critical questions in biological
sciences, and train students, postdoctoral fellows and practicing
scientists in the use of MS and encourage its wide and appropriate
use.
We are a nationally funded technology platform supported by Biocentre Finland, spearheading mass spectrometric strategies for
quantitative analysis of proteins and proteomes, and structural
analysis of PTMs. Analytical services
The facility offers access to sophisticated instruments and performs
structural analytical protein and proteome measurements. Most
services involve mass spectral methods integrated with protein
and peptide enrichment workflows for large-scale analysis of
proteomes or detailed characterisation of single proteins. We aim to
offer the best possible analytical proteomics services to bioscience
researchers in academia and industry, both locally and nationally
through Biocentre Finland coordinated activities. A broad range of
mass spectral analyses are performed, and at the nationally level
the facility spearheads developments in two of its services; MSbased quantitative proteomics and phosphorylation determination.
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A full representation of our services are as follows:
• Quantitative proteomics – Targeted analysis of proteomes following isobaric or isotopic labelling with iTRAQ and SILAC reagents. Additionally we have established a framework for label-free quantitative analysis, particularly useful for large-scale clinical studies.
• Qualitative proteomics – ‘-omic-scale’ analysis of cells, tissues and fluids is available in all areas of life science. We have developed several integrated fractionation techniques to provide deep proteome coverage from minimal sample amounts.
• Post-translational modifications – a long standing
history with phosphorylation analysis exists on campus, and we are actively expanding our ‘PTM tool set’ through newly developed methods by various closely affiliated groups, such as sumoylation.
• Imaging mass spectrometry – imaging of tissues is offered as a collaborative service with the proteomics research group. IMS is expanding its activities in Turku in the new Master’s Degree Programme in Turku Bioimaging. • Biological mass spectrometry – various analytical measurements for protein, peptide and small molecule structure determination, mass determination and peptide and protein purity are offered.
• Protein separation – numerous separation technologies including liquid chromatography and a variety of gel based methods such as 1-DE, 2-DE, peptide-IPG and blue native gel electrophoresis.
• Bioinformatics – in all areas of proteomics bioinformatics services are offered including identification, quantitation and validation studies, reporting and software development.
Funding:
Biocenter Finland, The Academy of Finland, TEKES, City of Turku,
Ministry of Education/Proteomics and the Centre of Expertise of
Southwest Finland, Turku University and Åbo Akademi University,
Bruker Daltonics, the Systems Biology Research Program.
Users:
Biocentre Finland universities, The University of Turku, Åbo Akademi
University, Turku Polytechnic, VTT - Molecular Biotechnology.
CoE’s in: Translational Genome-Scale Biology; Evolutionary
Genetics and Physiology; Integrative Photosynthesis and Bioactive
Compound Research at Systems Biology Level; and Åbo Akademi
CoE in Cell Stress. The Systems Biology Research Program,
national research groups, Turku Hospitals, the Finnish Red Cross
and the National Animal Research Centre.
PROTEIN CRYSTALLOGRAPHY
CORE FACILITY
http://crystal.btk.fi
Head:
Anastassios C. Papageorgiou, Ph.D., Adjunct Professor in
Biochemistry and Structural Biology Turku Centre for Biotechnology,
BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-3338012, Fax +358-2-3338000.
Technical Team:
Technical support: Juha Strandén, Pasi Viljakainen.
Computational support: Petri Vahakoski, Mårten Hedman
Steering committee:
Jyrki Heino, Professor, Department of Biochemistry and Food
Chemistry, University of Turku Reijo Lahti, Professor, Department
of Biochemistry and Food Chemistry, University of Turku Tiina Salminen, Senior lecturer, Department of Biochemistry, Åbo Akademi
Description of the Facility
X-ray crystallography is a proven technique for detailed structurefunction studies of biological macromolecules. The Protein Crystallography Core Facility at CBT uses state-of-the-art equipment
to determine the crystal structures of various proteins and their
complexes. The Facility consists of an X-ray generator (soon to
be replaced by a new one), Mar345 imaging plate detector, Osmic confocal mirrors, a Cryostream Cooler (Oxford Cryosystems)
and several computers running under Linux operating systems for
heavy duty calculations. The Facility has several workstations to
run a variety of molecular graphics software (O, XtalView, Grasp,
COOT, CCP4mg, PyMol, Chimera), modeling and docking programs (MODELLER, Hex, Discovery Studio, ROSETTA), and various crystallographic packages (HKL, XDS, CNS, CCP4, SHELX,
SOLVE, SHARP, PHENIX) for data processing, analysis, phasing
and refinement. The Facility has long expertise in all steps of a
crystal structure determination: protein purification, crystallization,
data collection (both in-house and in synchrotron radiation sources), data processing, phase determination, refinement and detailed
analysis of the final structure. Incubators at different temperatures
(4° C, 16 °C and 23 °C) for crystallization set-ups and a number of
commercial screens for establishing initial crystallization conditions
are available. In addition, we can provide homology modeling services and design of mutants for functional studies as well as ab initio predictions of protein structures. Since protein crystallography
requires highly pure protein preparations, we can offer full support
and consultation on protein purification strategies apart from the
services in structure determination and modeling. The Facility is
able to undertake research projects for academic groups and companies, either in the form of collaborative efforts or as services. Protein Crystallography requires a multi-disciplinary approach and we
are especially interested in bringing together expertise from various
groups in order to better understand the structure-function relationship of biological macromolecules in key biological processes.
Funding:
Systems Biology research program, Biocenter Finland, University
of Turku
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BIOINFORMATICS CORE
Coordination:
Konstantin Denessiouk, Ph.D., Docent in Biochemistry. Bioinformatics Group leader. Centre for Biotechnology, Tykistökatu 6,
BioCity 5th floor, Turku, 20520 Turku. E-mail: [email protected]
Attila Gyenesei, Ph.D., Senior Scientist, Turku Centre for
Biotechnology, BioCity, Tykistökatu 6A, P.O. Box 123,
FIN-2050 Turku, Finland.
Tel. +3582-333 8634, Fax +358-2-333 8000.
Personnel:
Bhanupratap Singh Chouhan, Sini Junttila, Asta Laiho,
Leena Kytömäki, Seppo Tamminen
Description of the Facility:
The bioinformatics core at the Turku Centre for Biotechnology is divided into Structural Bioinformatics and High-throughput Bioinformatics facilities. The main goal of the Structural Bioinformatics Core
is to apply methods and techniques of bioinformatics to study biological macromolecules, their interactions and function. We work in
close collaboration with experimental groups and are able to provide
structure-related analysis and prediction in different biological systems. The core works closely with the CSC Finnish IT Center for Science, the Finnish national supercomputing centre and the Structural
Bioinformatics Laboratory at the Åbo Akademi University.
High-throughput bioinformatics complements experimental genomics and transcriptomics by storing, analysing and integrating
data and generating hypotheses to guide the design of new experiments to further elucidate gene function. The core provides
services in the analysis of microarray and deep sequencing data.
In addition to providing data analysis and data integration services
we have robust methods for the design of experiments and novel
microarrays for both diagnostics and biological marker selection.
Our analysts are supported by robust super-computing facilities and
state-of-the-art software. Team members are engaged in the ongoing development of advanced analysis tools and research on generating novel approaches for the analysis of high-throughput data sets.
The main services of our core are:
• Experimental design consultation
• Data analysis of various microarray and deep
sequencing data types
• Data analysis education and training
• Computer-based analysis of protein-protein and
protein-ligand interactions
• Computer-aided prediction and intelligent molecular
modeling and design
• Computer-based ligand docking
• Analysis and prediction of effects of molecular recognition and mutations on protein function
Selected Publications:
Kankare M, Salminen T, Laiho A, Vesala L, Hoikkala A. Changes
in gene expression linked with adult reproductive diapause in a
northern malt fly species: a candidate gene microarray study. BMC
Ecol. 2010 Feb 1;10:3.PMID: 20122138
Sirén A, Polvi A, Chahine L, Labuda M, Bourgoin S, Anttonen AK,
Kousi M, Hirvonen K, Simola KO, Andermann E, Laiho A, Soini J,
Koivikko M, Laaksonen R, Pandolfo M, Lehesjoki AE. Suggestive
evidence for a new locus for epilepsy with heterogeneous phenotypes on chromosome 17q. Epilepsy Res. 2010 Jan;88(1):6575.
Epub 2009 Nov 14.PMID: 19914042
Huvila J, Brandt A, Rojas CR, Pasanen S, Talve L, Hirsimäki P, Fey
V, Kytömäki L, Saukko P, Carpén O, Soini JT, Grénman S, Auranen
A. Gene Expression profiling og endometrial adenocarcinomas reveals increased apolipoprotein E expression in poorly differentiated
tumors. Int J Gynecol Cancer. 2009 Oct;19(7):1226-31.
Oksala N, Levula M, Airla N, Pelto-Huikko M, Ortiz RM, Järvinen
O, Salenius JP, Ozsait B, Komurcu-Bayrak E, Erginel-Unaltuna
N, Huovila AP, Kytömäki L, Soini JT, Kähönen M, Karhunen PJ,
Laaksonen R, Lehtimäki T. ADAM-9, ADAM-15, and ADAM-17 are
upregulated in macrophages in advanced human atherosclerotic
plaques in aorta and carotid and femoral arteries--Tampere vascular study. Ann Med. 2009;41(4):279-90.
Levula M, Airla N, Oksala N, Hernesniemi JA, Pelto-Huikko M,
Salenius JP, Zeitlin R, Järvinen O, Huovila AP, Nikkari ST, Jaakkola
O, Ilveskoski E, Mikkelsson J, Perola M, Laaksonen R, Kytömäki
L, Soini JT, Kahonen M, Parkkinen J, Karhunen PJ, Lehtimäki T.
ADAM8 and its single nucleotide polymorphism 2662 T/G are
associated with advanced atherosclerosis and fatal myocardial
infarction: Tampere vascular study. Ann Med. 2009 Jul 2:1-11.
Fan YM, Karhunen PJ, Levula M, Ilveskoski E, Mikkelsson J, Kajander OA, Järvinen O, Oksala N, Thusberg J, Vihinen M, Salenius
JP, Kytömäki L, Soini JT, Laaksonen R, Lehtimäki T. Expression
of sterol regulatory element-binding transcription factor (SREBF) 2
and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac
death. Thromb J. 2008 Dec 30;6:17.
Funding:
Grants from the Sigrid Jusélius Foundation, and the Borg Foundation
(Åbo Akademi University); Grant from the National Graduate School
in Informational and Structural Biology (ISB). Biocenter Finland
Infrastructure fund.
Users:
The Bioinformatics core has users from Finnish universities,
biocenters and research institutes in the field of biosciences.
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From left to right: Sini Junttila, Asta Laiho, Leena Kytömäki, Attila Gyenesei.
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VIRUS VECTOR FACILITY
http://virusvec.btk.fi
Coordination
Eleanor Coffey, Ph.D., Adjunct Professor in Cellular and Molecular
Biology, Turku Center for Biotechnology, BioCity, 5th floor,
Tykistokatu 6, FI-20521, Finland.
Jukka Westermarck, M.D., Ph.D., Professor of the Cancer Society
of Finland, Turku Center for Biotechnology, BioCity, 5th floor,
Tykistokatu 6, FI-20521, Finland.
Research, Development and Training
Anna Cvrljevic, postdoctoral researcher (Westermarck lab),
Turku Centre for Biotechnology, BioCity 5th floor, Tykistökatu 6,
FI-20521, Finland. E-mail: [email protected]
Technical Team
Ketlin Adel, Laboratory Technician, E-mail: [email protected]
The Virus Vector Facility produces viral vectors for local and national
research groups. During 2010, the Virus Vector Facility joined the
national infrastructure network on Viral Gene Transfer, funded by
Biocenter Finland. Our primary function is to facilitate the use of
viral vectors by national researchers. To meet these goals the virus
vector facility
Produces on demand adenoviruses and lentiviruses expressing
genes of interest, as a research service
•
provides a fully equipped bio-safety level-2 lab for researchers wishing to produce their own vectors (replication deficient viruses only)
•
•
•
supplies working protocols for production of adeno and lenti vectors and trains researchers in the safe preparation and handling of viral vectors
organises seminars and courses emphasizing practical issues related to gene transfer technology coordinates a network of local experts from whom consultation on design of viral vectors can be sought
The virus vector facility has a national user base with regular
customers from the universities of Turku, Oulu and Helsinki as well
as customers from biotech companies. In addition to customer
service, our infrastructure is used by 16 local research groups
producing adenoviruses, adeno-associated virus, retro- and lentivirus for their own research purposes. These viruses are typically
used to obtain high efficiency gene transfer in difficult to transfect
cells such as primary cultures of T lymphocytes and neurons and
for in vivo cancer studies. Another typical application is the use of
viral vectors for delivery of shRNA. Protocol optimization has been
completed for high efficiency gene silencing in primary cultured
neurons and T lymphocytes and more recently investigators are
using virally delivered miRNAs for gene knockdown studies.
To build on local expertise in gene transfer technologies, the
Virus Vector Facility networks with experts in viral vector design.
Thus a number of local experts on retroviruses and alpha-viruses
are available for consultation on vector design, production and
concentration.
From left to right: Ketlin Adel, Susanna Pyökäri, Jukka Westermarck, Eleanor Coffey
26
27
COORDINATION OF EUROPEAN
BIOBANKING
www.bbmri.eu,
www.bbmri.se/en/About-BBMRIse/BBMRI-Nordic,
www.bbmri.fi
Head:
Eero Vuorio, Professor, Director, Biocenter Finland, P.O. Box 56,
University of Helsinki, FI-00014 Helsinki, Finland
Mobile phone +358-50-415 6595, E-mail: [email protected]
Project Manager:
Heli Salminen-Mankonen, Ph.D., Docent, University of Turku,
Centre for Biotechnology, Tykistökatu 6, FI-20520 Turku, Finland,
Tel: +358-2-333 8566, E-mail: [email protected]
is the generation of an IT infrastructure capable of linking the
existing biobank-derived genetic and molecular phenotyping data
with data from clinical phenotyping and health-related registries.
The new European legal entity (ERIC) developed by the European
Commission to support the needs and operation of research
infrastructures, foresees the establishment of operational sites
(National Nodes) in different Member States under one legislation.
The BBMRI Management Office in Turku has also played an active
part in establishing the Finnish National Node, BBMRI.fi, and in
organizing the collaboration of Nordic biobanks where many of the
operational concepts and principles of BBMRI have been tested.
Funding:
The preparatory phase (1.2.2008-31.1.2011) of BBMRI has
been financially supported by the European Commission (grant
agreement 212111).
Description of project:
Human biological samples, such as blood, tissues or DNA, plus
associated clinical and research data, as well as biomolecular
research tools are key resources in unravelling genetic and
environmental factors underlying diseases and influencing
their outcome. Biological samples are used in high-throughput
techniques which allow examination of changes in the genome,
transcriptome, proteome, or metabolome. Insights derived
from these are expected to assist with the development of new
diagnostic, prognostic, and therapeutic tools. Consequently,
biological resources are considered as the essential raw material
for the advancement of biotechnology, human health and research
and development in life sciences. This is the landscape where
the pan-European Biobanking and Biomolecular Resources
Research Infrastructure (BBMRI) is expected and prepared to
integrate the existing quality controlled biobanks, biomolecular
resources and enabling technologies into a novel pan-European
biomedical research infrastructure, and to guide the way towards
establishment of high quality de novo European biobanks adhering
to the guidelines drafted by BBMRI.
The European Commission has granted 5 Mio € funding (20082011) to the Preparatory Phase of BBMRI to conceptualise and
secure funding for the construction of the European research
infrastructure for biobanking and biomolecular resources.
Management of BBMRI during the Preparatory Phase is divided
between Universities of Turku and Graz. Eero Vuorio has served as
a part-time Executive Manager and Heli Salminen as the Scientific
Manager of BBMRI. This has been a sizeable task as BBMRI
comprises 53 partners and nearly 250 associated organizations
from 33 countries.
The objectives addressed by the BBMRI consortium during the
Preparatory Phase were to develop a plan to integrate existing
quality controlled biobanks, biomolecular resources and enabling
technologies into a novel pan-European biomedical research
infrastructure (BBMRI-ERIC). BBMRI will not only provide a
comprehensive source of information about existing biological
sample collections and biomolecular resources, but will also
provide an operational concept for a sustainable infrastructure,
deliver standard operational procedures for future biobanking and
codes of conduct for European biobanks. A particular challenge
28
29
MECHANISMS AND BIOSENSORS
OF GTPASES
Principle investigator:
Daniel Abankwa, Ph.D., Turku Centre for Biotechnology, BioCity,
5th floor, Tykistökatu 6B, FI-20521, Finland. Tel. +358-2-3336969,
Fax +358-2-3338000. E-mail: [email protected]
Biography:
Daniel Abankwa (b. 1972) graduated in Chemistry (Dipl. Chem.)
from the Georg-August University in Göttingen in 1997 and
received his Ph.D. in Molecular Neurobiology from the HeinrichHeine University Düsseldorf (2001). In 2002, he joined Prof. Horst
Vogel at the EPFL in Lausanne as a Postdoc to become proficient
in quantitative fluorescence techniques. In 2006, he went to the
Institute for Molecular Biosciences in Brisbane, Australia with
a Fellowship from the Swiss National Science Foundation. With
Prof. John Hancock he worked as a senior postdoctoral fellow on
Ras nanocluster and discovered a novel switch III in Ras that is
associated with a previously undescribed nucleotide dependent
orientation of Ras on the membrane. In 2008 he joined Prof. Kirill
Alexandrov as a senior scientist at the same institute, to work on
Rab nanoclustering and a chemical screening project to identify
lipid transferase inhibitors. In July 2010, Daniel joined the Turku
Centre for Biotechnology.
Personnel:
Graduate student: Arafath Kaja Najumudeen, MSc
Graduate student: Ms Maja Solman, MSc
Postdoc: Camilo Guzman, PhD
Scientific Programmer: Mr. Zuhair Iftikhar, MSc
Description of the project:
Despite 30 years of intensive research, it is still not possible to
block small GTPases, in particular Ras, specifically to treat cancer
and other diseases. The major problem is to find a structural
‘pocket’ or mechanism that is characteristic for one out of the over
150 structurally highly related small GTPases. Crystal structures
provided detailed insight into the soluble G domain, revealing
that two parts of the molecule change their conformation upon
GTP-mediated activation. These structural elements, switch I
and II, are conserved in all GTPases and therefore not suitable
for specific drug-targeting. However, in the last few years novel
structural insight emerged that takes the organisation of Ras in the
membrane into account.
For almost two decades, the lipid modified C-terminal
HyperVariable Region (HVR) of small GTPases was recognized as
the primary structural determinant for isoform specificity. However,
a mechanistic explanation as to how the HVR realizes this was
missing. For Ras, we now have mechanistic insight how the HVR
is actually involved in this. Distinct HVRs of H-, N- and K-ras4B
guide the lateral segregation into distinct nanoscopic proteo-lipid
domains (nanoclusters) in the plasma membrane. From these
distinct nanoclusters, isoform specific signalling emerges.
In the last three years, we have described an additional mechanism,
which provides the missing structure-function link for small GTPase
specificity. Using a combination of computational biology and ex
vivo biophysical measurements, we have recently described a
novel switch III. This is formed by the b2-b3 loop and helix a5,
30
and is associated with the orientation of the G domain on the
membrane. Thus the Ras orientation is stabilized by the HVR and
helix a4 (Figure). We also showed that this orientation-switch is
specific for different Ras isoforms, regulates GTPase signalling and
combines with lateral segregation of Ras.
Research Questions:
• We are interested in understanding the molecular and structural determinants of GTPase isoform specificity.
• Building on our novel mechanistic insight, we are constructing specific biosensors to detect GTPase activity in cells.
• Finally, we are applying our insight into the design of novel screening assays, which will allow to identify novel isoform specific drugs.
The balance-model for isoform specificity – the missing
structure-function link for small GTPases. (A)
The two computationally simulated conformers of membrane
anchored H-Ras are primarily stabilized either by helix α4 (left) or the
HVR (right). (B) Schematic representation of the equilibrium, where
the orientation of the G domain is represented by a ‘balance’-bar.
Our balance-model explains that the conformational equilibrium
depends on the relative membrane affinities of the HVR and helix
α4, which differ among the Ras isoforms. The specific equilibrium
then profoundly influences downstream interactions and signalling.
We propose that this mechanism also operates in other members
of the Ras-superfamily.
Funding:
The Academy of Finland, University of Turku, Åbo Akademi
University, EU 7th framework (Marie-Curie grant), Cancer Society
Finland, Biocenter Finland, Sigrid-Juselius Foundation.
Collaborators:
Prof. Alemayehu Gorfe and Prof. John Hancock (UT Medical School,
Houston, USA), Prof. Kirill Alexandrov (Institute for Molecular
Bioscience, Brisbane, Australia), Dr. Christian Eggeling (Max-Planck
Institute Göttingen, Germany), Prof. Johanna Ivaska (VTT, Turku
Centre for Biotechnology), Dr. Harri Härmä (University of Turku),
Prof. Dimitrios Stamou (University of Copenhagen, Denmark),
Prof. Jukka Westermarck (Turku Centre for Biotechnology), Prof.
Parton (Institute for Molecular Bioscience, Brisbane, Australia), Dr.
Krishnaraj Rajalingam (University of Frankfurt, Germany), Prof. Mike
Waters (Institute for Molecular Bioscience, Brisbane, Australia)
Sinha, B., Koster, D., Ruez, R., Gonnord, P., Bastiani, M., Abankwa,
D., Stan, R. V., Butler-Browne, G., Vedie, B., Johannes, L., Morone,
N., Parton, R. G., Raposo, G., Sens, P., Lamaze, C., and Nassoy,
P. (2011) Cells respond to mechanical stress by rapid disassembly
of caveolae Cell 144, 402-413.
31
Nguyen, U. T., Goodall, A., Alexandrov, K., and Abankwa, D. (2011)
Isoprenoid Modifications. in Post-Translational Modifications in
Health and Disease (Vidal, C. J. ed.), 1st Ed., Springer. pp 486
Crouthamel, M., Abankwa, D., Zhang, L., Dilizio, C., Manning, D.
R., Hancock, J. F., and Wedegaertner, P. B. (2010) An N-terminal
polybasic motif of G{alpha}q is required for signaling and influences
membrane nanodomain distribution Mol Pharmacol
Abankwa, D., Gorfe, A. A., Inder, K., and Hancock, J. F. (2010)
Ras membrane orientation and nanodomain localization generate
isoform diversity Proc Natl Acad Sci U S A 107, 1130-1135.
Bastiani, M., Liu, L., Hill, M. M., Jedrychowski, M. P., Nixon, S. J., Lo,
H. P., Abankwa, D., Luetterforst, R., Fernandez-Rojo, M., Breen, M. R.,
Gygi, S. P., Vinten, J., Walser, P. J., North, K. N., Hancock, J. F., Pilch, P.
F., and Parton, R. G. (2009) MURC/Cavin-4 and cavin family members
form tissue-specific caveolar complexes J Cell Biol 185, 1259-1273.
Hill, M. M., Bastiani, M., Luetterforst, R., Kirkham, M., Kirkham, A., Nixon,
S. J., Walser, P., Abankwa, D., Oorschot, V. M., Martin, S., Hancock,
J. F., and Parton, R. G. (2008) PTRF-Cavin, a conserved cytoplasmic
protein required for caveola formation and function Cell 132, 113-124.
Abankwa, D., Hanzal-Bayer, M., Ariotti, N., Plowman, S. J., Gorfe,
A. A., Parton, R. G., McCammon, J. A., and Hancock, J. F. (2008)
A novel switch region regulates H-ras membrane orientation and
signal output Embo J 27, 727-735.
Abankwa, D., Gorfe, A. A., and Hancock, J. F. (2008) Mechanisms
of Ras membrane organization and signalling: Ras on a rocker Cell
Cycle 7, 2667-2673.
Gorfe, A. A., Bayer, M.-H., Abankwa, D., Hancock, J. F., and
McCammon, J. A. (2007) Structure and dynamics of the fulllength lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3phosphocholine bilayer J Med Chem 50, 674-684.
Abankwa, D., and Vogel, H. (2007) A FRET map of membrane
anchors suggests distinct microdomains of heterotrimeric G
proteins J Cell Sci 120, 2953-2962.
Abankwa, D., Gorfe, A. A., and Hancock, J. F. (2007) Ras
nanoclusters: molecular structure and assembly Seminars in cell &
developmental biology 18, 599-607.
Perez, J. B., Segura, J. M., Abankwa, D., Piguet, J., Martinez, K. L.,
and Vogel, H. (2006) Monitoring the Diffusion of Single Heterotrimeric
G Proteins in Supported Cell-membrane Sheets Reveals their
Partitioning into Microdomains J Mol Biol 363, 918-930.
From left to right: Daniel Abwanka, Arafath Kaja Najumudeen.
32
33
PROTEIN KINASE REGULATION OF
BRAIN DEVELOPMENT AND DISEASE
http://www.btk.fi/index.php?id=1240
Principal investigator:
Eleanor Coffey, Ph.D., Academy Research Fellow,
Turku Centre for Biotechnology, Åbo Akademi and Turku University,
BioCity, Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. +358-2-3338605, Fax +358-2-3338000. E-mail: [email protected]
Biography:
Eleanor Coffey (b. 1967) graduated from Trinity College Dublin in
1990 and received her Ph.D. from the University of Dundee in 1994.
She received a Wellcome Trust fellowship to carry out postdoctoral
research in Prof. Karl Åkerman’s laboratory from 1994-1997. In
1997 she founded the Neuronal Signalling group at Åbo Akademi
and in 2000 joined Turku Centre for Biotechnology as a group
leader in molecular and cellular biology. In addition to running a
research group, she directs the Cell Imaging Core at Turku Centre
for Biotechnology and coordinates the nordic network on Imaging
in Biology and Medicine. She was appointed to an Academy of
Finland Research Fellow post from 2008 to 2013.
Personnel:
Graduate students: Artur Padzik, M.Sc., Justyna Zdrojewska,
M.Sc., Emilia Komulainen, M.Sc., Raghu Mysore, M.Sc., Lihua Sun,
M.Sc., Hasan Mohammed, M.Sc., Prasanna Deshpande, M.Sc.
Undergraduate students: Hanna Heikelä
Description of the project :
Neurodegenerative disorders such as Alzheimer’s and Parkinson’s
disease as well as stroke are characterised by the irreversible loss
of nerve cell function. These diseases for which no cure is known
are among the most costly to society. The protein kinase JNK is
recognised as a critical player in stroke and neurodegeneration.
However exactly how this family of kinases mediates cell death in
the brain remains largely unknown. Although targeting of JNK for
drug-based therapy is already underway, our understanding of the
physiological function of JNK in the brain is in its infancy.
A major challenge for signal transduction therapy is to selectively
target the pathological function of signalling molecules without
interfering with important physiological roles. To achieve this, our
lab established a proteomics-based screen to identify protein
kinase substrates and thereby broaden our understanding
of kinase function. While we have used this methodology to
successfully identify both novel and known substrates for JNK,
p38 and PIM kinases (collaboration with Päivi Koskinen), among
others (collaboration Erwin Wagner), the main focus of our research
is to elucidate the molecular mechanism of JNK and JNK targets
in the brain. Identification of novel JNK targets such as SCG10
and MAP2, as well as others under study, has highlighted a
critical role for JNK in maintaining microtubule homeostasis and
subsequently regulating axodendritic architecture and nerve
cell movement. Identification of the JNK phosphorylation site on
kinesin-1 helped characterize a role for JNK in regulation of fast
axonal transport in neurons. We combine biochemical, proteomic,
cell biology and imaging methods with neuronal and organotypic
cultures as well as transgenic mice to validate kinase targets and
elucidate their function. In collaboration with Laurent Nyguen, we
34
have established methods to track radial migration of neurons in
the developing telencephalon using 4D imaging. In addition, we
are examining dendrite and spine morphology in JNK1-/- brains
using lucifer yellow iontophoretic loading followed by quantitative
3D image analysis.
An important finding from our lab is the compartmentalization of
JNK function in neurons into physiological and pathological pools
residing in the cytoplasm and nucleus respectively. By using
compartment-targeted peptide inhibitors of JNK, we have shown
that nuclear JNK activity is critical for neuronal death in response
to trophic deprivation (neuronal death that occurs during brain
development) and excitotoxic stimuli (neuronal death that occurs
during epilepsy, stroke and is contributory in neurodegenerative
disorders). To explore the therapeutic potential of compartmental
targeted JNK inhibitors, we are collaborating with Peter Clarke
(University of Lausanne). This study investigates the value of
nuclear-targeted peptide inhibitors of JNK as protectants from
brain damage that occurs following stroke.
Interestingly, although JNK is highly localised to the cytoplasm in
neurons, we find that cytosolic JNK does not to these particular
death mechanisms in neurons of the central nervous system.
Instead, JNK plays a critical role in corticogenesis, being required
to control the duration of two critical steps during formation of the
cortex, i.e. multipolar stage transition and radial migration. This
function of JNK is mediated by SCG10 and is independent of
nuclear JNK activity.
An important new study in our lab is a proteomic screen for LRRK2
substrates. LRRK2 is a kinase that is the most frequently mutated
protein in Parkinson’s disease, both familial and sporadic. Mutations
in LRRK2 lead to a gain of function in kinase activity which is believed
to underlie Parkinson’s pathology. Yet, substrates for LRRK2 have
remained elusive and therefore the disease mechanism is unknown.
In collaboration with European partners, we are searching for
LRRK2 targets in brain using a shot-gun approach. We then
examine the function of these targets in neurotoxicity and assess
their potential as biomarkers for earlier detection of Parkinson’s.
We hope that in the long run this will contribute helpful information
for therapeutic treatment of Parkinson’s and in the shorter term,
contribute tools that can be used for earlier clinical diagnosis.
Funding:
The Academy of Finland, the Sigrid Juselius Foundation, Finnish
Graduate School in Neurosciences, Turku University Biomedical
Sciences Graduate School, Sitra.
Collaborators:
Michael Courtney (University of Kuopio), Tuula Kallunki (Danish
Cancer Society), Thomas Herdegen (University of Kiel), Peter
Clarke (University of Lausanne), Erwin Wagner (Research Institute of
Molecular Pathology), Scott Brady (Univeristy of Illinois at Chicago),
Laurent Nguyen (University of Liege), Päivi Koskinen (University of
Turku), Aideen Long (Trinity College, Dublin).
Westerlund N, Zdrojewska J, Padzik A, Komulainen E, Björkblom
B, Rannikko E, Tararuk T, Garcia-Frigola C, Sandholm J, Nguyen
L, Kallunki T, Courtney MJ, Coffey ET. Phosphorylation of SCG10/
stathmin-2 determines multipolar stage exit and neuronal migration
rate. Nat Neurosci. 2011 Feb 6
35
Matlawska-Wasowska K, Finn R, Mustel A, O’Byrne CP, Baird AW,
Coffey ET, Boyd A. The Vibrio parahaemolyticus Type III Secretion
Systems manipulate host cell MAPK for critical steps in pathogenesis. BMC Microbiol. 2010 Dec 30;10:329.
Uusi-Oukari M, Kontturi LS, Coffey ET, Kallinen SA. (2010) AMPAR
signaling mediating GABA(A)R delta subunit up-regulation in cultured mouse cerebellar granule cells. Neurochem Int.
Filén S, Ylikoski E, Tripathi S, West A, Björkman M, Nyström J, Ahlfors H, Coffey E, Rao KV, Rasool O, Lahesmaa R. (2010) Activating
transcription factor 3 is a positive regulator of human IFNG gene
expression. J Immunol. 184:4990-4999.
Podkowa M, Zhao X, Chow CW, Coffey ET, Davis RJ, Attisano
L. (2010) Microtubule stabilization by bone morphogenetic protein
receptor-mediated scaffolding of c-Jun N-terminal kinase promotes
dendrite formation. Mol Cell Biol. 30:2241-2250.
Morfini, G., You, Y., Pollema, S., Kaminska, A., Pigino, G., Liu, K.,
Yoshioka, K., Björkblom, B., Coffey, E.T., Bagnato, C., Han, D.,
Huang, C., Banker, G. and Brady, S.T. (2009) Inhibition of fast axonal
transport by pathogenic Huntingtin involves activation of JNK3 and
phosphorylation of kinesin-1. Nature Neuroscience, 12:864-871.
Waetzig, V, Wacker, U, Haeusgen, Björkblom,B, Courtney, M.J.,
Coffey, E.T. Herdegen, T. (2009) Concurrent protective and
destructive signalling of JNK2 in neuroblastoma cells. Cellular
Signalling, 21: 873-880.
Naumanen, T., Johansen, L.D., Coffey, E.T., Kallunki, T. (2008) Loss
of function of IKAP/ELP1: Could neuronal migration defect underlie
familial disautonomia? Cell Adhesion and Migration, 2:236-239.
Björkblom B, Vainio JC, Hongisto V, Herdegen T, Courtney MJ,
Coffey ET. (2008) All JNKs can kill, but nuclear localization is critical
for neuronal death. Journal of Biological Chemistry, 283:19704-13.
Hongisto, V., Vainio, J.C., Thompson, R., Courtney, M.J., Coffey,
E.T. (2008) The Wnt pool of GSK-3-beta is critical for trophic
deprivation induced neuronal death. Molecular and Cellular Biology,
285:1515-27.
Dan Johansen, L., Naumanen, T., Knudsen, A., Westerlund, N.,
Gromova, I., Junttila, M., Nielsen, C., Bottzauw, T., Tolkovsky,
A., Westermarck, J., Coffey, E.T., Jäättelä, M., Kallunki, T. (2008)
IKAP localizes to membrane ruffles with filamin A and regulates
actin cytoskeleton organization and cell migration. Journal of Cell
Science, 121:854-64.
Westerlund, N., Zdrojewska, J., Courtney, M., Coffey, E. (2008)
SCG10 as a molecular effector of JNK1: Implications for the
therapeutic targeting of JNK in nerve regeneration. Expert Opinion
on Therapeutic Targets. 12:31-43. Review.
Semanova, M.M., Mäki-Hokkanen, A.M.J., Cao, C., Komarovski, V.,
Forsberg, K.M., Koistinaho, M., Coffey, E.T., Courtney, M.J. (2007)
Rho mediates calcium-dependent activation of p38a and subsequent
excitotoxic cell death. Nature Neuroscience, 10(4):436-443.
Tararuk, R., Östman, N., Li, W., Björkblom, B., Padzik, A.,
Zdrojewska, J., Hongisto, V., Herdegen, T., Konopka, W., Courtney,
M.J., Coffey, E.T. (2006) JNK1 phosphorylation of SCG10
determines microtubule dynamics and axodendritic length. Journal
of Cell Biology. 173: 265-277.
Björkblom, B., Östman, N., Hongisto, V., Komarovski, V., Filen, J.,
Nyman, T., Kallunki, T., Courtney, M., Coffey, E. (2005) Constitutively
36
From left to right: Prasannakumar Deshpande, Artur Padzik, Justyna Zdrojewska,
Eleanor Coffey, Mohammad Hasan, Lihua Sun.
active cytoplasmic JNK1 is a dominant regulator of dendritic
architecture; role of MAP2 as an effector. Journal of Neuroscience.
25: 6350-6361.
Yang, J., Lindahl, M., Lindholm, P., Virtanen, H., Coffey, E.,
Runeberg-Roos, P., Saarma, M. (2004) PSPN/GFRalpha4 has a
significantly weaker capacity than GDNF/GFRalpha1 to recruit RET
to rafts, but promotes neuronal survival and neurite outgrowth.
FEBS Letters.569: 267-271.
Cao, J., Semenova, M.M., Solovyan, V.T., Han, J., Coffey, E.T.,
Courtney, M.J. (2004) Distinct requirements for p38alpha and c-Jun
N-terminal kinase stress-activated protein kinase s in different
forms of apoptotic neuronal death. Journal of Biological Chemistry.
279: 35903-35913.
Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney, M.J.,
Coffey, E.T. (2003) Lithium blocks the c-Jun stress response and
protects neurons via its action on glycogen synthase kinase 3.
Molecular and Cellular Biology. 23: 6027-6036.
Coffey, E.T., Smiciene, G., Hongisto, V., Cao, J., Brecht, S.,
Herdegen, T., Courtney, M.J. (2002) c-Jun N-terminal protein
kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun
activation, in the presence of constitutive JNK1 activity in cerebellar
neurons. Journal of Neuroscience. 22: 4335-4345.
Hietakangas, V., Elo, I., Rosenstrom, H., Coffey, E.T., Kyriakis, J.M.,
Eriksson, J.E., Sistonen, L. (2001) Activation of the MKK4-JNK
pathway during erythroid differentiation of K562 cells is inhibited by
the heat shock factor 2-beta isoform. FEBS Letters. 505: 168-172.
Coffey, E.T., Hongisto, V., Dickens, M., Davis, R.J. and Courtney,
M.J. (2000) Dual roles for c-Jun N-terminal kinase in developmental
and stress responses in cerebellar granule neurons. Journal of
Neuroscience. 20: 7602-7613.
Courtney, M.J. and Coffey, E.T. (1999) The mechanisms of ARA-C
induced apoptosis of differentiating cerebellar granule neurons.
European Journal of Neuroscience. 11: 1073-1084.
Coffey, E.T. and Courtney, M.J. (1997) Regulation of SAPKs in CNS
neurons. Biochem Soc Trans. 25: S568.
37
TRANSLATIONAL PROTEOMICS
http://www.btk.fi/?id=109
Garry Corthals, Ph.D. Address: Turku Centre for Biotechnology,
BioCity, Tykistökatu 6, FI-20521 Turku, Finland.
Tel. +358-2-333 8889, Fax. +358-2-333 8000.
Biography:
Garry Corthals completed his Ph.D. in 1997 at Macquarie University
in Sydney; and has since worked in the field of biomedical
proteomics oriented mass spectrometry. After completing his
post-doctoral studies with Ruedi Aebersold at the Department
of Molecular Biotechnology, University of Washington, Seattle,
he moved to the Garvan Institute for Medical Research in Sydney
where he started a research group and was head of the Proteomics
Facility. In 2001 he was recruited to Geneva University Hospital
where his research continued to focus on technological aspects of
biomedical mass spectrometry and to coordinate and develop the
Mass spectrometry facility at Medical Faculty. Now at the Centre
for Biotechnology his group focuses on translational aspects of
proteomics based mass spectrometry. Additionally he is head of
the Turku Proteomics Facility and coordinates the ProtMet.net, the
Finnish Proteomics and Metabolomics infrastructure of Biocenter
Finland. Further activities include the coordination of several Nordic
networks including Nordic Quantitative Proteomics research schools,
the Nordic Signals research network and the Nordic MS imaging
network. He is chair of the Education Committee of the EuPA and
serves on the HUPO education committee. He is also an editor of
SciTopics Biochemistry, Genetics and Molecular Biology section.
Personnel:
Seniors scientists: Anne Rokka, Ph.D., Petri Kouvonen, Ph.D.
Graduate students: Anni Vehmas, Olli Kannaste, Veronika Suni,
Hugo de Santos
Technicians: Arttu Heinonen, Fanni Virtanen, Sini Eerola, Emmi
Hakanen, Anneliis Ihermann
Undergraduate students: Ahmed BulBul, Thaman Chand, Noora
Jaakkola, Eliza Ralph, Firouz Saeidi, Avinash Yadav
Our group’s focus is to develop and apply powerful proteomics
tools to be used in translational and systems biology based
projects, where technological developments are driven by biological
questions. Of particular interest to our group are endometriosis,
epilepsy and prostate cancer, as well as several others biomedical
projects that exist through collaborations.
The group of researchers involved in our work has a diverse set
of skills, ranging from chemistry and biochemistry, to clinical
backgrounds, to computational scientists and mathematicians,
reflecting a multidisciplinary environment. All of our research
essentially evolves around mass spectrometry (MS), as over the
past two decades MS has emerged as the method of choice to
discover, measure and characterise proteins in biological systems.
For the analysis of tissues we are interested in defining and
measuring abundance changes of proteins and peptides, which of
these have an impact on their microenvironment, which enter the
38
blood system, and ultimately which impact on disease progression
or reflect a class of disease. We therefore require methods that
enable highly sensitive identification and quantitation of proteins
in tissues and body fluids. Measurement of proteins in tissues
substructures is pursued via laser capture microdissection (LCM)
of minute amounts of cryosectioned tissues, that ultimately
enable exquisite detail of the molecular components of cellular
substructures, adding important localised detail about the tissue
status. The quantitative aspect of these measurements focuses
on measuring protein change in tissues. To this end we are
investigating novel computational methods that enable quantitative
measurements of proteins in tissues.
We are also pursuing the use of MALDI imaging MS, which now
allows the simultaneous analysis of the distributions of up to
hundreds of peptides and proteins directly from a tissue section or
tissue array. The technique uses the masses of the peptides and
proteins to distinguish between different species and thus does
not require any form of labeling. These profiles can be used to
obtain biomolecular signatures associated with specific histological
features, adding a further handle in our quest to distinguish different
regions within a tissue and to differentiate and classify tissues.
Another of interest for the group is the identification and quantitation
of phosphopeptides and proteins. Again we have a two-tiered
approach where we are developing both laboratory procedures
as well as computational methods. Our recent observations
have focused the on the use of planar surfaces that act as an
enrichment and analytical platform for phosphopeptide analysis,
paving the way for array based analyses. Our computational
methods in phosphorylation analysis focus on increasing the speed
and validation of phosphorylation analysis – nowadays seen as a
bottleneck delaying true HTP phosphorylation analysis. Additionally
we are developing several bioinformatics tools that allow the
efficient investigation of proteomics workflows in the laboratory.
Funding:
The Academy of Finland, TEKES, Finnish Cancer Foundations,
Nordforsk, the Systems Biology Research Program, Turku Centre
for Computer Science Graduate Programme (TUCS), The National
Graduate School in Informational and Structural Biology (ISB), the
University of Turku, Bruker Daltonics.
Kouvonen P.; Rainio E.M.; Suni V.; Koskinen P.; Corthals G.L. (2010)
Data combination from multiple matrix-assisted laser desorption/
ionization (MALDI) matrices: opportunities and limitations for MALDI
analysis, Rapid Commun Mass Spectrom. 24(23):3493-5.
Abrahams J-P.; Apweiler R.; Balling R.; Bertero M.; Bujnicki J.M.;
Chayen N.E.; Chène P.; Corthals G.L.; Dyląg T.; Förster F.; Heck
A.J.R.; Henderson P.J.F.; Herwig R.; Jehenson P.; Kokalj S.J.; Laue
E.; Legrain P.; Martens L.; Migliorini C.; Musacchio A.; Podobnik
M.; Schertler G.F.X.; Schreiber G.; Sixma T.K.; Smit A.B.; Stuart
D.; Svergun D.; and Taussig M.J. (2010) 4D Biology for Health and
Disease, N Biotechnology [Epub ahead of print]
do Carmo Costa M.; Bajanca F.; Rodrigues A-J.; Tomé R.J.; Paulson
H.L.; Corthals G.L.; Macedo-Ribeiro S.; Logarinho E.; Maciel P
(2010) Ataxin-3 plays a role in mouse myogenic differentiation
through regulation of integrin subunit levels, PLoS One 5(7):e11728.
39
Medina-Aunon J.A.; Paradela A.; Macht M.; Thiele H.; Corthals
G.L. and Albar J.P.; PIKE: discovering biological information from
proteomics data, Proteomics 10(18):3262-71.
McDonnell L.A.; Corthals G.L.; Willems S.M.; van Remoortere A.;
van Zeijl R.J.; Deelder A.M. (2010) Peptide and protein imaging mass
spectrometry in cancer research. J Proteomics 73(10):1921-44.
Moulder R.; Lönnberg T.; Elo LL.; Filén J.J.; Rainio E.; Corthals
G.; Oresic M.; Nyman T.A.; Aittokallio T.; Lahesmaa R. (2010)
Quantitative Proteomics Analysis of the Nuclear Fraction of Human
CD4+ Cells in the Early Phases of IL-4 Induced Th2 Differentiation.
Mol Cell Proteomics 9(9):1937-53.
Mutka; A.L.; Haapanen A.; Käkelä R.; Lindfors M.; Wright A.K.; Inkinen
T.; Hermansson M.; Rokka A.; Corthals G.; Jauhiainen M.; Gillingwater
T.H.; Ikonen E.; Tyynelä J.; (2010) Murine cathepsin D deficiency is
associated with dysmyelination/myelin disruption and accumulation of
cholesteryl esters in the brain, J Neurochem. 112(1):193- 203.
CYTOSKELETAL AND SURVIVAL
SIGNALING
Principal Investigator:
John E. Eriksson, Ph.D., Professor. Address: Dept. of Biology,
Åbo Akademi University, FI-20520 Turku, Finland.
Tel. int. + 358–2–215 3313.
Laboratory address: Turku Centre for Biotechnology, BioCity,
Tykistökatu 6B, P.O. Box 123, FIN-20521 Turku, Finland.
Tel. int. + 358–2–333 8036, Fax int. +358–2–333 8000.
Biography:
John E. Eriksson (b. 1957) received his Ph.D. at the Åbo Akademi
University in 1990. He was a post-doctoral fellow at Northwestern
University in Dr. Robert D. Goldman’s laboratory during 1990-1993
(Fogarty International Fellowship from the National Institutes of
Health 1991-1993). In November 1993 he joined the Centre for
Biotechnology as a senior research fellow in cell biology. In 1999
he was appointed as Professor of Zoology at the Department of
Biology, University of Turku. In 2006 he was appointed as Professor
of Cell Biology at the Department of Biology, Åbo Akademi University
and became Head of Cell Biology at the department in 2007. He is
also the Chair of Turku BioImaging, Chair of the Biocenter Finland
Imaging Infrastructure Network, and Chair of the Workpackage 12
(User access) in the Eurobioimaging ESFRI network.
Personnel:
Post-doctoral fellows: Senthil Kumar, Ph.D., Hanna-Mari Pallari,
Ph.D., Emilia Peuhu, Ph.D.. Graduate students: Tomoko Asaoka,
MSc, Saima Ferraris, MSc, Claire Hyder, MSc, Kimmo Isoniemi,
MSc, Julia Lindqvist, MSc, Ponnuswamy Mohanasundaram, MSc,
Preethy Paul, MSc, Mika Remes, MSc, Undegraduate students:
Jolanta Lundgren, Max Roberts. Technician: Helena Saarento.
Secretary: Beata Paziewska
Description of the Project:
Post-translational modifications (PTMs) modulate the activity
of most eukaryotic proteins and are responsible for producing
highly complex proteomes from relatively simple genomes. We
use a selection of signaling networks that represent the core of
our expertise to identify PTM targets and interactions when a
cell is embarking upon fate-determining responses, such as
activating transcriptional or post-translational defense and survival
mechanisms or triggering death machineries. Our main models
are apoptotic, stress-mediated, and cytoskeletal signaling and
we are also interested in their interrelationship. By exploring the
interactions between these completely different signaling modes,
we hope to advance our understanding how critical intracellular
signals are processed and integrated.
From left to right, back row: Avinash Yadav, Motonori Imamura, Petri Kouvonen,
Veronika Suni, middle row: Susanne Nees, Sini Eerola, Anni Vehmas, front row:
Thaman Chand, Sususmu Imanishi, Anne Rokka, Garry Corthals.
40
We are especially interested in the interaction between death
receptor, stress, and survival signaling. Early on, we observed that
growth signaling through the mitogen-activated kinase (MAPK/ERK)
pathway has a dominant inhibiting effect on apoptosis induced by
death receptors (Fas, TRAIL, and TNF receptors) and have shown
that this mode of regulation has ramifications both in regulating
death receptor responses of recently activated T-cells and in the
resistance of certain tumor cell lines to death receptor stimulation.
41
On the other hand death receptors are also able to activate
survival signals, both MAPK/ERK and NF-kB and stress signaling
facilitates death receptor-mediated apoptosis in a independently
of heat shock protein expression. The survival of cells is, therefore,
determined by a continuum between these signaling modalities.
Toivonen H.T., Meinander A., Asaoka T., Westerlund M., Pettersson
F., Mikhailov A., Eriksson J.E. & Saxen H. (2011).Modeling reveals
that dynamic regulation of c-FLIP levels determines cell-to-cell
distribution of CD95-mediated apoptosis. J Biol Chem. 2011 Feb
15. [Epub ahead of print]
An example of a signaling hub protein that affects the survival in all of
the above signaling modes is c-FLIP, which is a specific inhibitor of
death receptor signaling. Targeted FLIP degradation by ubiquitylation
is responsible for the sensitization to death receptor signals following
heat stress and during differentiation erythroid cells. We have
found a PKCalpha/beta-mediated signaling module that regulates
the turnover FLIP by an isoform and phosphorylation site-specific
mechanism. These findings help understanding the regulation of
death receptor responses during stress, fever, or inflammation, as
well as during cell growth and differentiation-related processes.
Yang J., Dominguez B., de Winter F., Gould T.W., Eriksson J.E. & Lee
K.F. (2011). Nestin negatively regulates postsynaptic differentiation
of the neuromuscular synapse. Nat. Neurosci. 14: 324-330.
Intermediate filaments (IFs) are major cytoskeletal proteins important
for ultrastructural organization and protection against various
mechanical and other types of stresses. We have established that
intermediate filaments are important signaling determinants, a question
that relates to how the organization of the cytoskeleton will affect
different signaling modules. By employing the interactions of different
IFs (keratin 8/18, vimentin, nestin) with their signaling partners as
models, we have elucidated the relationship between the cytoskeletal
structure and the signaling state of the cell, and how this relationship
will affect cell differentiation, growth, and survival. We observed that
IFs act as general scaffolds for signaling proteins, and have focused
on the association of IFs with JNKs, Cdk5, PKC isoforms, 14-3-3,
and surface adhesion molecules are all involved in key regulatory
processes in the cell. Recently, we determined that vimentin is a
regulator of lymphocyte adhesion and transcellular migration, showing
that the vimentin IFs form a highly dynamic anchoring structure,
which is involved in organizing the surface molecules crucial for the
migration. Another topical highlight includes the discovery of nestin
as regulator of Cdk5 signaling. We have shown that nestin forms a
scaffold and rheostat for the Cdk5/p35 signaling complex and shown
that this function is important both during the differentiation of muscle
cells and in apoptosis of neuronal cells.
Asaoka T., Kaunisto A. & Eriksson J.E. (2011). Regulation of cell
death by c-FLIP phosphorylation. Adv. Exp. Med. Biol. 691: 625-30.
Peuhu E., Kaunisto A., Laihia J.K., Leino L. & Eriksson J.E. (2010).
Molecular targets for the protodynamic action of cis-urocanic acid
in human bladder carcinoma cells. BMC Cancer. 10:521.
Blom T., Bergelin N., Meinander A., Löf C., Slotte J.P., Eriksson
J.E., Törnquist K. (2010). An autocrine sphingosine-1-phosphate
signaling loop enhances NF-kappaB-activation and survival. BMC
Cell Biol. 11: 45.
Rosenholm J.M., Peuhu E., Bate-Eya L.T., Eriksson J.E., Sahlgren
C. & Lindén M. (2010). Cancer-cell-specific induction of apoptosis
using mesoporous silica nanoparticles as drug-delivery vectors.
Small 6:1234-1241.
Blomster H.A., Imanishi S.Y., Siimes J., Kastu J., Morrice
N.A., Eriksson J.E. & Sistonen L. (2010). In vivo identification of
sumoylation sites by a signature tag and cysteine-targeted affinity
purification. J. Biol. Chem. 285:19324-9
de Thonel A., Ferraris S.E., Pallari H.M., Imanishi S.Y., Kochin V.,
Hosokawa T., Hisanaga S., Sahlgren C. & Eriksson J.E. (2010).
Protein kinase Czeta regulates Cdk5/p25 signaling during
myogenesis. Mol. Biol. Cell 21:1423-1434.
Shen W.J., Patel S., Eriksson J.E., Kraemer F.B. (2010). Vimentin
is a functional partner of hormone sensitive lipase and facilitates
lipolysis. J. Proteome Res. 9:1786-1794.
Collaborators:
The studies on apoptosis-related signaling are done in collaboration
with Birgit Lane and David Lane (Institute of Medical Biology, A*Star,
Singapore), Henning Walczak (Imperial College, London, UK), and
Lea Sistonen (Turku Centre for Biotechnology).
Peuhu E., Rivero-Müller A., Stykki H., Torvaldson E., Holmbom T.,
Eklund P., Unkila M., Sjöholm R. & Eriksson J.E. (2010). Inhibition of
Akt signaling by the lignan matairesinol sensitizes prostate cancer
cells to TRAIL-induced apoptosis. Oncogene 29:898-908.
The studies on IF-related signaling functions are carried out as a
collaboration with Robert Goldman (Northwestern Univ., Chicago,
USA), Johanna Ivaska (Univ. of Turku), Sirpa Jalkanen (Univ. of
Turku), Hannu Kalimo (Univ. of Turku), Andras Nagy (Univ. of
Toronto, Canada), Kuo-Fen Lee (Salk Institute, CA, USA).
Imanishi S.Y., Kouvonen P., Smått J.H., Heikkilä M., Peuhu E.,
Mikhailov A., Ritala M., Lindén M., Corthals G.L. & Eriksson J.E.
(2009). Phosphopeptide enrichment with stable spatial coordination
on a titanium dioxide coated glass slide. Rapid Commun. Mass
Spectrom. 23:3661-3667.
Funding:
The Academy of Finland, TEKES, the European Union, the Finnish
Cancer Organizations, the Sigrid Jusélius Foundation, and the Åbo
Akademi Foundation.
Rosenholm J.M., Peuhu E., Eriksson J.E., Sahlgren C. & Lindén M.
(2009). Targeted intracellular delivery of hydrophobic agents using
mesoporous hybrid silica nanoparticles as carrier systems. Nano
Lett. 9:3308-3311.
Pallari H.M., Lindqvist J., Torvaldson E., Ferraris S.E., He T., Sahlgren
C. & Eriksson J.E. (2011). Nestin as a regulator of Cdk5 in differentiating
myoblasts. Mol Biol Cell. 2011 Feb 23. [Epub ahead of print]
Eriksson J.E., Dechat T., Grin B., Helfand B., Mendez M., Pallari
H.M., Goldman R.D. (2009). Introducing intermediate filaments:
from discovery to disease. J. Clin. Invest. 119:1763-1771 (review).
Rosenholm J., Meinander A. Peuhu E., Niemi R., Eriksson J.E.,
42
43
Sahlgren C. & Lindén M. (2009). Selective uptake of porous silica
nanoparticles by cancer cells. Amer. Chem. Soc. 27:197-206.
Kaunisto A, Kochin V, Asaoka T, Mikhailov A, Poukkula M, Meinander
A. & Eriksson JE. (2009). PKC-mediated phosphorylation regulates
c-FLIP ubiquitylation and stability. Cell Death Differ.16:1215-26.
Mikhailov A., Sokolovskaya A., Yegutkin G.G., Amdahl H., West A.,
Yagita H., Lahesmaa R., Thompson L.F., Jalkanen S., Blokhin D. &
Eriksson J.E. (2008). CD73 participates in cellular multiresistance
program and protects against TRAIL-induced apoptosis. J.
Immunol. 181: 464-75.
Meinander, A., Söderström, T.S., Kaunisto, A., Poukkula, M.,
Sistonen, L. and Eriksson, J.E. (2007) Fever-like hyperthermia
controls T-lymphocyte persistence by inducing degradation of
c-FLIPshort. J. Immunol. 178: 3944-53.
Imanishi S.Y., Kochin V., Ferraris S.E., deThonel A., Pallari H-M.,
Corthals G.L. & Eriksson J.E. (2007). Reference-facilitated
phosphoproteomics: fast and reliable phosphopeptide validation
by mikro-LC-ESI-Q-TOF MS/MS. Mol. Cell. Proteomics 6: 13801391.
Nieminen, M., Henttinen, T., Merinen, M., Marttila-Ichihara,
F., Eriksson, J.E. and Jalkanen S. (2006) Vimentin function in
lymphocyte adhesion and transcellular migration. Nat. Cell Biol. 8:
156-162.
Kochin, V., Imanishi S.Y. and Eriksson, J.E. (2006) Fast track
to a phosphoprotein sketch – MALDI-TOF characterization of
TLCbased tryptic phosphopeptide maps at femtomolar detection
sensitivity. Proteomics 6: 5676-82.
Hietakangas, V., Poukkula, M., Heiskanen, K.M., Karvinen, J.T.,
Courtney, M.J., Sistonen, L. and Eriksson, J.E. (2003) Erythroid
differentiation in K562 leukemia cells leads to sensitization to
TRAIL-induced apoptosis by downregulation of FLIP. Mol. Cell.
Biol. 23: 1278-1291.
Hietakangas, V., Poukkula, M., Heiskanen, K.M., Karvinen, J.T.,
Sistonen, L. and Eriksson, J.E. (2003) Erythroid differentiation in K562
leukemia cells leads to sensitization to TRAIL-induced apoptosis by
downregulation of FLIP. Mol. Cell. Biol. 23: 1278- 1291.
Sahlgren, C.M., Mikhailov, A., Vaittinen, S., Pallari, H.M., Kalimo,
H., Pant, H.C. and Eriksson, J.E. (2003) Cdk5 regulates the
organization of Nestin and its association with p35. Mol. Cell. Biol.
23:5090-5106.
Tran, S.E.F., Meinander, A., Holmström, T.H., Rivero-Muller, A.,
Heiskanen, K.M., Linnau, E.K., Courtney, M.J., Mosser, D.D.,
Sistonen, L. and Eriksson, J.E. (2003) Heat stress downregulates
FLIP and sensitizes to Fas receptor-mediated apoptosis. Cell Death
Differ. 10: 1137-1147.
Tran, S.E.F., Holmström, T.H., Ahonen, M., Kähäri, V-M. and Eriksson
J.E. (2001) MAPK/ERK overrides the apoptotic signaling from Fas,
TNF, and TRAIL receptors. J. Biol. Chem. 276: 16484- 16490.
Holmström, T.H., Schmitz, I., Söderström, T., Poukkula, M.,
Johnson, V.L., Krammer, P. H., Chow, S.C. and Eriksson, J.E. (2000)
MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated
apoptosis downstream of DISC assembly. EMBO J. 19: 5418-28
Sahlgren, C.M., Pallari, H-P., He, T., Chou, Y-H., Goldman, R.D.
and Eriksson, J.E. (2006) An essential role of a nestin scaffold
for regulation of Cdk5/p35 signaling in oxidant-induced death of
neuronal progenitor cells. EMBO J 25: 4808-4819.
Imanishi, S.Y., Kochin, V. and Eriksson, J.E. (2006) Optimization
of phosphopeptide elution conditions in immobilized Fe(III) affinity
chromatography. Proteomics 7: 174-176.
Pallari, H.M. and Eriksson, J.E. (2006) Intermediate filaments as
signaling platforms. Science STKE. 19: pe53 (review).
Söderström, T.S., Nyberg, S., Nieminen, M.I. and Eriksson, J.E.
(2005) CD95 capping is ROCK-dependent and dispensable for
apoptosis. J. Cell Sci. 118: 2211-2223.
Poukkula, M., Kaunisto, A., Hietakangas, V., Denessiouk, K.,
Katajamäki, T., Johnson, M.J., Sistonen, L. and Eriksson, J.E.
(2005) Rapid turnover of c-FLIPshort is determined by its unique
C-terminal tail. J. Biol. Chem. 280: 27345-27355.
Goswami, A., Burikhanov, R., de Thonel, A., Fujita, N., Goswami,
M., Zhao, Y., Eriksson, J.E., Tsuruo, T. and Rangnekar, V.M. (2005).
Binding and phosphorylation of Par-4 by Akt is essential for cancer
cell survival. (2005) Mol. Cell. 20: 33-44.
Eriksson, J.E., He, T., Trejo-Skalli, A.V., Härmälä-Brasken, A.S.,
Hellman, J., Chou, Y.H. and Goldman, R.D. (2004) Specific in
vivo phosphorylation sites determine the assembly dynamics of
vimentin intermediate filaments. J. Cell Sci. 117:919-32.
44
From left to right, first row: Saima Ferraris, Beata Paziewska, Jolanta Lundgren,
Tomoko Asaoka, Helena Saarento, John Eriksson, second row: Julia Lindqvist, Claire
Hyder, Max Roberts, Preethy Paul, Kimmo Isoniemi, Elin Torvaldson, Mika Remes.
45
CELL ADHESION AND CANCER
http://www.btk.fi/research/research-groups/ivaska-johanna-celladhesion-and-cancer/
Johanna Ivaska, Professor, Ph.D., VTT Medical Biotechnology,
Itäinen Pitkäkatu 4C, FI-20520 Turku, Finland.
Phone: + 358 40 7203971. Fax + 358 20 722 2840,
Biography:
Johanna Ivaska (b. 1972) received her MSc in Biochemistry in
1995 and Ph.D. in 2000 from the University of Turku. In 2000 she
received a Post-doctoral Fellowship from the Academy of Finland.
In 2001 she received the EMBO Long Term Fellowship. She was a
post-doctoral fellow at Cancer Research UK in Prof. Peter Parker’s
laboratory during 2000-2003. She returned to Finland in 2003 and
joined VTT Medical Biotechnology and University of Turku Centre
for Biotechnology as senior research fellow of the Academy of Finland and established her own research group. She was selected
as a member of the EMBO Young Investigator program for 20072009. She was nominated professor of Molecular Cell Biology at
University of Turku for 2008-2014 and her research group received
ERC Starting Grant funding for 2008-2012 in their Cancer Signalosome project.
Personnel:
Post-doctoral researchers: Elina Mattila, Ph.D.; Jeroen Pouwels,
Ph.D.; Stefan Veltel, Ph.D.; Ghaffar Muharram, Ph.D., Saara Tuomi,
Ph.D. Graduate students: Anja Mai, M.Sc; Antti Arjonen, M.Sc;
Reetta Virtakoivu, M.Sc; Gunilla Högnäs; M.Sc., Riina Kaukonen,
M.Sc, Jonna Alanko, M.Sc, Nicola De Franceschi, M.Sc. Technicians: Jenni Siivonen (on maternity leave) and Laura Lahtinen.
We investigate the relationship between cell adhesion and cancer.
Cancer is a disease where cells grow out of control and invade,
erode and destroy normal tissue. Invasive and metastatic behavior
of malignant cells is the major cause of mortality in all cancer
patients. Migration and cell proliferation are critically regulated by
physical adhesion of cells to each other and to their non-cellular
surroundings (i.e. extracellular matrix) mediated by a family of
adhesion receptors called integrins. Adhesion dependency of
signaling pathways is well established but incompletely understood.
In normal cells permissive signaling from integrins are prerequisite
for receptor tyrosine kinase (RTKs) induced proliferation. This
regulation is lost upon transformation. In the past few years, we
have performed genome-wide screens to identify integrin-binding
intracellular proteins to gain novel insight into integrin signaling and
traffic in cancer cells. Our results demonstrate that integrins can
also convey negative regulation on RTKs via a mechanism that is
often lost in epithelial carcinomas. Our aim is to extend our studies
on identifying integrin binding proteins to understand the diverse
and sometimes unexpected biological roles of integrins. In addition
to defining cytoplasmic integrin triggered pathways, we are also
actively investigating regulation of integrin activity by cytosolic
proteins. We aim to understand adhesion regulated signaling
and the biological function of integrin membrane traffic in human
malignancies.
46
Vuoriluoto, K., Haugen, H., Kiviluoto, S., Mpindi, J-P, Nevo, J.,
Gjerdrum, C., Lorens, J.B. and Ivaska, J. (2010) Vimentin regulates
EMT induction and migration by governing Axl expression in breast
cancer. Oncogene. Nov 8. E-pub ahead of print
Nevo, J., Mai, A., Tuomi, S., Pellinen, T., Pentikäinen, O.T., Heikkilä,
P., Lundin, J., Joensuu, H., Bono, P. and Ivaska, J. (2010) Mammary
derived growth inhibitor (MDGI) interacts with integrin α-subunits
and suppresses integrin activity and invasion. Oncogene. 29:64526463.
Plantard, L. Arjonen, A., Lock, J.G., Nurani, G., Ivaska, J. and
Strömblad S. (2010) PtdIns(3,4,5)P3 is a regulator of Myosin-X
localization and filopodia formation. J. Cell Sci. 123:3525-3534.
Tuomi, S., Mai, A., Nevo, J., Laine, JO, Vilkki, V., Öhman, TJ.,
Gahmberg, CG., Parker, PJ. and Ivaska, J. (2009) PKCε Regulation of an α5 Integrin-ZO-1 Complex Controls Lamellae Formation in
Migrating Cancer Cells. Sci. Sign., 2 (77): ra32.
Nevo, J., Mattila, E., Pellinen, T., Yamamoto, D.L., Sara, H., Iljin,
K., Kallioniemi, O., Bono, P., Joensuu, H., Wärri, A. and Ivaska, J.
(2009) Mammary Derived growth inhibitor facilitates escape from
EGFR inhibitory therapy. Clin. Cancer Res. 15:6570-6578.
Pellinen T., Tuomi, S., Arjonen, A., Wolf, M., Edgren, H., Meyer, H.,
Grosse, R., Kitzing, T., Rantala, JK., Kallioniemi O., Fässler, R., Kallio, M., and Ivaska, J. (2008) Integrin traffic regulated by Rab21 is
necessary for cytokinesis. Dev. Cell, 15:371-385.
Back row from left to right: Ghaffar Muharram, Anja Mai, Johanna Ivaska, Reetta
Virtakoivu, Nicola de Franceschi, Stefan Veltel, Antti Arjonen, Elina Mattila, Jeroen
Pouwels, Riina Kaukonen, Saara Tuomi. Sitting in the front from left to right: Gunilla
Högnäs, Jenni Siivonen, Jonna Alanko, Laura Lahtinen.
47
Mattila, E., Koskinen, K., Salmi, M. and Ivaska, J. (2008) Protein
tyrosine phosphatase TCPTP controls VEGFR-2 signalling. J. Cell
Sci. 121:3570-80.
Vuoriluoto, K., Jokinen, J., Salmivirta, M. Heino, J. and Ivaska, J.
(2008) Distinct syndecans function as integrin α2β1 co-receptors
in 2D and 3D collagen. Exp. Cell Res. 314:3369-81.
Pellinen T, Arjonen A, Vuoriluoto K, Kallio K, Fransen JA, Ivaska J.
(2006) Small GTPase Rab21 regulates cell adhesion and controls
endosomal traffic of beta1-integrins. J. Cell Biol. 2006 173:767-80.
Pellinen T. and Ivaska J. Integrin traffic, invited commentary (2006).
J Cell. Sci. 119:3723-31.
Mattila E., Pellinen, T., Nevo, J., Vuoriluoto, K. Arjonen, A. and
Ivaska, J (2005) Negative regulation of EGFR signalling via integrin
α1β1-mediated activation of protein tyrosine phosphatase TCPTP.
Nat. Cell Biol. 7: 78-85.
Ivaska, J., Vuoriluoto, K., Huovinen, T., Izawa, I., Inagiki, K., and
Parker, PJ. (2005) PKCβ-mediated phosphorylation of vimentin
controls integrin recycling and motility. EMBO J. 24:3834-3845.
HYPOXIA IN CELL SURVIVAL
Panu Jaakkola, M.D., Ph.D.,
Address: Turku Centre for Biotechnology, Biocity, Tykistökatu 6B,
P.O. Box 123, FIN-20521, Turku, Finland,
Tel. +358 2 3338030, Fax +358 2 3338000,
Biography:
Panu Jaakkola (b. 1965) received his M.D. in 1992 and Ph.D. in
1998 at the University of Turku. In 1999 he received a Junior Fellowship from the Academy of Finland. He was a postdoctoral fellow at the University of Oxford in Prof. Peter Ratcliffe’s laboratory
during 1999-2001. He joined the Turku Centre for Biotechnology
in the fall 2001. In 2002 he was appointed as a senior fellow of the
Academy of Finland.
Personnel:
Post-doctoral scientist: Juha Pursiheimo, (Ph.D.) Graduate students: Terhi Jokilehto, (M.Sc.), Pekka Heikkinen, (M.Sc.), Heidi Högel, (M.Sc.), Krista Rantanen, (M.Sc.) Technicians: Taina KalevoMattila Undergraduate students: Marika Nummela, Katri Piilonen,
Siri Tähtinen
Hypoxia (reduced O2 tension) is the main tissue damaging factor
in several ischemic diseases. In contrast to the normal tissue, tumours use hypoxia as a growth-promoting factor. During ischemic
assaults such as strokes, hypoxia activates apoptosis and leads to
severe tissue damage. During cancer progression hypoxia causes
inhibition of apoptosis and enhances tumour aggressiveness and
metastasis. In keeping with this, it has been known for much of
the past century that hypoxia causes resistance cancer treatments
-both to chemotherapy and radiotherapy -and leads to poor prognosis. The aim of the project is to reveal mechanisms by which
hypoxia regulates survival decisions in ischemic diseases and cancer progression. Our group has undertaken two major avenues
to tackle the issue. The reduced oxygen is sensed by a family of
enzymes called the HIF prolyl hydroxylases (PHD1-3). Under normoxia the hypoxia-inducible factor (HIF) is hydroxylated by PHDs
at critical proline residues. This leads to ubiquitylation and proteosomal destruction of HIF. Under hypoxic conditions the hydroxylation ceases and HIF is stabilised. HIF then exerts its effects by
activation of at least 80 genes. These have key functions in glucose
homeostasis, angiogenesis, as well as cell survival and metastasis
formation. Our studies have revealed novel and separate functions
for two PHD isoforms (PHD2 and -3) in regulating cell growth, differentiation of cancer cells as well as regulation of apoptosis. Besides studying several aspects of molecular and cellular biology of
the hydroxylases, we study the clinical importance of these factors. Transforming growth factor-β (TGF-β) is one of the bestcharacterised tumour growth regulating factors. It restricts the growth
of early stage tumours, but at later stages of tumour progression
cancer cells begin to exploit it as a malignancy, invasion and metastasis promoting cytokine. This paradox of TGF-β was originally
described in skin cancer models over ten years ago and since
then the paradox has been recapitulated in several other cancer
models. Our group has recently identified a putative mechanism by
which this may occur. We have found that hypoxia is an environ-
48
49
mental factor in tumours that can convert the TGF-β response into
supporting tumorigenesis. Mechanistically, this involves hypoxic
dephosphorylation of a TGF-β effector Smad3. Moreover, we have
recently discovered that hypoxia converts Smad7, an inhibitor of
the TGF-β signaling, from an inhibitor into a promoter of cell invasion.
Funding:
The Academy of Finland, Sigrid Juselius Foundation, Emil Aaltonen
Foundation
Collaborators:
Peter Ratcliffe and Chris Pugh (Oxford University, UK), Eric Metzen
(Luebeck University, Germany), Joachim Fandrey (Essen University, Germany), Reidar Grenman (Turku University), Veli-Matti Kähäri
(Turku University), Heikki Minn (PET Centre, Turku University Hospital)
Epstein, A.C.R., Gleadle, J.M., McNeill, L.A., Hewitson, K.S.,
O’Rourke, J., Mole, D.R., Mukherji, M., Metzen, E., Wilson, M.I.,
Dhanda, A., Tian, Y.-M., Masson, N., Hamilton, D.L., Jaakkola, P.,
Barstead, R., Hodgkin, J., Maxwell, P.H., Pugh, C.W., Schofield,
C.J., Ratcliffe, P.J. C.elegans EGL-9 and mammalian homologues
define a family of dioxygenases that regulate HIF through prolyl
hydroxylation. (2001) Cell 107; 43-54.
Pursiheimo, J., Taskén, K., Jalkanen, M. and Jaakkola, P. Involvement of Protein Kinase A in FGF-2 Activated Transcription. (2000)
Proc. Natl. Acad. Sci. USA, 97(1): 168–173.
Cockman, M.E., Masson, N, Mole, D.R., Jaakkola, P, Chang, G.W.,
Clifford, S.C, Maher, E.R, Pugh, C.W., Ratcliffe, P.J., Maxwell,
P.H. Hypoxia inducible factor-alpha binding and ubiquitylation by
the von hippel-lindau tumor suppressor protein. (2000) J. Biol.
Chem. 275: 25733-25741.
Heikkinen P., Nummela M., Kähäri V.M. and Jaakkola P.M. (2010).
Hypoxia converts Smad7 from tumor suppressor into tumor promoter. Cancer Res., In Press.
Heikkinen P.T., Nummela M., Leivonen S.K., Westermarck J.,
Hill C.S., Kähäri V.-M., Jaakkola P.M. (2010). Hypoxia activated
Smad3-specific dephosphorylation by PP2A. (2010). J Biol.Chem.,
285(6):3740-9. Epub 2009 Dec 1.
Jokilehto T., Högel H., Heikkinen, P., Rantanen K., Elenius, K.,
Sundström J., Jaakkola P.M. (2010). Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorageindependent carcinoma cell growth. Exp. Cell Res. 316(7):1169
78. Epub 2010 Feb 12.
Pursiheimo J., Rantanen K., Heikkinen P.T., Johansen T., Jaakkola
P.M. (2009). Hypoxia-activated autophagy accelerates degradation
of SQSTM1/p62. Oncogene, 28(3):334-344.
Rantanen K., Pursiheimo J., Högel H., Himanen V., Metzen E.,
Jaakkola P.M. (2008) Prolyl Hydroxylase PHD3 Activates Oxygendependent Protein Aggregation. Mol Biol Cell 19(5): 2231-40.
Jokilehto, T., Rantanen, K., Luukkaa, M., Grenman, R., Minn, H.,
Kronqvist, P., Jaakkola P.M. (2006). Overexpression and nuclear
translocation of HIF prolyl hydroxylase PHD2 in head and neck
squamous cell carcinoma associates with tumor aggressiveness.
Clin Cancer Res 12(4):1080-1087
Marxsen, J. H., Stengel, P., Doege, K., Heikkinen, P., Jokilehto,
T., Wagner, T., Jelkmann, W., Jaakkola, P., and Metzen, E. (2004)
Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases. Biochem J 381, 761
From left to right, front row: Panu Jaakkola, Krista Rantanen, Taina Kalevo-Mattila,
second row: Heidi Högel, Maiju Nuutila, Terhi Jokilehto, Marika Nummela.
Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M.I., Gielbert, J.,
Gaskell, S.J., Kriegsheim, Av, Hebestreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J. Targeting of
HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2regulated prolyl hydroxylation. (2001) Science 292; 468-72.
50
51
KINETOCHORE AND CANCER
RESEARCH GROUP
Marko Kallio, Ph.D. Docent, Chief Research Scientist and Team Leader,
VTT Medical Biotechnology, Itäinen Pitkäkatu 4C, FI-20521, Turku,
Finland and Turku Centre for Biotechnology, BioCity,
Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. +358-(0)2-4788614, Fax +358(0)20-7222840
Biography:
Marko Kallio (b. 1967) graduated in Genetics from University of
Turku in 1992 and received his Ph.D. degree from Department
of Human Genetics at University of Turku 1996 with an honorary
mention. In 1996-1998 Dr. Kallio was in the laboratory of Prof.
Gary Gorbsky (Univ. Virginia, USA) as a Post-doctoral Fellow and in
1998-2000 in the laboratories of Prof. John Eriksson and Prof. Lea
Sistonen (Univ. Turku, Finland) as a Senior Post-doctoral Fellow. In
2000-2003 Dr. Kallio worked as an Assistant Research Professor
at University of Oklahoma HSC, USA. His research group received
Marie Curie Excellence grant for 2004-2008. In early 2004, Dr.
Kallio moved back to Finland and has since been a group leader at
VTT Medical Biotechnology, a research institute affiliated with the
University of Turku.
Personnel:
Post-doctoral researchers: Kimmo Jaakkola, M.D., Leena Laine,
Ph.D., Elli Narvi, Ph.D., Christina Oetken-Lindholm, Ph.D.,
Sebastian Winsel, Ph.D.
Graduate students: Anu Kukkonen-Macchi, M.Sc., Jenni Mäki-Jouppila,
M.Sc., Anna-Leena Salmela, M.Sc., Mariaana Vuoriluoto, M.Sc.
Technicians: Pauliina Toivonen
Alumni: Tim Holmström, Ph.D., Jeroen Pouwels, Ph.D., Oana
Sicora, Ph.D., Asta Varis, Ph.D., Chang-Dong Zhang, Ph.D.
Description of the projects:
The Kinetochore and Cancer Team investigates mechanisms of cell
division in somatic cells and in meiotic systems. Understanding cell
division errors may help to explain origin of genomic instability and
is expected to identify novel therapeutic possibilities for treatment
of cancer. We are especially interested of conditions that suppress
cancer cell’s viability as a consequence of premature inactivation
of the spindle assembly checkpoint (SAC), a conserved signalling
pathway monitoring fidelity of mitosis.
To this end, we have performed a number of high-throughput
screens (HTS) for anti-mitotic small molecules, siRNAs, and
miRNAs. These activities have led to the identification of (i) novel
pharmacophores targeting key mitotic proteins such as Hec1,
Aurora B and Plk1, (ii) new mitotic gene functions and (iii) mitosis
regulating miRNAs. Finally, we have launched a project to explore
the mechanisms of acquired resistance to microtubule (mt)-drugs,
a growing clinical problem in the treatment of cancer. Resistance to
mt-drugs has links to malfunction of tubulin and mitotic checkpoint
proteins but these mechanisms are poorly understood.
Errors during cell division may result in unequal distribution of
DNA between the daughter cells. Gain or loss in the number of
52
chromosomes of the genome is a known cause for miscarriages
and birth defects in human, and a hallmark of cancer. Mitotic
processes are also clinically relevant drug targets in cancer
treatment as demonstrated by the great anti-cancer efficacy
of microtubule-drugs. In our main projects, we are working to
validate the mechanism of action of three putative anti-Hec1
compounds and five SAC targeting miRNAs that effectively perturb
normal mitosis and trigger cancer cell killing in cell culture assays.
Moreover, we are characterizing the phenotypes of a handful of
new mitosis targeting siRNAs that we recently discovered. In our
work we use various cell-based and biochemical assays in vitro as
well as VTT biochip technologies. The results from these activities
are expected to catalyze cancer drug discovery by identification of
new possibilities for inhibition of Hec1 and SAC in general.
Lastly, in a collaborative project with Prof. Olli Kallioniemi we have
investigated the mechanisms of microtubule-drug resistance using
parental lung and ovarian cancer cell lines and their microtubuledrug resistant variants. We have recently discovered that loss of
function of certain tubulin isoforms and microtubule-associated
proteins affect the cell’s sensitivity to microtubule-drugs, alter the
morphology of mitotic spindles and causes mistakes in the SAC
signalling. We expect these findings may have diagnostic/therapeutic
value in the development of individually optimized treatment regimens
for cancer patients with taxane-resistant tumours.
Funding:
VTT Technical Research Centre of Finland, The Academy of Finland,
Finnish Cancer Organisations, TuBS and DDGS Graduate Schools,
Bayer Schering Pharma AG
Collaborators:
Gary Gorbsky (OMRF, Oklahoma USA), Todd Stukenberg (Univ.
Virginia, USA), Olli Kallioniemi (FIMM). Lauri Aaltonen (Biomedicum
Helsinki), Lea Sistonen (Turku Centre for Biotechnology).
Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm
C, Pouwels J, Laine L, and Kallio MJ. (2010) Loss of p38gamma
MAPK induces pleiotropic mitotic defects and massive cell death.
J Cell Sci. in Press.
Salmela AL, Pouwels J, Varis A, Kukkonen AM, Toivonen P, Halonen
PK, Perälä M, Kallioniemi O, Gorbsky GJ, and Kallio MJ. (2009)
Dietary flavonoid fisetin induces a forced exit from mitosis by targeting
the mitotic spindle checkpoint. Carcinogenesis, 30:1032-1040.
Pellinen T, Tuomi S, Arjonen A, Wolf M, Edgren H, Meyer H,
Grosse R, Kilzing T, Rantala JK, Kallioniemi O, Fässler R, Kallio
M, and lvaska J. (2008). Integrin trafficking regulated by Rab21 is
necessary for cytokinesis. Dev Cell, 15:371 -385.
Pouwels J, Kukkonen AM, Lan W, Daum JR, Gorbsky GJ,
Stukenberg T, and Kallio MJ. (2007) Shugoshin 1 plays a central
role in kinetochore assembly and is required for kinetochore
targeting of Plk1. Cell Cycle. 6, 1579-1585.
Wang VY, Parvinen M, Toppari J, and Kallio MJ. (2006) Inhibition
of Aurora kinases perturbs chromosome alignment and spindle
checkpoint signaling in rat spermatocytes. Exp CelI Res. 312,
3459-3470.
53
Ahonen LJ, Kallio MJ, Daum JR, Bolton M, Manke IA, Yaffe MB,
Stukenberg PT, and Gorbsky GJ. (2005) Polo-like kinase 1 creates
the tension-sensing 3F3/2 phosphoepitope and modulates the
association of spindle-checkpoint proteins at kinetochores. Curr
Biol. 15, 1078-1089.
McCleland ML, Kallio MJ, Barrett-Wilt GA, Kestner CA, Shabanowitz
J, Hunt DF, Gorbsky GJ, and Stukenberg PT. (2004) The vertebrate
Ndc80 complex contains functional homologs of Spc24 and Spc25
and is required to establish and maintain kinetochore-microtubule
attachment. Curr Biol. 14, 131-137.
McCleland ML, Gardner RD, Kallio MJ, Daum JR, Gorbsky GJ, Burke
DJ, and Stukenberg PT. (2003) The highly conserved Ndc80 complex
is required for kinetochore assembly, chromosome congression, and
spindle checkpoint activity. Genes Dev. 17, 101-114.
Kallio MJ, McCleland ML, Stukenberg PT, and Gorbsky GJ. (2002)
Inhibition of aurora B kinase blocks chromosome segregation,
overrides the spindle checkpoint, and perturbs microtubule
dynamics in mitosis. Curr. Biol. 12, 900-905.
CANCEROMICS RESEARCH
PROGRAMME
Olli Kallioniemi, M.D., Ph.D., Director, Institute for
Molecular Medicine Finland (FIMM), University of Helsinki,
Tukholmankatu 8, 00140 University of Helsinki, Finland.
Director of the Academy of Finland Centre of Excellence on
Translational Genome-scale Biology (2006-2011),
Medical Biotechnology, VTT Technical Research Centre of Finland
and University of Turku.
Laboratory address: Medical Biotechnology, PharmaCity, Itäinen
Pitkäkatu 4C, FI-20521 Turku, Finland. Tel. +358-20-722 2800.
Fax +358-20-722 2840. E-mail: [email protected].
Biography:
Dr. Olli Kallioniemi received his M.D. in 1984 and Ph.D. in 1988 at
the University of Tampere in Finland. Olli Kallioniemi held several
positions in the US over a 10-year period, such as Head of Translational Genomics Section at the Cancer Genetics Branch, National
Human Genome Research Institute, at the NIH, Bethesda, Maryland during 1995-2002. In 2003, he was appointed as Professor
of Medical Biotechnology at the VTT Technical Research Centre of
Finland with a joint appointment at the University of Turku. Academy of Finland Professor in 2004-2007. In 2007, he was nominated
as a director of the Institute for Molecular Medicine Finland (FIMM),
a Nordic EMBL Partnership in Molecular Medicine. He continues
to direct the ongoing projects in Turku until the end of 2011. He is
an author of 263 publications and editor or member of the editorial board of six journals. Inventor of 18 issued patents, with a focus on technology development, such as Comparative Genomic
Hybridization (CGH) in 1992, tissue microarrays in 1998 and cellbased RNAi microarrays in 2003. EACR young investigator award
in 1994, Anders Jahre Prize in 1998, NIH Director’s lecture in 2000,
Medal of the Swedish Medical Society in 2003, National Academy
of Sciences (Finland) in 2005, EMBO Membership in 2006, and the
Abbot-IFCC award in Molecular Diagnostics 2009.
Personnel:
Ph.D-students and postdocs at the University of Turku: Anna
Aakula, M.Sc., Santosh Gupta, M.Sc., Kirsi Ketola, M.Sc., Pekka
Kohonen, Ph.D. Paula Vainio, M.D., Sirkku Pollari, M.Sc., Technicians: Pirjo Käpylä, Coordinator: Terhi Jokilehto, M.Sc.
The overall purpose of this research program is to develop and
apply high-throughput technologies to understand mechanisms of
progression of breast and prostate cancers as well as to identify
mechanisms of drug response.
1. Apply cancer genomics to identify key genes and pathways in breast and prostate cancer
2. Apply high-throughput RNA interference and chemical biology to identify living cells, with particular attention towards cancer-
specific vulnerabilities and steroid-dependent signaling and
From left to right: Christina Oetken-Lindholm, Anu Kukkonen-Macchi, Pauliina
Toivonen, Jenni Mäki-Jouppila, Sebastian Winsel, Marko Kallio.
54
3. Translate the molecular discoveries towards drug discovery, clinical diagnostics and personalized medicine.
55
We use systems biology and chemical biology approaches to characterize the deregulation of cancer cell functions. The research is
carried out in collaboration between the Institute for Molecular
Medicine Finland (FIMM), the Medical Biotechnology Centre of the
VTT Technical Research Centre of Finland and the Turku Centre for
Biotechnology. Our group coordinates Academy of Finland Centre
of Excellence in Translational Genome-Scale Cell Biology. We have
developed and are applying biochip technologies, next-generation
RNA sequencing, bioinformatics, systems biology, drug development technologies, cell microarrays, protein lysate microarrays, in
silico profiling of gene expression in clinical samples and many others.
Collaborators:
Tomi Mäkelä, Lauri Aaltonen, Jussi Taipale, Päivi Ojala, Sampsa
Hautaniemi, Heli Nevanlionna, Heikki Joensuu, Kari Alitalo, Jonathan Knowles, Emmy Verschuren, Sergey Kuznetshov, Samuli
Ripatti, Krister Wennerberg (FIMM and Biomedicum Helsinki), Antti
Poso, Samuel Kaski, Tapio Visakorpi, Jukka Westermarck and
many others in other Universities in Finland. We have over 100
partners in EU-FP7 collaborative projects such as Epitron, Genica,
APO-SYS, Prosper, Meta-Cancer and Systems Microscopy.
Funding:
The Academy of Finland, Tekes, Finnish Cancer Organizations and
Sigrid Juselius Foundation. Our biggest source of funding comes
from the EU framework projects.
Selected recent publications:
Mpindi JP, Sara H, Haapa-Paananen S, Kilpinen S, Pisto T, Bucher E, Ojala K, Iljin K, Vainio P, Björkman M, Gupta S, Kohonen P,
Nees M, Kallioniemi O. GTI: A Novel Algorithm for Identifying Outlier Gene Expression Profiles from Integrated Microarray Datasets.
PLoS One. 2011 Feb 18;6(2):e17259.
Hanash SM, Baik CS, Kallioniemi O. Emerging molecular biomarkers-blood-based strategies to detect and monitor cancer. Nat Rev
Clin Oncol. 2011 Mar;8(3):142-50.
Ostling P, Leivonen SK, Aakula A, Kohonen P, Mäkelä R, Hagman
Z, Edsjö A, Kangaspeska S, Edgren H, Nicorici D, Bjartell A, Ceder
Y, Perälä M, Kallioniemi O. Systematic Analysis of MicroRNAs Targeting the Androgen Receptor in Prostate Cancer Cells. Cancer
Res. 2011 Mar 1;71(5):1956-1967. Epub 2011 Feb 22.
Vainio P, Gupta S, Ketola K, Mirtti T, Mpindi JP, Kohonen P, Fey V,
Perälä M, Smit F, Verhaegh G, Schalken J, Alanen KA, Kallioniemi
O, Iljin K. Arachidonic acid pathway members PLA2G7, HPGD,
EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. Am J Pathol. 2011 Feb;178(2):525-36.
Edgren H, Murumagi A, Kangaspeska S, Nicorici D, Hongisto V,
Kleivi K, Rye IH, Nyberg S, Wolf M, Borresen-Dale AL, Kallioniemi
O. Identification of fusion genes in breast cancer by paired-end
RNA-sequencing. Genome Biol. 2011 Jan 19;12(1):R6.
Kilpinen S, Ojala K, Kallioniemi O. Analysis of kinase gene expression patterns across 5681 human tissue samples reveals functional genomic taxonomy of the kinome. PLoS One. 2010 Dec
3;5(12):e15068.
56
From left to right, first row: Paula Vainio, Mari Björkman, Riina Plosila, Pekka
Kohonen, Back row: Kirsi Ketola, Anna Aakula, Santosh Gupta, Olli Kallioniemi,
Sirkku Pollari, Elmar Bucher.
57
Rantala JK, Edgren H, Lehtinen L, Wolf M, Kleivi K, Vollan HK,
Aaltola AR, Laasola P, Kilpinen S, Saviranta P, Iljin K, Kallioniemi
O. Integrative functional genomics analysis of sustained polyploidy
phenotypes in breast cancer cells identifies an oncogenic profile for
GINS2. Neoplasia. 2010 Nov;12(11):877-88.
Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P, Rantala J,
Alanen K, Nees M, Kallioniemi O. FZD4 as a mediator of ERG
oncogene-induced WNT signaling and epithelial-to-mesenchymal
transition in human prostate cancer cells. Cancer Res. 2010 Sep
1;70(17):6735-45. Epub 2010 Aug 16.
Härmä V, Virtanen J, Mäkelä R, Happonen A, Mpindi JP, Knuuttila
M, Kohonen P, Lötjönen J, Kallioniemi O, Nees M. A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. PLoS One. 2010 May
3;5(5):e10431.
International Cancer Genome Consortium, Hudson TJ,et al. International network of cancer genome projects. Nature. 2010 Apr
15;464(7291):993-8.
Pollari S, Käkönen SM, Edgren H, Wolf M, Kohonen P, Sara H,
Guise T, Nees M, Kallioniemi O. Enhanced serine production by
bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat. 2011 Jan;125(2):421-30. Epub 2010
Mar 30.
Leivonen SK, Mäkelä R, Ostling P, Kohonen P, Haapa-Paananen
S, Kleivi K, Enerly E, Aakula A, Hellström K, Sahlberg N, Kristensen
VN, Børresen-Dale AL, Saviranta P, Perälä M, Kallioniemi O. Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines. Oncogene,
28(44):3926-3936, 2009.
Iljin K, Ketola K, Vainio P, Halonen P, Kohonen P, Fey V, Grafström RC, Perälä M, Kallioniemi O. High-throughput cellbased screening of 4910 known drugs and drug-like small
molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res., 15(19):6070-6078, 2009.
Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He, W-W,
Ojala P, Taipale J. Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling. Cell, 133:537-548, 2008.
Pellinen T, Tuomi S, Arjonen A, Wolf M, Edgren H, Meyer H, Rantala JK, Kallioniemi O, Fässler R, Kallio M and Ivaska J. Integrin
traffic regulated by Rab21 is necessary for cytokinesis. Dev. Cell.,
15(3):371-385, 2008.
Kilpinen S, Autio R, Ojala K, Iljin K, Bucher E, Sara H, Pisto T, Saarela M, Skotheim R, Björkman M, Mpindi J. P., Haapa-Paananen S,
Vainio P, Edgren H, Wolf M, Astola J, Nees M, Hautaniemi S, Kallioniemi Olli. Systematic bioinformatic analysis of expression levels
of 17,330 human genes across 9,783 samples from 175 types of
healthy and pathological tissues. Genome Biol., 9(9):R139, 2008.
58
SIGNALING PATHWAYS REGULATED
BY ONCOGENIC PIM KINASES
Päivi J. Koskinen, Ph.D., Senior Assistant, Adj. Prof. in
Molecular and Cell Biology. Laboratory address: Turku Centre for
Biotechnology, BioCity, Tykistökatu 6 B, P.O. Box 123,
FIN-20521 Turku, Finland. Tel. + 358-2-3338044,
Fax + 358-2-3338000. E-mail: [email protected]
Biography:
Päivi Koskinen (b. 1961) received her Ph.D. at the University of
Helsinki in 1992. During years 1993-1996 she worked as a
postdoctoral fellow in Dr. Robert Eisenman´s laboratory at the Fred
Hutchinson Cancer Research Center in Seattle, USA. In 1996 she
joined the Turku Centre for Biotechnology as a group leader and
a research fellow of the Academy of Finland. Since 2006 she has
been employed by the Department of Biology, University of Turku.
Personnel:
Postdoctoral researchers: Eeva Rainio, Ph.D. Graduate students:
Jouko Sandholm, M.Sc., Riitta Vahakoski, M.Sc., Niina Santio,
M.Sc. Undergraduate students: Juho Virtanen, Sini Eerola, Heidi
Ekman.
The studies of our research group focus on the signalling pathways
regulated by the oncogenic Pim family of serine/threonine-specific
protein kinases. We have shown that the three highly homologous members of this family are expressed in partially overlapping
patterns, mainly in cells of the immune or the nervous system. In
hematopoietic cells, pim expression can be induced by multiple
cytokines and also by some hormones, suggesting a role for Pim
kinases in signal transduction initiated by cytokine or hormone receptors. When overexpressed in lymphoid tissues of transgenic
mice, pim genes promote lymphomagenesis, especially in cooperation with other oncogenes that either enhance cell proliferation
(myc) or cell survival (bcl-2). We and others have observed that in
human cancer patients, elevated levels of pim-1 mRNA and protein
can be found in leukemias, lymphomas and solid tumors such as
prostate cancer. Recently we have noticed that pim-1 overexpression also promotes radioresistance in patients suffering from squamocellular head and neck carcinomas.
We have previously shown that Pim-1 stimulates activities of several cellular or viral transcription factors such as Myb, NFATc, EBNA2
as well as RUNX family members. More recently also LANA, the
latency-associated nuclear antigen of Kaposi sarcoma-associated
herpesvirus has been identified as a direct Pim substrate. We have
also analysed expression of pim family genes during cytokine-dependent T helper cell differentiation. Furthermore, we have shown
that Pim kinases promote cytokine-independent survival and inhibit
apoptosis by several mechanisms, including upregulated expression of the anti-apoptotic Bcl-2 protein and phosphorylation-induced inactivation of the pro-apoptotic Bad protein. Altogether, our
studies based on domestic or international collaborations have had
a major impact to the understanding of Pim kinase activities in both
normal and transformed cells and have explained why Pim kinases
59
can so efficiently co-operate with Myc family transcription factors in
murine, and most likely also in human tumorigenesis. Even though
Myc-overexpressing cells proliferate faster, they are more prone to
apoptosis, so it is advantageous for them to co-overexpress also
Pim kinases, which regulate the balance between anti- and proapoptotic factors and boost activities of transcription factors that
are essential for production of cytokines and other survival factors.
To further characterize the signalling pathways downstream of
Pim kinases, we have used phosphoproteomics to reveal novel
substrates for Pim kinases. These proteins have recently been
confirmed as true Pim substrates and their functional validation
is underway using both overexpression and RNA interferencebased approaches. Since we aim to identify the relevant
phosphorylation target sites in the novel Pim substrates, we have
participated in developing sensitivity of the methodology to identify
phosphopeptides. In addition, we have been collaborating with
two groups of chemists to identify and validate Pim-specific small
molecule inhibitors, which appear to be great tools for our research,
but may also have therapeutic value. Using these inhibitors, we
have recently revealed a novel role for Pim kinases in stimulation of
cancer cell migration and invasion.
Aho, T.L.T., Lund, R., Ylikoski, E., Matikainen, S., Lahesmaa, R.
and Koskinen, P.J. (2005) Expression of human pim family genes
is selectively upregulated by cytokines promoting Th1, but not Th2
cell differentiation. Immunol. 116: 82-88.
Glazova, M., Aho, T.L.T., Palmetshofer, A., Murashov, A., Scheinin,
M. and Koskinen, P.J. (2005). Pim-1 kinase enhances NFATc activity and neuroendocrine functions in PC12 cells. Mol. Brain Res.
138: 116-123.
Rainio, E.M., Ahlfors, H., Carter, K., Ruuska, M., Matikainen, S.,
Kieff, E. and Koskinen, P.J. (2005) Pim kinases are upregulated by
Epstein-Barr virus infection and enhance EBNA2 activity. Virol. 333:
201-206.
Peltola, K.J., Paukku, K., Aho, T.L.T., Ruuska, M., Silvennoinen, O.
and Koskinen, P.J. (2004). Pim-1 kinase inhibits Stat5-dependent
transcription via its interactions with SOCS1 and SOCS3. Blood
103: 3744-3750.
Aho, T.L.T., Sandholm, J., Peltola, K.J., Mankonen, H.P., Lilly, M.
and Koskinen, P.J. (2004) Pim-1 kinase promotes inactivation of
the pro-apoptotic Bad protein by phosphorylating it on the Ser
gatekeeper site. FEBS Lett. 571: 43-49.
112
Funding:
The Academy of Finland, The Drug Discovery Graduate School.
Key Collaborators:
Jari Yli-Kauhaluoma (Viikki Biocenter, Helsinki), Pascale Moreau
(CNRS, France), Margarita Glazova (Sechenov Institute, St.
Petersburg, Russia), Päivi Ojala (Biomedicum Helsinki), Garry
Corthals (CBT), Eleanor Coffey (CBT), Sirpa Jalkanen (UTU).
Santio, N.M., Vahakoski, R.L., Rainio, E.M., Sandholm, J.A.,
Virtanen, S.S., Prudhomme, M., Anizon, F., Moreau, P. and
Koskinen, P.J. (2010) Pim-selective inhibitor DHPCC-9 reveals Pim
kinases as potent stimulators of cancer cell migration and invasion.
Mol. Cancer 19: 279.
Yan, B., Zemskova, M., Kraft, A., Koskinen, P.J. and Lilly, M. (2003).
The Pim-2 kinase phosphorylates Bad on serine-112 and reverses
Bad-induced cell death. J. Biol. Chem. 278: 45358-45367.
Rainio, E.M., Sandholm, J. and Koskinen, P.J. (2002). Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase. J. Immunol.168: 1524-1527.
Eichmann, A., Yuan, L., Bréant, C., Alitalo, K. and Koskinen, P.J.
(2000). Developmental expression of Pim kinases suggests functions also outside of the hematopoietic system. Oncogene 19:
1215-1224.
Kouvonen, P., Rainio, E.M., Suni, V., Koskinen, P. and Corthals,
G.L. (2010) Data combination from multiple matrix-assisted
laser desorption/ionization (MALDI) matrices: opportunities and
limitations for MALDI analysis. Rapid Commun. Mass Spectrom.
15: 3493-3495.
Peltola, K.J., Hollmén, M., Maula, S.M., Rainio, E.M., Ristamäki,
R., Luukkaa, M., Sandholm, J., Sundvall, M., Elenius, K., Koskinen,
P.J., Grenman, R. and Jalkanen, S. (2009) Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of
head and neck and is under the control of epidermal growth factor
receptor. Neoplasia 11: 629-636.
Cheng, F., Weidner-Glunde, M., Varjosalo, M., Rainio, E.M.,
Lehtonen, A., Schulz, T.F., Koskinen, P.J., Taipale, J. and Ojala,
P.M. (2009) KSHV reactivation from latency requires Pim-1 and
Pim-3 kinases to inactivate the latency-associated nuclear antigen
LANA. PLoS Pathogens, 5, e1000324.
Aho, T.L.T., Peltola, K.J. and Koskinen, P.J. (2006) Pim-1 kinase
phosphorylates RUNX family transcription factors and enhances
their activity. BMC Cell Biol. 7: 1-9.
60
From left to right: Niina Santio, Sini Eerola, Eeva Rainio, Riitta Vahakoski,
Päivi Koskinen.
61
MOLECULAR SYSTEMS IMMUNOLOGY
AND STEM CELL BIOLOGY
Riitta Lahesmaa, M.D., Ph.D., Professor, Turku Centre for
Biotechnology, BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-333 8601, Fax. +358-2-333 8000.
Biography:
Riitta Lahesmaa received her M.D. in 1984 and Ph.D. in 1987 from
the University of Turku, and was appointed Docent in Immunology
in 1990. She was a postdoctoral fellow at Stanford University Medical Center with Professor Lawrence Steinman during the years
1990-1993 (NIH Fogarty Fellowship). In 1994 she moved to Syntex
Research Institute (later Roche Bioscience) in Palo Alto, California.
As a Principal Scientist she focused on lymphocyte signaling and
drug discovery with state-of-the-art functional genomics tools. In
1998 she was appointed Director of Turku Centre for Biotechnology. In 2009 she carried out research in Professor Anjana Rao’s
laboratory in Immune Disease Institute, Harvard Medical School,
Boston. She also directs BioCity Turku Systems Biology Research
Program since 2000.
Personnel:
Senior scientists/ Post-doctoral researchers: Reija Autio, Dr. Tech.,
Zhi Chen, Ph.D., Sanna Edelman, Ph.D., Laura Elo-Uhlgren, Ph.D.,
Riikka Lund, Ph.D., Robert Moulder, Ph.D., Juha-Pekka Pursiheimo, Ph.D., Omid Rasool, Ph.D., Emaheswa Reddy, Ph.D., Louis
Sparvero, Ph.D., Johanna Tahvanainen, Ph.D.
Visiting Scientists: Kanury Rao, Ph.D., (Director, Immunology Group
at ICGEB, New Delhi, India); Brigitta Stockinger, Ph.D. (Principal Investigator, Division of Molecular Immunology, NIMR, London, UK);
Anjana Rao, Ph.D. (Prof., La Jolla Institute of Allergy and Immunology and Harvard Medical School).
Graduate students: Henna Järvenpää, M.Sc.; Juha Korhonen,
M.D.; Minna Kyläniemi, M.Sc. Tapio Lönnberg, M.Sc.; Elisa Närvä,
M.Sc.;Mirkka Heinonen, M.Sc. Nelly Rahkonen, M.Sc.; Alexey
Sarapulov, M.Sc., Soile Tuomela, M.Sc. Subhash Tripathi, M.Tech,
M.Sc.
Technicians: Elina Arojoki, Marjo Hakkarainen, Sarita Heinonen,
Päivi Junni
Coordinator: Terhi Jokilehto, M.Sc.
Undergraduate students: Veera Alanen, Essi Laajala, Lotta Oikari,
Anna Rajavuori, Verna Salo, Joona Valtonen
Our research is focused on molecular systems immunology and
stem cell biology. We use holistic genome and proteome wide
methods and systems biology to reveal molecular mechanisms of
cell signaling, transcriptional and epigenetic programs that determine
cell differentiation and fate. These approaches are exploited to
understand molecular mechanisms of human immune mediated
diseases and certain types of cancer to provide novel therapeutic
means to modulate harmful cellular and immune responses.
62
T helper cell activation and differentiation to functionally distinct
subsets. Selective activation of T helper (Th) cell subsets plays an
important role in the pathogenesis of human allergy and inflammatory
diseases. Dissecting pathways and regulatory networks leading to
the development of Th1, Th2, Th17 or regulatory T cells (Treg) is
essential to understand the pathogenesis of allergy and inflammatory
diseases. Th2 cytokines lead to a series of inflammatory processes
characteristic for asthma and other atopic diseases whereas Th1
and Th17 cells play a role in the pathogenesis of autoimmune
diseases (e.g. type I diabetes). Treg cells have an important role in
inhibiting all these T effector cell functions. We have applied a holistic
approach to identify genes involved in human Th cell differentiation.
Detailed analysis of upstream T cell Receptor (TCR)/key cytokine
receptor induced differentiation will increase our understanding
of these processes central for human health and disease
and provide novel insights into new therapeutic interventions.
STAT6 is known to be an essential upstream mediator of IL-4R
signaling and Th2 differentiation. Importantly, we identified for the
first time STAT6 target genes on a genome wide scale in human
CD4+ T cells - only small fraction of which were previously known
to be STAT-6 regulated. This study, published in Immunity, revealed
that in human surprisingly high proportion, up to 80% of IL-4 induced
response is STAT6 regulated revealing several new candidates for
therapeutic intervention (Elo L et al. 2010). Our studies on IL-4
R signaling in lymphocytes also resulted in identification of new
IL4R/STAT-6 regulated proteins in human (Moulder R. et al. 2010,
Tuomela S. et al. 2009, Cho CH et al. 2009). Our results have led
to novel hypotheses on the key factors involved in human Th cell
differentiation (Lund et al., 2007, Rautajoki et al. 2007). Elucidating
their functions further we discovered that ATF3 and SATB1
are important regulators of human Th cell differentiation. ATF3
promotes Th1 differentiation (Filen S. et al. 2010) whereas SATB1
regulates multiple genes during early Th cell differentiation (Ahlfors
et al. 2010).
Human embryonic stem cells (hESC) have a unique capacity to
differentiate to any type of cell or tissue providing an enormous
potential for therapeutic applications. Our recent results based on
the use of high resolution microarray technology demonstrate that
it is essential to monitor stem cell lines carefully to minimize the
risk of malignancies in stem cell therapies. Our study published in
Nature Biotechnology and highlighted in Nature Methods revealed
that in prolonged culture human embryonic stem cells acquire
chromosomal abnormalities and changes in gene expression,
many of which are linked to cancer. (Närvä et al. 2010). To follow
up this we used the same approach to study in collaboration with
Timo Otonkoski’s group if the reprogramming somatic cells into
induced pluripotent stem cells (iPSCs) compromises genomic
integrity and through this the efficiency of induced pluripotent stem
cells (iPSCs) establishment. We found significantly higher levels of
CNVs in early compared to intermediate passage hiPSCs, and to
fibroblasts and hESCs. Most CNVs are formed de novo and result
in genetic mosaicism in early passage hiPSCs. Many of such novel
CNVs render the cells at a selective disadvantage and during the
expansion mutated cells disappear resulting in hiPSCs resembling
hESCs. (Hussein et. al. 2011).
Our goal is to elucidate the molecular mechanisms regulating self
renewal and pluripotency of hESC and induced pluripotent stem
cells hiPSCs. Our visiting professor Anjana Rao demonstrated
63
that Tet1 and Tet2 are key players in regulating the genetic and
epigenetic control of a network of pluripotency genes and
influence stem cell differentiation potential (Koh et al. 2011). We
have identified novel genes and signaling pathways characteristic
for the pluripotent hESC and iPS cells based on a genome wide
transcriptome analyses of hESC. Current work aims at further
characterization and functional analysis of a panel of selected
factors in the maintenance of undifferentiated status of hESC. Type 1 diabetes (T1D) is the most common metabolic-endocrine
disorder in children in western countries and the annual incidence
of T1D in Finland is record high. In almost all children, progression
to clinical T1D is associated with the presence of ß cell specific
autoantibodies. Clinical T1D occurs when 80-90% of the ß cells
have been destroyed. At this point T1D patient is dependent on
a daily insulin substitution for the rest of his/her life and there is
a high risk of developing acute and long-term complications.
Development of early diagnostics would enable early therapy and
possibly preventive treatments resulting in a significant reduction in
the health care costs.
Our objective is to study molecular mechanisms of T1D and
to discover molecular markers that indicate development of
autoimmunity and progression towards clinical T1D. Exploiting the
unique biobank of the Type 1 Diabetes Prediction and Prevention
Project in Finland (DIPP) we investigated transcriptomic profiles
of prospective whole-blood samples from children who have
developed T1D-associated autoantibodies and eventually clinical T1D.
Gene-level investigation of the data showed systematic differential
expression of 520 probesets. A network-based analysis revealed then a
highly significant down-regulated network of genes involved in antigen
presentation as well as T-cell receptor and insulin signaling. (Elo et al.
2010). Further studies include analysis of larger cohort of longitudinal
samples using transciptomics, proteomics and integrating the data
with our previous metbolomics results (Oresic et al. 2008).
Funding:
The Academy of Finland, The National Technology Agency of Finland
(TEKES), EU 6th framework “ESTOOLS”, JDRF, The Sigrid Jusélius
Foundation, The Finnish Cancer Organizations, Turku University
Hospital Fund, Graduate Schools (TuBS, DDGS, ISB), University
of Turku, Åbo Akademi University, European Research Council,
EU 7th framework “SYBILLA”, EU 7th framework “DIABIMMUNE”
EU 7th framework “NANOMMUNE”, EraSysBioPlus, European
Research Council
Collaborators:
T cell work:
Harri Lähdesmäki (Tampere University of Technology and Aalto
University, Tero Aittokallio & Olli Nevalainen (UTU Matej Oresic (VTT
Technical Research Centre of Finland, Turku), Brigitta Stockinger
(NIMR, London, UK and visiting professor at CBT), Kanury V.S.
Rao (ICGEB, New Delhi, India and visiting professor at CBT),
Anjana Rao (Immune Disease Institute, Harvard Medical School,
Boston, MA, USA), Thomas Tushl (Rockefeller University, New
York, NY, USA), Christopher Burge (MIT, Cambridge, MA, USA),
David Goodlett (University of Washington, Seattle, WA, USA),
Matthias Gstaiger & Ruedi Aebersold (ETZ, Zürich, Switzerland)
and the rest of EU FP7 SYBILLA partners (Altogether 14), Juha
Kere (Karolinska Institute, Stockholm, Sweden), Bing Ren (Ludwig
Institute for Cancer Research, University of California, San Diego,
USA), David Hawkins (Turku Centre for Biotechnology), Bengt
64
Fadeel (Karolinska Institute, Stockholm, Sweden ) and the rest of
EU FP7 DIABIMMUNE partners (Altogether 14 partners).
Stem Cell work:
University, Reija Autio & Olli Yli-Harja (Tampere University of
Technology ), Peter Andrews (University of Sheffield, UK) and the
rest of EU FP6 ESTOOLS consortium (Altogether 20 partners),
Outi Hovatta (Karolinska Institute, Stockholm, Sweden), Anjana
Rao (Immune Disease Institute, Harvard Medical School, Boston,
MA, USA), Panu Jaakkola (Turku Centre for Biotechnology) Timo
Otonkoski (University of Helsinki), David Hawkins (Turku Centre
for Biotechnology), Sanjeev Galande (Indian Institute of Science
Education and Research, Pune, India)
T1D:
University, Matej Oresic (VTT Technical Research Centre of Finland,
Turku), David Goodlett (University of Washington, Seattle, WA,
USA), Olli Simell & Jorma Ilonen (University of Turku), Heikki Hyöty
(University of Tampere), Mikael Knip (University of Helsinki) and the
rest of EU FP7 DIABIMMUNE partners (Altogether 12), Sanjeev
Galande (Indian Institute of Science Education and Research,
Pune, India)
Aflakian N, Ravichandran S, Sarwar Jamaal Md. S, Jarvenpää
H, Lahesmaa, R, Rao KVS. Integration of signals from the B-cell
antigen receptor and the IL-4 receptor leads to a cooperative shift
in the cellular response axis. Mol Biosyst. 2009, 5: 1661-71.
Ahlfors H, Limaye A, Elo-Uhlgrén L, Notani D, Gottimukkala K,
Burute M, Tuomela S, Rasool O, Galande S* & Lahesmaa R*.
SATB1 dictates expression of multiple genes including IL-5 involved
in human T helper cell differentiation. *Equal contribution. Blood.
2010, 116:1443-53
Chen, Z., Lund, R., Aittokallio, T., Nevalainen, O. and Lahesmaa, R.
Identification of early, positively and negatively regulated targets of
STAT6 in IL-4 stimulated CD4+ T lymphocytes induced to polarize
to Th2 cells. J Immunol. 2003, 171: 3627-3635.
Cho SH, Goenka S, Henttinen T, Gudapati P, Reinikainen A,
Lahesmaa R, Boothby M. PARP-14, a member of the B aggressive
lymphoma (BAL) family, transduces survival signals in primary B
cells. Blood. 2009, 113:2416-25.
Elo LL#, Järvenpää H#, Tuomela S#, Raghav S#, Ahlfors H, Laurila
K, Gupta B, Lund RJ, Tahvanainen J, Hawkins RD, Orešic M,
Lähdesmäki H, Rasool O, Rao KVS*, Aittokallio T*, Lahesmaa R.
IL-4- and STAT6-mediated transcriptional regulation to initiate Th2
program in human T cells. Immunity, 2010, 32:852-62. #, * Equal
contribution.
Elo LL*, Mykkänen J*, Nikula T, Järvenpää H, Aittokallio T, Hyöty H,
Ilonen J, Veijola R, Knip M, Simell O, Lahesmaa R. Genome-wide
gene expression profiling reveals early suppression of immune
response pathways in prediabetic children. *Equal contribution. J
Autoimmun. 2010, 35:70-6.
65
Filén JJ, Filén S, Moulder R, Tuomela S, Ahlfors H, West A,
Kouvonen P, Kantola S, Björkman M, Katajamaa M, Rasool O,
Nyman TA, Lahesmaa R. Quantitative Proteomics Reveals GIMAP
Family Proteins 1 and 4 to Be Differentially Regulated during Human
T Helper Cell Differentiation. Mol Cell Proteomics. 2009, 8:32-44.
Tahvanainen J, Kallonen T, Lähteenmäki H, Heiskanen KM,
Westermarck J, Rao KV, Lahesmaa R. PRELI is a mitochondrial
regulator of human primary T helper cell apoptosis, STAT6 and Th2
cell differentiation. Blood, 2009, 113:1268-77.
Filén S, Ylikoski E, Tripathi S, West A, Björkman M, Nyström J,
Ahlfors H, Rao KVS, Coffey E, Rasool O, and Lahesmaa R. ATF3 is
a Positive Regulator of Human IFNG Gene Expression. J Immunol.
2010,184:4990-9.
Hussein S, Batada N, Vuoristo S, Autio R, Närvä E, Ng S,
Hämäläinen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz
M, Brüstle O, Alitalo K, Lahesmaa R, Nagy A #, Otonkoski T#
Increased mutation load is associated with reprogramming of human
somatic cells .#.Equal contribution. Nature, 2011, 471:58-62.
Koh KP, Yabuuchi A, Rao S, Cunniff K, Laiho A, Tahiliani M,
Huang Y, Thompson E, Nardone J, Sommer CA, Mostoslavsky G,
Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A. Tet1 and
related 5-methylcytosine hydroxylases modulate pluripotency and
cell lineage specification in mouse embryonic stem cells. Cell Stem
Cell, 2011, 8:200-13.
Kumar D, Srikanth R, Ahlfors H, Lahesmaa R, Rao K, Capturing
cell-fate decisions from the molecular signatures of a receptordependent signaling response. Molecular Systems Biology,
2007:3:150.
Moulder R*, Lönnberg T*, Filén J-J, Elo L, Rainio E, Corthals G,
Oresic M, Nyman TA, Aittokallio T, Lahesmaa R (*equal contribution).
Quantitative Proteomics Analysis of the Nuclear Fraction of Human
CD4+ Cells in the Early Phases of IL-4 Induced Th2 Differentiation.
Mol Cell Proteomics. 2010, 9:1937-53.
Närvä E, Autio R, Rahkonen N, Kong L, Harrison N, Kitsberg D,
Borghese L, Itskovitz-Eldor J, Rasool O, Dvorak P, Hovatta O,
Otonkoski T, Tuuri T, Cui W, Brüstle O, Baker D, Maltby E, Moore
HD, Benvenisty N, Andrews PW, Yli-Harja O & Lahesmaa R.
High resolution genome wide DNA analysis on a large panel of
Human Embryonic Stem Cell lines reveals novel genomic changes
associated with culture and affecting gene expression. Nat
Biotechnol. 2010, 28:371-7.
Oresic M, Simell S*, Sysi-Aho M*, Näntö-Salonen K*, SeppänenLaakso T*, Parikka V*, Katajamaa M*, Hekkala A, Mattila I, Keskinen
P, Yetukuri L, Reinikainen A, Lähde J, Suortti T, Hakalax J, Simell
T, Hyöty H, Veijola R, Ilonen J, Lahesmaa R, Knip M, Simell O.
Dysregulation of lipid and amino acid metabolism precedes islet
autoimmunity in children who later progress to type 1 diabetes. *
Equal contribution. J Exp Med. 2008, 205:2975-84.
From left to right: Marjo Hakkarainen, Robert Moulder, Elina Arojoki, Tapio Lönnberg,
Mirkka Heinonen, Lotta Oikari , Sanna Edelman, Minna Kyläniemi, Riitta Lahesmaa,
Verna Salo, Maheswara Reddy Emani, Päivi Junni, Soile Tuomela, Terhi Jokilehto,
Juha-Pekka Pursiheimo, Sarita Heinonen, Nelly Rahkonen, Omid Rasool, Alexey
Sarapulov, Subhash Triphathi.
O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic
views of STAT function in CD4+ T helper cell differentiation. Nature
Rev. Immunol. 2011, 11:237-249.
Rautajoki, K., Marttila, E., Nyman, T., Lahesmaa, R. Interleukin-4
inhibits caspase-3 by regulating several proteins in the Fas pathway
during initial stages of human T helper 2 cell differentiation. Mol.
Cell Proteomics, 2007, 6: 238-251.
66
67
PROTEIN CRYSTALLOGRAPHY
Anastassios C. Papageorgiou, Ph.D., Adjunct Professor in
Biochemistry and Structural Biology Turku Centre for Biotechnology,
BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-3338012, Fax +358-2-3338000.
Biography:
Tassos Papageorgiou (b. 1962) obtained his Ph.D. from the University of Athens in 1992. He was a postdoctoral fellow at the University of Oxford and University of Bath (UK). In May 2000, he joined
the Centre for Biotechnology as senior scientist in protein crystallography
Personnel:
Graduate students: Prathusha Dhavala, Teemu Haikarainen,
Sachin Wakadkar
Undergraduate students: Simon Le Boulh, Pia Kinaret.
Omid Mohammadi, Bishwa Subedi, Abdi Muleta, Jesse Mattsson
We use X-crystallography, molecular biology and biophysical techniques to study the structure and function of biological molecules.
One of our major projects has been the Dps family of proteins that
are widely spread among procaryotes and responsible for protection against oxidative stress due to their ability to oxidize and store
iron. Although Dps proteins are structurally similar to ferritins, they
form a spherical shell of 12 subunits instead of 24 and have a different ferroxidase center compared to that of ferritins. The crystal
structures of Dps-like peroxide resistance protein (Dpr) from the
pathogenic bacterium Streptococcus suis in the iron-free, the ironbound and zinc-bound form have been recently determined. In
addition, EXAFS experiments performed at EMBL Hamburg have
provided detailed information of the geometry of the iron core and
showed a ferrihydrite-like structure. Based on our recent results,
several mutants have been generated to study the iron core formation using X-ray crystallography, microcalorimetry, EXAFS (with
Wolfram Meyer-Klaucke, EMBL-Hamburg), magnetization (with
Petriina Paturi, University of Turku) and Mössbauer spectroscopy (with Johan Linden, Åbo Akademi University) techniques. The
magnetic properties of the iron core in the wild type protein and the
mutants were studied.
Studies on oxidative stress protection and detoxification
mechanisms have been extended by determining high-resolution
crystal structures of a tau family glutathione transferase (GST)
from Glycine max in free form and in the presence of a substrate
analogue. Importantly, the crystal structures revealed a novel site
on the surface of the protein that may be utilised for storage and/
or transport of dangerous compounds for detoxification. Docking
calculations were carried out to study the binding of diphenylether
herbicides in the active site. Work is currently underway on chimeric
GSTs or mutants created through directed evolution approaches
to produce new GSTs with altered specificity for new applications
in agriculture, biomedicine and environmental security. Crystals of
human GST-A1 have been grown in our lab for use in structureassisted drug design efforts. In addition, the structure of a novel
glutathione transferase was determined by the SAD method using
the anomalous signal of bromide. The overall fold and the geometry
68
of the active site suggest a new member (eta) of the glutathione
transferase superfamily. Newly emerged GSTs from Agrobacterium
tumefaciensHomology, a soil borne pathogen responsible for crown
gall in over 90 families of plants, were characterized by homology
modeling to assist their biochemical characterization.
In the theme of enzyme function and stability, we continued our
work on PhaZ7, an extracellular depolymerase involved in the
degradation of poly(R)-hydroxyalkanoates (PHAs), a group of thermoplastic polyesters considered as biodegradable substitutes for
non-degradable plastics. The crystal structure of PhaZ7 depolymerase at atomic (1.2) Å resolution in the presence of the serine
protease inhibitor PMSF has been previously determined. Several
mutants have been generated by our collaborators and characterized for their ability to bind PHAs. Crystal structure determination
has revealed a large conformational change that might paly a role in
the enzyme’s function. Further analysis is currently underway. Work
on the Atu (acyclic terpene utilization) catabolic pathway found in
P. Aeruginosa has been initiated using a combination of X-ray crystallography, biophysics, molecular biology, homology modelling,
computational and bioinformatics tools. Atu enzymes are involved
in the metabolisn of acyclic terpenes that possess a great potential
in biotechnology, for example in the food, drink and pharmaceutical
industry. A preliminary structure of AtuE has been obtained to 2.6 Å
resolution and is currently under refinement.
Funding
Academy of Finland, University of Turku, Biocenter Finland,
Informational and Structural Biology Graduate School, Federation of
European Microbiology Societies, EU FP7 (access to synchrotrons)
Collaborators
Jukka Finne (University of Helsinki), Sauli Haataja (University of
Turku), Dieter Jendrossek (University of Stuttgart), Nikos Labrou
(Agricultural University of Athens), Li Duochuan (Shandong
Agricultural University)
Selected publications:
Haikarainen, T., Thanassoulas, A., Stavros, P., Nounesis, G.,
Haataja, S. & Papageorgiou, A.C. (2011) Structural and thermodynamic characterization of metal ion binding in Streptococcus suis
Dpr. J. Mol. Biol 405: 448-460.
Wakadkar, S., Zhang,L.Q., Li, D.-C., Haikarainen, T., Dhavala, P. &
Papageorgiou, A.C. (2011) Expression, purification and crystallization of Chetomium thermophilum Cu, Zn superoxide dismutase.
Acta Cryst F 66: 648-655.
Haikarainen, T., Tsou, C.C., Wu, J.J. & Papageorgiou, A.C. (2010)
Structural characterization and biological implications of di-zink
binding in the ferroxidase center of Strepococcus pyogenes Dpr.
Bichem. Biophys. Res. Comm. 398: 361-365.
Haikarainen, T. & Papageorgiou, A.C. (2010) Dps-like proteins:
Structural and functional insights into a versatile protein family. Cell.
Mol. Life Sci. 67: 341-351.
Axarli, I., Georgiadou, C., Dhavala, P., Papageorgiou, A.C. &
Labrou, N. (2010) Investigation of the role of conserved residues
Ser13, Asn48 and Pro49 in the catalytic mechanism of the tau
class glutathione transferase from Glycine max. Bioch. Biophys.
Acta 1804: 662-667.
69
Labrou, N., Papageorgiou, A.C. & Avramis, V.I. (2010) Structurefunction relationships and clinical applications of L-asparaginases.
Curr. Med. Chem. 17: 2183-2195.
Wakadkar, S., Hermawan, S., Jendrossek, D. & Papageorgiou,
A.C. (2010) The crystal structure of PhaZ7 at atomic (1.2 Å) resolution reveals details of the active site and suggests a substratebinding mode. Acta Cryst. F 66: 648-654.
Melissis, S.C., Papageorgiou, A.C., Labrou, N.E & Clonis,
Y.D. (2010) Purification of moloney murine leukemia virus reverse transcriptase lacking RNase activity (M-MLVH-RT) on a
9-aminoethyladenine[1,6-diamine-hexane]-triazine selected from a
combinatorial library of dNTP-mimetic ligands. J. Chromatogr. Sci.
48: 496-502.
Haikarainen, T., Tsou, C.C., Wu, J.J. & Papageorgiou, A.C. (2010)
Crystal structures of Streptococcus pyogenes Dpr reveal a dodecameric iron-binding protein with a ferroxidase site. J. Biol. Inorg. Chem. 15: 183-194.
Axarli, I. Dhavala, P., Papageorgiou, A.C. & Labrou, N.E. (2009)
Crystallographic and functional characterization of the fluorodifeninducible glutathione transferase from Glycine max reveals an active site topography suited for diphenylether herbicides and a novel
L-site. J. Mol. Biol. 385: 984-1002.
Axarli, I. Dhavala, P., Papageorgiou, A.C. & Labrou, N.E. (2009)
Crystal structrure of Glycine max glutathione transferase in complex with glutathione: investigation of the induced-fit mechanism
operating by the tau class glutathione transferases. Biochem. J.
422: 247-256.
Weckström, K. & Papageorgiou, A.C. (2007) Lower consolute
boundaries of the nonionic surfactant C(8)E(5) in aqueous alkali
halide solutions: An approach to reproduce the effects of alkali halides on the cloud-point temperature. J Colloid Interface Sci. 310:
151-162
Zhao, J., Hayashi, T., Saarinen, S., Papageorgiou, A.C., Kato,
H., Imanishi, K., Kirikae, T., Abe, R., Uchiyama, T. & MiyoshiAkiyama, T. (2007) Cloning, expression and characterization
of the superantigen streptococcal pyrogenic exotoxin-G from
Streptococcus dysgalactiae. Inf. Immun. 75: 1721-1729
Kauko, A., Pulliainen, A.T., Haataja, S., Meyer-Klaucke, W., Finne,
J. & Papageorgiou, A.C. (2006) Iron incorporation in Streptococcus suis Dps-like peroxide resistance protein Dpr requires mobility
in the ferroxidase center and leads to the formation of a ferrihydritelike core. J. Mol. Biol. 364: 97-109
Papageorgiou, A.C., Saarinen, S., Ramirez-Bartutis, R., Kato, H.,
Uchiyama, T., Kirikae, T. & Miyoshi-Akiyama, T. (2006) Expression,
purification and crystallisation of Streptococcus dysgalactiae-derived mitogen. Acta Crystallogr. F. 62: 242-244
Kapetaniou, E.G., Thanassoulas, A., Dubnovitsky, A.P., Nounesis,
G. & Papageorgiou, A.C. (2006) The effect of pH on the structure
and stability of Bacillus circulans ssp. alkalophilus phosphoserine
aminotransferase: Thermodynamic and crystallographic studies.
Proteins: Struct. Funct. Bioinform. 63: 742-753
Mitsiki, E., Papageorgiou, A. C., Iyer, S., Thiyagarajan, N., Prior, S.
H., Sleep, D., Finnis, C. & Acharya, K. R. (2009) Structures of native
human thymidine phosphorylase and in complex with 5-iodouracil.
Biochem. Biophys. Res. Commun. 386: 666-670.
Dhavala, P. & Papageorgiou, A.C. (2009) The crystal structure of
Helicobacter pylori L-asparaginase at 1.4 Å resolution. Acta Crystallogr. D 65: 1253-1261.
Havukainen, H., Haataja, S., Kauko, A., Pulliainen, A.T., Salminen,
A., Haikarainen, T., Finne, J. & Papageorgiou, A.C. (2008) Structural basis of zinc- and terbium-mediated inhibition of ferroxidase
activity in Dps ferritin-like proteins. Protein Sci. 17: 1513-1521
Papageorgiou, A.C., Posypanova, G.A., Andersson, C.A., Sokolov,
N.N & Krasotkina, J. (2008) Structural and functional insights into
Erwinia carotovora L-asparaginase. FEBS J. 275: 4306-4316.
Dhavala, P., Krasotkina, J., Dubreuil, C. & Papageorgiou, A.C.
(2008) Expression, purification and crystallization of Helicobacter
pylori L-asparaginase. Acta Crystallogr Sect F Struct Biol Cryst
Commun. 64: 740-742
Papageorgiou, A.C., Hermawan, S., Singh C.B. & Jendrossek, D.
(2008) Structural basis of poly(3-hydroxybutyrate) hydrolysis by
PhaZ7 depolymerase from Paucimonas lemoignei. J. Mol. Biol.
382: 1184-1194
Saarinen S., Kato, H., Uchiyama, T., Miyoshi-Akiyama, T. & Papageorgiou, A.C. (2007) Crystal structure of Streptococcus dysgalactiae-derived mitogen reveals a zinc-binding site and alterations in
TcR binding. J. Mol. Biol. 373: 1089-1097
70
From left to right: Tassos Papageorgiou, Jesse Mattsson, Bishwa Subedi, Teemu
Haikarainen, Abdi Muleta.
71
CELL FATE
Cecilia Sahlgren, Ph.D., Docent in Cell and Development Biology,
(Åbo Akademi University). Academy Research Fellow,
Turku Centre for Biotechnology, Åbo Akademi and Turku
University, BioCity, Tykistokatu 6B, FI-20521 Turku, Finland.
Tel. +358-2-3338611, Fax +358-2-3338000.
Biography:
Cecilia Sahlgren received her Ph.D. from Turku Centre of
Biotechnology, Åbo Akademi University December 2002. She
was appointed research fellow at the Department of Biology at
Åbo Akademi University from 2003-2005. 2005-2007 she was a
postdoctoral fellow in Prof. Urban Lendahls lab at the Department
of Cell and Molecular Biology at the Karolinska Institute. 2008
she was appointed senior research fellow (attending the position
as professor of Biology) at Åbo Akademi University. In 2009 she
founded the Cell fate group at the Turku Centre for Biotechnology.
She currently holds an Academy of Finland Research Fellow
position.
Personnel:
Senior Scientist: Cecilia Sahlgren, Ph.D.
Post-doctoral researcher: Veronika Mamaeva
Graduate Students: Marika Hietamäki, M.Sc., Sebastian Landor,
M.Sc, Anders Mutvei, M.Sc (KI), Laurel Tabe Bate-Eya, M.Sci
Undergraduate Students: Daniel Antfolk, B.Sc, Christian Antila,
B.Sc, Cecilia Granqvist, B.Sc, Rasmus Niemi
Description of project:
Cell-cell communication in development and disease: Targeting the
Notch signaling pathway
The specific focus of this project is to understand how Notch
responds to inherent changes in the tumour environment or
changes occuring as a consequence of treatment, and how such
“tumour stress” influence Notch activity to drive the disease. We
have recently identified a Notch-hypoxia crosstalk of relevance
for tumor progression (Sahlgren et al., 2008). We have shown
that Notch signaling converts hypoxia inherent to the tumor
microenvironment into epithelial mesenchymal transition (EMT)
required for the hypoxia-induced invasiveness of epithelial tumor
cells. We have participated in a project to elucidate the Notchhypoxia transcriptome to gain insight in how such a crosstalk is
manifested on the transcriptome level and to obtain a molecular
platform to better understand the intersection between the two
signaling cascades in normal development and cancer (Main et
al., 2010). More recent data from the lab show that there is an
elaborate crosstalk between Notch and cell metabolism and that
Notch is important for metabolic flexibility. Metabolic flexibility is one
of the hallmarks of cancer and metabolic “transformation” helps
cancer cells to survive and drives aggressive metastatic cancer.
Preliminary data also indicate that Notch functions as a sensor for
metabolic constrains. Based on our observations we propose that
Notch functions as the cells survival artist by sensing environmental
and metabolic stress and providing cells with various mechanisms
to counteract these challenges. The key goal is to understand how
Notch gets derailed in cancer and how derailed Notch signaling
influence the progression of the disease. We have created 3D
72
cellular models and mouse models of breast cancer via orthotopic
xenotransplantation using breast cancer cells expressing different
and tunable levels of Notch activity to address these questions.
Interaction between key signaling mechanisms is important to
generate the diversity in signaling output required for proper control
of cellular differentiation and function. Notch crosstalks with other
major signaling pathways that modulate the signaling outcome. We
have contributed to working out the relationship between Notch
and the Notch antagonist, Numb (Chapman et al 2006) and to
establishing data on a PDGF-Notch signaling crosstalk of relevance
for vascular smooth muscle cell differentiation and function (Jin et
al., 2008). Current research focus includes interactions between
Notch receptors and ligands and the intermediate filament
cytoskeleton, and how these interactions determine trafficking,
signaling activity and Notch-driven stem cell functions. We aim to
extend our studies on Notch signaling crosstalk and implement
proteomics and mass-spec analysis to identify novel Notch binding
proteins and posttranslational modifications of Notch. A systematic
attempt to characterize how posttranslational modifications of
Notch affect signaling and to identify interacting proteins is likely to
reveal novel modes of regulation of Notch signaling.
The Notch pathway is highlighted as an interesting therapeutic
target, and developing strategies for local containment of Notch
inhibitors to the primary tumor would be a productive way towards
improving cancer therapy. Specific control over Notch activity is also
of interest for regulating stem cell differentiation and regenerative
therapy. We have recently described an approach to specifically
target cell populations with nanoparticles and this technology is
being further developed with the aim to specifically deliver Notch
inhibitors to tumor cells to prevent cancer progression (Rosenholm
et al 2009 a,b,c, Rosenholm et al., 2010). The developed technology
provides a system for efficient and tight dose control of Notch
signaling activity in a cell specific manner. In addition to the obvious
therapeutic value, such cell-specific action and tight dose control
of the Notch pathway should provide a useful tool for analyses of
the biological output of the pleiotropic and dose-dependent Notch
pathway. Further aims include developing the technology for a
precise control of Notch driven stem cells functions and for imaging
of stem cell functions and behaviour in vivo.
Funding:
The Academy of Finland, Åbo Akademi University (CoE in cell
stress and ageing), Turku Graduate School of Biomedical Sciences, Magnus Ehrnrooth’s Stiftelse, Sigrid Jusélius foundation, Finnish Cancer Organizations, the Tor Joe och Pentti Borgs foundation
(Åbo Akademi University).
Collaborators:
Prof. Milos Pekny (Sahlgrenska academy at Göteborg University),
Prof. John Eriksson (Turku Centre for Biotechnology). Prof. Urban
Lendahl (Karolinska Institute), Ph.D Susumu Imanishi (Turku Centre for Biotechnology), Prof. Lea Sistonen (Turku Centre for Biotechnology). Dr.Tech Jessica Rosenholm (Laboratory for Physical
Chemistry, Åbo Akademi, Turku), Prof. Mika Linden (Dept of Chemistry, Ulm University, Germany).
73
Selected Publications (#equal contribution):
Hanna-Mari Pallari, Julia Lindqvist, Elin Torvaldson, Saima E.
Ferraris, Tao He, Cecilia Sahlgren and John E. Eriksson. Nestin as
aregulator of Cdk5 in differentiating myoblasts MBC in press
Sahlgren, C, Gustafsson, M, Jin, S, Poellinger, L and Lendahl, U.
Notch signaling mediates hypoxia induced tumor cell migration
and invasion. (2008) Proceedings of National Academy of Sciences
of the United States of America 105:6392-7.
Jessica M. Rosenholm, Cecilia Sahlgren#, Mika Linden#.
Multifunctional mesoporous silica nanoparticles for combined
therapeutic, diagnostic and targeted action in cancer treatment
Current Drug Targets in press # equal co-author contribution
Gavin Chapman#, Lining Liu#, Cecilia Sahlgren, Camilla Dahlqvist,
and Urban Lendahl. High levels of Notch signaling downregulate
Numb and Numblike. (2006) Journal of Cell Biology, 175(4):535
40.
Das D, Lanner F, Main H, Andersson ER, Bergmann O, Sahlgren
C, Heldring N, Hermanson O, Hansson EM, Lendahl U. Notch
induces cyclin-D1-dependent proliferation during a specific
temporal window of neural differentiation in ES cells. Dev Biol.
2010 348(2):153-66.
Sahlgren C and Lendahl U. (2006) Notch, stem cell control and
integration with other signaling mechanisms Regenerative Medicine
1 (2):195-20
Rosenholm JM, Sahlgren C, Linden M. Towards mul1ifunctional,
targeted drug delivery systems using mesoporous silica
nanoparticles - opportunities & challenges. Nanoscale. 2010
2(10):1870-83.
Jessica M. Rosenholm, Emilia Peuhu, Laurel Tabe Bate-Eya, John
E. Eriksson, Cecilia Sahlgren#, Mika Lindén#. Cancer-Cell Specific
Induction of Apoptosis using Mesoporous Silica Nanoparticles as
Drug Delivery Vectors Small 2010 Jun 6;6(11):1234-41.# equal coauthor contribution
Aurelie de Thonel, Saima E. Ferraris, Hanna-Mari Pallari, Susumu
Y. Imanishi, Vitaly Kochin, Tomohisa Hosokawa, Shin-ichi Hisanga,
Cecilia Sahlgren, and John E. Eriksson. PKCζ regulates CDK5/
p25 signaling during myogenesis in press (2010) MBC 21:1423-34
Heather Main*, Kian Leong Lee*, Henry Yang, Saija Haapa-Paananen, Henrik Edgren, Shaobo Jin, Cecilia Sahlgren, Olli Kallioniemi,
Lorenz Poellinger, Bing Lim and Urban Lendahl. Integration between Notch- and hypoxia-induced transcriptomes in embryonic
stem cells. (2010) Exp Cell Res. 316:1610-24
Jessica M Rosenholm, Dr., Emilia Peuhu, M.Sc., John Eriksson,
Prof. Dr., Cecilia Sahlgren, Dr. #, Mika Linden, Dr#. Targeted Intracellular Delivery of Hydrophobic Agents using Mesoporous Hybrid Silica Nanoparticles as Carrier Systems (2009) Nano Letters
9:3308-11 # equal co-author contribution
From left to right: Daniel Antfolk, Veronika Mamaeva, Cecilia Sahlgren, Sebastian
Landor, Rasmus Niemi, Christian Antila, Helena Saarento, Cecilia Granqvist.
Jessica Rosenholm, Cecilia Sahlgren, Mika Lindén. Cancer cellspecific targeting of and targeted delivery by mesoporous silica
nanoparticles. (2010) Highlight to Journal of Material Chemistry
14:2707-2713
Jessica M Rosenholm, Dr., Annika Meinander, Dr., Emilia Peuhu,
M.Sc., Rasmus Niemi, Mr., John Eriksson, Prof. Dr., Cecilia Sahlgren, Dr.#, Mika Linden, Dr#. Targeting of porous hybrid silica
nanoparticles to cancer cells. (2009) ACSNano 3:197-206 # equal
co-author contribution
Shaobo Jin, Emil M. Hansson, Saara Ihalainen, Cecilia Sahlgren,
Marc Baumann, Hannu Kalimo and Urban Lendahl. Notch signaling regulates PDGF-receptorβ expression in vascular smooth
muscle cells. (2008) Circulation research 102:1483-91
74
75
TARGETING STRATEGIES
FOR GENE THERAPY
Mikko Savontaus, M.D., Ph.D. Address:
Turku Centre for Biotechnology, Biocity, Tykistökatu 6B,
P.O. Box 123, FIN-20521 Turku, Finland. Tel. +358 2 333 8025,
Fax +358 2 333 8000. E-mail: [email protected]
Biography:
Mikko Savontaus (b. 1970) received his M.D. in 1996 and Ph.D. in
1997 from the University of Turku. He was a postdoctoral fellow at
the Institute for Gene Therapy and Molecular Medicine at Mount
Sinai School of Medicine in New York during 1999-2002. He is
currently a senior scientist at the Turku Centre for Biotechnology
as well as a cardiologist at the Department of Medicine at Turku
University Hospital.
Personnel:
Graduate students: Minttu Mattila, M.Sc., Kim Eerola, M.Sc.
Gene therapy is rapidly developing into a novel biomedical discipline
that could have a major impact on health and healthcare in the
21st century. Traditionally gene therapy has been envisioned as a
means to cure monogenic diseases with precisely defined genetic
defects. However, recent clinical trials have demonstrated that gene
therapy for complex multigenic disorders such as cardiovascular
diseases and cancer are especially promising and may become a
routine treatment modality in the near future. On the other hand,
these trials have demonstrated that technical advances in gene
therapy vector development are a key issue in developing clinically
applicable gene therapy approaches.
Our laboratory endeavors to tackle this problem of developing
improved adenoviral gene therapy vectors for cardiovascular
diseases and cancer by attempting to meet two objectives: 1.
The expression of therapeutic genes must be tightly regulated
(transcriptional targeting). 2. The tropism of the gene delivery vector
must be restricted to the target tissue (transductional targeting).
Such targeted vectors will increase efficacy and diminish the
possibility of side effects by limiting transgene expression to the
target cell population. In our previous work we have constructed
conditionally replicating adenoviruses (CRADs) targeting tumor
endothelial cells and have demonstrated that these vectors are
able to specifically replicate in dividing endothelial cells and destroy
tumor vasculature. In addition, we have used a similar strategy
to target tumor cells via the telomerase reverse transcriptase
promoter. We have also demonstrated that a hybrid Ad5/35
adenovirus, where the fiber gene of adenovirus serotype 5 has
been replaced with the fiber from serotype 35, is highly efficient in
infecting endothelial cells.
cells have been constructed by combining hybrid serotype vectors
with transcriptional targeting. In addition, we are utilizing lentivirus
technology for long-term expression of therapeutic genes for heart
failure and hypertension. The effect of these vectors is currently
studied in vivo using ultrasound-guided intramyocardial injection
in mouse heart failure models. Our ultimate goal is to develop
gene therapy vectors for use in clinical trials by combining these
approaches.
Funding:
Academy of Finland, Finnish Medical Foundation, Turku University
Hospital
Toivonen R, Mäyränpää MI, Kovanen PT, Savontaus M. (2010)
Dilated cardiomyopathy alters the expression patterns of CAR and
other adenoviral receptors in human heart. Histochem Cell Biol.
133(3):349-57.
Toivonen, R., Suominen, E., Grenman, R. and Savontaus, M. (2009)
Retargeting Improves the Efficacy of a Telomerase-Dependent
Oncolytic Adenovirus for Head and Neck Cancer. Oncology
Reports 21: 165-171
Suominen, E., Toivonen, R., Grenman, R. and Savontaus, M. (2006)
Head and Neck Cancer Cells are efficiently infected by Ad5/35
Hybrid Virus. Journal of Gene Medicine 8:1223-1231.
Shinozaki, K., Suominen, E., Carrick, F., Sauter, B., Kähäri, V.-M.,
Lieber, A., Woo, S.L.C. and Savontaus, M. (2006). Efficient infection
of endothelial cells by a capsid-modified adenovirus. Gene Therapy
13:52-59.
Hutter, R., Valdiviezo, C., Sauter, B.V., Savontaus, M., Chereshnev,
I., Carrick, F.E., Bauriedel, G., Luderitz, B., Fallon, J.T., Fuster, V.
and Badimon, J.J. (2004) Caspase-3 and tissue factor expression
in lipid-rich plaque macrophages: evidence for apoptosis as
link between inflammation and atherothrombosis. Circulation
27;109(16):2001-8.
Ebert, O., Shinozaki, K., Huang, T.-G., Savontaus, M., GarciaSastre, A. and Woo S.L.C. (2003) VSV as oncolytic virus for
treatment of orthotopic hepatocellular carcinoma in immunecompetent rats. Cancer Research 63(13):3605-11.
Huang, T.-G., Savontaus, M., Shinozaki, K., Sauter, B. and Woo,
S.L.C. (2003) Telomerase dependent oncolytic adenovirus for
cancer treatment. Gene Therapy 10(15):1241-7.
Savontaus, M., Sauter, B.V., Huang, T.-G. and Woo, S.L.C. (2002)
Transcriptional Targeting of conditionally Replicating Adenovirus to
Dividing Endothelial Cells. Gene Therapy 9(14): 972-979
In our current project we are building on these findings by analyzing
the adenovirus receptor expression and vector transduction
efficiency in primary tumor cell lines and in samples from patients
with ischemic or dilated cardiomyopathy. Novel vectors with
improved transcriptional and transductional efficiency for target
76
77
REGULATION AND FUNCTION OF
HEAT SHOCK TRANSCRIPTION
FACTORS
Lea Sistonen, Ph.D., Professor of Cell and Molecular Biology,
Department of Biosciences, Åbo Akademi University.
Laboratory address: Centre for Biotechnology, BioCity,
Tykistökatu 6, P.O.BOX 123, FIN-20521 Turku, Finland.
Tel. +358-2-333 8028, 215 3311; Fax +358-2-333 8000;
E-mail: [email protected], [email protected]
Biography:
Lea Sistonen (b. 1959) completed her undergraduate studies at
Åbo Akademi University in 1984 and received her Ph.D. from the
University of Helsinki in 1990. She was a post-doctoral fellow at
Northwestern University in Dr. Richard I. Morimoto’s laboratory
in 1990-1993 (Fogarty International Fellowship 1991-1993). In
November 1993 she joined the Centre for Biotechnology as a
senior research fellow in molecular biology. In April 2000 she was
appointed as Professor of Cell and Molecular Biology at Åbo
Akademi University. During the 5-year period 2004-2009 she was
Academy Professor, the Academy of Finland.
Personnel:
Post-doctoral fellows: Johanna Ahlskog, Ph.D., Julius Anckar,
Ph.D., Henri Blomster, Ph.D., Eva Henriksson, Ph.D., Cornelia
Ludwig, Ph.D., Anton Sandqvist, Ph.D., Malin Åkerfelt, Ph.D.
Graduate students: Johanna Björk, M.Sc., Marek Budzynski,
M.Sc., Zhanna Chitikova, M.Sc., Alexandra Elsing, M.Sc., Jenny
Joutsen, M.Sc., Anniina Vihervaara, M.Sc.
Technician: Helena Saarento, M.Sc.
Undergraduate students: Heidi Bergman, Malin Blom, Mikael
Puustinen, Hanser Jose Seijas Biel, Aki Vartiainen, Jenni Vasara
Description of the Project
The heat shock response is an evolutionarily well-conserved
cellular defence mechanism against protein-damaging stresses,
such as elevated temperatures or hyperthermia, heavy metals,
and viral and bacterial infections. The heat shock proteins (Hsps)
function as molecular chaperones to protect cells by binding to
partially denatured proteins, dissociating protein aggregates, and
regulating the correct folding and intracellular translocation of newly
synthesized polypeptides. Hsps are transcriptionally regulated by
heat shock factors, HSFs. The mammalian HSF family consists of
four members HSF1-4. Although HSFs are best known as inducible
transcriptional regulators of genes encoding molecular chaperones
and other stress proteins, they are also important for normal
developmental processes and longevity pathways. The repertoire
of HSF targets has recently expanded well beyond the heat shock
genes, and the known functions governed by HSFs span from the
heat shock response to development, metabolism, lifespan and
disease, especially cancer and neurodegenerative disorders.
Our focus is on the molecular mechanisms by which the
different members of the HSF family are regulated during normal
development and under stressful conditions. In particular, we
78
investigate both the expression and activity of HSF1 and HSF2.
We have found that HSF1 is ubiquitously expressed and its activity
is primarily regulated by various post-translational modifications
(PTMs), such as acetylation, phosphorylation and sumoylation. All
these PTMs are induced by stress stimuli but their effects on HSF1
vary. In response to stress, HSF1 undergoes phosphorylationdependent sumoylation within a bipartite motif which we found in
many transcription factors and co-factors and gave name PDSM
(phosphorylation-dependent sumoylation motif. Stress-inducible
hyperphosphorylation and sumoylation of HSF1 occur very rapidly,
whereas acetylation of HSF1 increases gradually, indicating a role
for acetylation in the attenuation phase of the HSF1 activity cycle.
We have shown that among multiple lysine residues targeted by
acetylation, K80 is located within the DNA-binding domain of HSF1
and its acetylation is required for reducing HSF1 DNA-binding
activity. Importantly, the duration of HSF1 DNA-binding activity
can be prolonged or diminished by chemical compounds either
activating or inhibiting the activity of the longevity factor deacetylase
SIRT1. Thus, SIRT1-mediated deacetylation of HSF1 may maintain
HSF1 in a state competent for DNA-binding, thereby linking our
research to HSF1-mediated regulation of lifespan. Currently, our
focus is on a complex network of PTMs to decipher the posttranslational signature of HSF1.
In contrast to HSF1, which is a stable protein evenly expressed
in most tissues and cell types, the amount of HSF2 varies and
correlates with its activity. Our recent results provide the first
evidence for the ubiquitin E3 ligase APC/C (anaphase-promoting
complex/cyclosome) mediating ubiquitination and degradation
of HSF2 during the acute phase of the heat shock response. In
developmental processes, using mouse spermatogenesis as a
model system, we have discovered an inverse correlation between
the cell- and stage-specific wave-like expression patterns of HSF2
and a specific microRNA, miR-18, which is a member of the
Oncomir-1/miR-17~92 cluster. Intriguingly, miR-18 was found to
repress the expression of HSF2 by directly targeting its 3’UTR. To
investigate the in vivo function of miR-18, we developed a novel
method T-GIST (Transfection of Germ cells in Intact Seminiferous
Tubules) and were able to show that inhibition of miR-18 in intact
mouse seminiferous tubules leads to increased HSF2 protein
levels and altered expression of HSF2 target genes, including the
Y-chromosomal multi-copy genes that we previously have reported
as novel HSF2 targets in the testis. Our original finding that miR-18
regulates HSF2 activity in spermatogenesis links miR-18 to HSF2mediated physiological processes and opens a whole new window
of opportunities to elucidate the physiological and stress-related
functions of HSF2, either alone or in conjunction with HSF1.
Our studies on the formation of heterotrimers between HSF1 and
HSF2 and their impact on already established and newly discovered
targets genes should also shed light on the roles of HSFs in proteinmisfolding disorders, such as neurodegenerative diseases, as well
as in aging and cancer progression. So far, the studies have mostly
concentrated on HSF1, but it is important to consider the existence
of multiple HSFs and interactions between them, especially when
searching for potential drugs to modify either expression or activity
of these multi-faceted transcriptional regulators.
79
Funding:
The Academy of Finland, the Sigrid Jusélius Foundation, the
Finnish Cancer Organizations, and Åbo Akademi University (Centre
of Excellence in Cell Stress and Molecular Aging).
Collaborators:
Elisabeth Christians (University of Toulouse, France), Susumu
Imanishi and John Eriksson (Åbo Akademi University), Marko
Kallio (VTT Medical Biotechnology), Noora Kotaja and Jorma
Toppari (University of Turku), Pia Roos-Mattjus, Peter Slotte and
Kid Törnquist (Åbo Akademi University), Valérie Mezger (University
of Paris Diderot, France), Rick Morimoto (Northwestern University,
USA), Wei Liu and Rudolf Ladenstein (Karolinska Institute, Sweden),
Jorma Palvimo (University of Eastern Finland), Andrea Pichler (Max
Planck Institute of Immunobiology, Germany).
Selected Publications (2006-2010):
Ahlskog J.K., Björk J.K., Elsing A.N., Aspelin C., Kallio M., RoosMattjus P. and Sistonen L. (2010) Anaphase-promoting complex/
cyclosome participates in the acute response to protein-damaging
stress. Mol. Cell. Biol. 30: 5608-5620.
Östling P.*, Björk J.K.*, Roos-Mattjus P., Mezger V. and Sistonen
L. (2007) HSF2 contributes to inducible expression of hsp genes
through interplay with HSF1. J. Biol. Chem. 282: 7077-7086.
Chang Y.*, Östling P.*, Åkerfelt M., Trouillet D., Rallu M., Gitton Y.,
El Fatimy R., Fardeau V., Le Crom S., Morange M., Sistonen L. and
Mezger V. (2006) Role of heat shock factor 2 in cerebral cortex
formation and as a regulator of p35 expression. Genes Dev. 20:
836-847.
Anckar J.*, Hietakangas V.*, Denessiouk K., Thiele D.J., Johnson
M.S. and Sistonen L. (2006) Inhibition of DNA binding by differential
sumoylation of heat shock factors. Mol. Cell. Biol. 26: 955-964.
Hietakangas V.*, Anckar J.*, Blomster H.A., Fujimoto M.,
Palvimo J.J., Nakai A. and Sistonen L. (2006) PDSM, a motif for
phosphorylation-dependent SUMO modification. Proc. Natl. Acad.
Sci. USA 103: 45-50 (epub. Dec 21, 2005).
*equal contribution
Åkerfelt M.*, Vihervaara A.*, Laiho A., Conter A., Christians E.C.,
Sistonen L. and Henriksson E. (2010) Heat shock transcription
factor 1 localizes to sex chromatin during meiotic repression. J.
Biol. Chem. 285: 34469-34476.
Björk J.K.*, Sandqvist A.*, Elsing A.N., Kotaja N. and Sistonen
L. (2010) miR-18, a member of OncomiR-1, targets heat shock
transcription factor 2 in spermatogenesis. Development 137:
3177-3184.
Åkerfelt M., Morimoto R.I. and Sistonen L. (2010) Heat shock
factors: integrators of cell stress, development and lifespan. Nat.
Rev. Mol. Cell Biol. 11: 545-555.
Blomster H.A.*, Imanishi S.Y.*, Siimes J., Kastu J., Morrice N.A.,
Eriksson J.E. and Sistonen L. (2010) In vivo identification of
sumoylation sites by a signature tag and cysteine-targeted affinity
purification. J. Biol. Chem. 285: 19324-19329.
Blomster H.A., Hietakangas V., Wu J., Kouvonen P., Hautaniemi
S. and Sistonen L. (2009) Novel proteomics strategy brings insight
into the prevalence of SUMO-2 target sites. Mol. Cell. Proteomics
8: 1382-1390.
Westerheide S.D.*, Anckar J.*, Stevens S.M.Jr., Sistonen L. and
Morimoto R.I. (2009) Stress-inducible regulation of heat shock
factor 1 by the deacetylase SIRT1. Science 323: 1063-1066.
Sandqvist A., Björk J.K., Åkerfelt M., Chitikova Z., Grichine A.,
Vourc’h C., Jolly C., Salminen T.A., Nymalm Y. and Sistonen L.
(2009) Heterotrimerization of heat-shock factors 1 and 2 provides a
transcriptional switch in response to distinct stimuli. Mol. Biol. Cell
20: 1340-1347.
From left to right: Lea Sistonen, Mikael Puustinen, Johanna Björk, Anders
Backman, Sergey Abkin, Eva Henriksson, Malin Åkerfelt, Anniina Vihervaara, Beata
Paziewska, Johanna Ahlskog, Hanser Seijas, Anna Aalto, Emine Lundsten, Marek
Budzynski, Heidi Bergman, Jenni Vasara, Helena Saarento, Alexandra Elsing,
Jenny Joutsen.
Åkerfelt M.*, Henriksson E.*, Laiho A., Vihervaara A., Rautoma K.,
Kotaja N. and Sistonen L. (2008) Promoter ChIP-chip analysis in
mouse testis reveals Y chromosome occupancy by HSF2. Proc.
Natl. Acad. Sci. USA 105: 11224-11229.
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CANCER CELL SIGNALING
http: http://www.btk.fi/index.php?id=1279
Jukka Westermarck, M.D., Ph.D., Docent in Molecular Biology
(University of Turku). Address: Turku Centre for Biotechnology,
BioCity, Tykistökatu 6 B, P.O. Box 123, FIN-20251 Turku, Finland.
Tel. +358-2-333 8621, Fax +358-2-333 8000.
Biography:
Jukka Westermarck (b. 1969) received his M.D. in 1996 and Ph.D
in 1998 at the University of Turku. He was a postdoctoral fellow at
European Molecular Biology Laboratory in Heidelberg, Germany,
in Dr. Dirk Bohmann´s laboratory during 1999-2001. He was a
Academy of Finland senior scientist during 2002-2007 and 20062009 he was appointed as a Group leader at Institute of Medical
Technology (IMT), University of Tampere, Finland. In 2008 he was
appointed to a Research Professor position at the Finnish Cancer
Institute. 2009 he was appointed to Research director position at
Turku Centre for Biotechnology (leave of absence until 2011).
Personnel:
Seniors scientist: Jukka Westermarck, M.D., Ph.D. Post-doctoral
researchers: Christophe Come, Ph.D., Juha Okkeri, Ph.D., Yuba
Pokharel, Ph.D., Sami Ventelä, M.D., Ph.D. Graduate students:
Antoine Mialon, M.Sc., Minna Niemelä, M.Sc., Anni Laine, M.Sc.,
Tuuli Halonen, M.Sc., Amanpreet Kaur, M.Sc., Anchit Khanna,
M.Sc. (IMT) Technical personnel: Taina Kalevo-Mattila
Description of the project :
The goal of our research group is to identify novel signaling mechanisms involved in malignant cell growth by isolating protein complexes associated with proteins previously demonstrated to have
an important role in cancer progression. To identify protein complexes, we use tandem affinity purification (TAP) and Strep-tag purification methods, both proven to be suitable for purification of
signaling protein complexes from mammalian cells in culture. Identification of novel proteins involved in malignant growth may also
reveal novel possibilities for intervention in the therapy of cancer
and other hyperproliferative diseases.
Based on our recent work, we have identified several novel interacting proteins for signaling proteins such as AP-1 transcription factor c-Jun, MAPK kinase MEK1, and protein phosphatase
PP2A. Most of our future work will be focused on characterization
of PP2A interaction partner CIP2A, that we have demonstrated to
inhibit PP2A in human malignancies. As PP2A inhibition has been
recognized as a prerequisite for human cell transformation, it is
plausible that further understanding of the function of CIP2A will reveal fundamental novel information about the basic mechanisms of
cancer progression. The overall goal of the proposed project is to
study the function and importance of CIP2A in cancer progression
by using combination of molecular biology, cell biology and functional genetics methods. As our current results suggest that targeting CIP2A could be beneficial in the treatment of cancer, our goal
is also to develop research models for evaluating the suitability of
CIP2A as a novel drug target for cancer therapies. In addition, our
aim is to purify new protein complexes related cancer cell signaling.
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Funding:
The Academy of Finland, Medical Research Fund of Tampere University Hospital, Turku Graduate School of Biomedical Sciences,
Tampere Graduate School in Biomedicine and Biotechnology,
Emil Aaltonen Foundation, Sigrid Juselius Foundation, Cancer Research Foundation of Finland, Association of International Cancer
Research (UK).
Collaborators:
Tuula Kallunki (Danish Cancer Society), Rosalie Sears (Oregon
Health and Science University), Owen Sansom (Beatson Institute
for Cancer Research, Glasgow), Kirmo Wartiovaara (University of
Helsinki), Sampsa Hautaniemi (University of Helsinki), Ari Ristimäki
(University of Oulu), Jorma Toppari (University of Turku), Veli-Matti
Kähäri (Turku University Hospital), Reidar Grenman (Turku University Hospital).
Kerosuo L, Fox H, Perälä N, Ahlqvist K, Suomalainen A, Westermarck J, Sariola H, and Wartiovaara K; CIP2A increases self-renewal and is linked to Myc in neural progenitor cells. Differentiation,
in press, 2010
Heikkinen PT, Nummela M, Leivonen SK, Westermarck J, Hill CS,
Kähäri VM, and Jaakkola PM; Hypoxia activated Smad3-specific
dephosphorylation by PP2A. The Journal of Biological Chemistry,
285, 3740-3749, 2010.
Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, Jonkers
J, Ivaska J, Isola J, Darbon J-M, Kallioniemi O-P, and Thezenas S
and Westermarck J; CIP2A is associated with human breast cancer aggressivity. Clinical Cancer Research, 15, 5092-5100, 2009.
Khanna A, Böckelman C, Hemmes A, Junttila MR, Wiksten J-P,
Lundin P, Junnila S, Murphy D, Evan GI, Haglund C, Westermarck
J*, and Ristimäki A*; c-Myc-dependent regulation and prognostic
role of CIP2A in gastric cancer. Journal of the National Cancer Institute, 101, 793-805, 2009. *equal contribution
Puustinen P, Junttila MR, Vanhatupa S, Sablina AA, Hector ME,
Teittinen K, Raheem O, Ketola K, Lin S, Kast J, Haapasalo H, Hahn
WC, and Westermarck J; PME-1 Protects ERK Pathway activity
from Protein Phosphatase 2A-mediated Inactivation in human malignant glioma. Cancer Research, 69, 2870-2877, 2009.
Wu J, Ovaska K, Vallenius T, Westermarck J, Mäkelä TP, and Hautaniemi S; Protein-protein interaction portal for network level analysis. Nature Methods, 6, 75-77, 2009
Westermarck J, Hahn WC; Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends in Molecular Medicine, 14,152-160, 2008.
Junttila MR, Li S-P, Westermarck J; Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. The FASEB Journal, 22, 954-965, 2008.
Holmström TH, Mialon A, Kallio M, Nymalm Y, Mannermaa L, Holm
T, Johansson H, Black E, Gillespie DA, Salminen TA, Langel U,
Valdez BC, and Westermarck J; c-Jun supports ribosomal RNA
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processing and nucleolar localization of a RNA helicase DDX21.
The Journal of Biological Chemistry, 283, 7046-7053, 2008.
Junttila, MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw
T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu SL, Li S, Chan EKL,
Wang X-J, Grenman R, Kast J, Kallunki T, Sears R, Kähäri V-M,
Westermarck J; CIP2A Inhibits PP2A in Human Malignancies. Cell,
130, 51–62, 2007.
Junttila MR, Ala-aho R, Jokilehto T, Peltonen J, Grenman R, Jaakkola P, Westermarck J, and Kähäri V-M; p38alpha and p38delta
mitogen-activated protein kinase isoforms regulate invasion and
growth of head and neck squamous carcinoma cells. Oncogene,
26, 5267-5279, 2007.
From left to right: Anni Laine, Juha Okkeri, Anna Cvrljevic, Jukka Westermarck
(and Anna), Taina Kalevo-Mattila, Tuuli Halonen, Sergey Kolomeychuk, Amanpreet
Kaur, Yuba Raj Pokharel.
STRUCTURAL GROUP
BIOINFORMATICS
Group leader:
Konstantin Denessiouk, Ph.D., Docent in Biochemistry.
Bioinformatics Group leader. Centre for Biotechnology,
Tykistökatu 6, BioCity 5th floor, Turku, 20520 Turku.
Personnel:
Bhanupratap Singh Chouhan, Ph.D. Student.
The Structural Bioinformatics group provides support for Structural
Bioinformatics and Chemical Informatics (in conjunction with the
Structural Bioinformatics Laboratory, lead by Prof. Mark S. Johnson at the Åbo Akademi University); and separately, support for
projects and development of high-throughput screening (HTS) of
natural molecules (in conjunction with Prof. Pia Vuorela, Department of Biosciences, Åbo Akademi University). The Structural Bioinformatics Group has its main expertise in (a) computer-based
analysis of protein-protein and protein-ligand interactions;
(b) computer-aided prediction and intelligent molecular modeling
and design; (c) computer-based ligand docking and analysis;
(d) quantum chemistry, molecular dynamics; and
(d) analysis of effects of molecular recognition and mutations on
protein function.
Currently, in collaboration with Prof. Jyrki Heino, University of Turku,
the collaboration has been continued on the study of evolution of
different domains of integrins, and an in-depth structural analysis
of human integrin beta-propeller domains and identification of
structural features of integrins that distinguish human integrins
from the other protein superfamilies having the same fold (Johnson
et al., 2009; Chouhan et al., 2011, submitted), giving a new
insight into existence and evolution of the integrin-like proteins
in bacteria. Additionally, our on-going research was focused on
the analysis of effects of molecular recognition and mutations on
protein function in macromolecular receptor ErbB4 complexes
(in collaboration with Dr. Klaus Elenius, University of Turku); and
molecular dynamics of S100 proteins in collaboration with Prof. S.
Permyakov, Russian Academy of Sciences. Separately, the group
guides individual training of MSc students, in collaboration with the
Structural Bioinformatics Laboratory (Åbo Akademi University), and
leads a Ph.D. student in Bioinformatics and Computational Biology
within the National Graduate School of Informational and Structural
Biology (Åbo Akademi University).
Funding:
Grants from the Sigrid Jusélius Foundation, and the Borg Foundation (Åbo Akademi University); Grant from the National Graduate
School in Informational and Structural Biology (ISB).
Collaborators:
Prof. Riitta Lahesmaa (Turku Centre for Biotechnology), Prof. Mark
S. Johnson (Åbo Akademi University), Dr. Klaus Elenius (University
of Turku); Prof. Jyrki Heino (University of Turku); Prof. S. Permyakov, Russian Academy of Sciences.
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Chouhan B, Denesyuk A, Heino J, Johnson MS Denessiouk K.
(2011) Conservation of the human integrin-type beta-propeller domain in bacteria. Proteins: Structure, Function, and Bioinformatics
Submitted.
Johnson MS, Lu N, Denessiouk K, Heino J, Gullberg D.
(2009). Integrins during evolution: Evolutionary trees and model
organisms. Biochim Biophys Acta. 1788: 779-789.
Xhaard H, Backström V, Denessiouk K, Johnson MS. (2008).
Coordination of Na(+) by monoamine ligands in dopamine, norepinephrine, and serotonin transporters. J Chem Inf Model. 48:
1423-1437.
Denessiouk KA, Denesyuk AI, Johnson MS. (2008). Negative
modulation of signal transduction via interleukin splice variation.
Proteins. 71: 751-770.
DATA MINING AND MODELING
GROUP
Principal investigators:
Laura Elo, Ph.D., Department of Mathematics, University of Turku,
FI-20014 Turku, Finland. Tel. +358-2-3336030,
Fax. +358-2-3336595. E-mail: [email protected] Homepage: http://
users.utu.fi/laliel/.
Tero Aittokallio, Ph.D., Docent in Biomathematics, Department of
Mathematics, University of Turku, FI-20014 Turku, Finland.
Tel. +358-2-3336030, Fax +358-2-3336595.
E-mail: [email protected] Homepage: http://users.utu.fi/teanai/
Olli Nevalainen, Ph.D., Professor of Computer Science, Turku
Centre for Computer Science, University of Turku, FI-20014 Turku,
Finland. Tel. +358-2-3338631; E-mail: [email protected].
Jussi Salmi, Ph.D., Turku Centre for Computer Science,
University of Turku, FI-20014 Turku, Finland.
Tel. +358-2-3338659. E-mail: [email protected]
Biographies:
Laura L. Elo received her Ph.D. in Applied Mathematics from the
University of Turku in 2007. Currently she is an Academy of Finland
Postdoctoral Research Fellow in the Biomathematics Research
Group.
Tero Aittokallio received his Ph.D. in Applied Mathematics from the
University of Turku in 2001. In 2006-2007, he was a postdoctoral
research fellow in the Systems Biology Group at Institut Pasteur,
Paris. Currently he is an Academy Research Fellow in the Biomathematics Research Group.
Olli S. Nevalainen received his Ph.D. degree in 1976. From 1972
to 1976, he was a lecturer with the Department of Computer Science, University of Turku. From 1976 to 1999, he was an Associate
Professor, and since 1999 a Professor in the same department.
Personnel:
Graduate students: Bin Gao, M.Sc., Marja Heiskanen, M.Sc., Jukka Hiissa, M.Sc., Ville Koskinen, M.Sc., Rolf Linden, M.Sc., Sebastian Okser, M.Sc., Tomi Suomi, M.Sc., Johannes Tuikkala, M.Sc.,
Heidi Vähämaa, M.Sc.
Undergraduate students: Ville-Pekka Eronen, Aki Järvinen, Essi
Laajala, Teemu Daniel Laajala, Lari Natri.
The research group develops mathematical modeling methods and
implements computational analysis tools for mining data generated
by modern high-throughput biotechnologies. The large number of
components together with high technical and biological variability
can make it difficult to extract pertinent biological information from
the background noise. This has increased the need for computational models and tools that can efficiently integrate, visualize and
analyze the experimental data so that meaningful interpretations
can be made. The eventual aim is to model and explain the observations as a dynamic interaction of key molecular components and
mechanisms controlling the underlying system.
The data mining protocols developed by the group so far cover
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a wide range of high-throughput biotechnologies, including gene
and exon microarrays (cDNA, Affymetrix and Illumina platforms) for
global gene expression profiling, together with RNA interference
(RNAi) and chromatin immunoprecipitation (ChIP) studies (ChIPchip and ChIP-seq) for monitoring transcriptional regulation on a
global scale, as well as mass-spectrometry (MS)-based assays for
large-scale proteomic studies. One of the most important computational challenges is to take full advantage of all the accumulated
data, both from own laboratory and from public repositories, to
obtain a comprehensive view of the system under study.
We are developing data integration and data-driven optimization
approaches that can effectively correct for the technical variation
characteristic to various experimental platforms, and hence improve the comparability of different experiments, identification of
differentially expressed genes and proteins, and inference of their
interaction partners in global cellular networks. An integrative network-based modeling approach can provide robust and unbiased
means to reveal the key molecular mechanisms behind the systems behavior and to predict its response to various perturbations.
In clinically-oriented research, the modeling approach has the potential to improve our understanding of the disease pathogenesis
and help us to identify novel molecular markers for pharmaceutical
or diagnostics applications.
Funding:
The Academy of Finland, Systems Biology research programme,
and the Graduate School in Computational Biology, Bioinformatics,
and Biometry (ComBi).
Collaborators:
Riitta Lahesmaa (Turku Centre for Biotechnology), Tuula Nyman
(University of Helsinki), Matej Orešic (VTT Biotechnology), Benno
Schwikowski (Pasteur Institute, Paris), Mats Gyllenberg (University
of Helsinki), Esa Uusipaikka (University of Turku), Samuel Kaski
(Helsinki University of Technology), Timo Koski (Royal Institute of
Technology, Stockholm), Eija Korpelainen (CSC – IT Center for Science), Jan Westerholm (Åbo Akademi University), Esa Tyystjärvi
(University of Turku), and Mauno Vihinen (University of Tampere).
Vähämaa, H., Koskinen, V.R., Hosia, W., Moulder, R., Nevalainen,
O.S., Lahesmaa, R., Aittokallio, T. and Salmi, J. (2011) PolyAlign A versatile LC-MS data alignment tool for landmark-selected and
automated use. To appear in International Journal of Proteomics.
Lahti, L., Elo, L.L., Aittokallio, T. and Kaski, S. (2011) Probabilistic
analysis of probe reliability in differential gene expression studies
with short oligonucleotide arrays, IEEE/ACM Trans Comput Biol
Bioinform 8: 217-225.
Lietzén, N., Natri, L., Nevalainen, O.S., Salmi, J. and Nyman, T.A.
(2010) Compid: a new software tool to integrate and compare MS/
MS based protein identification results from Mascot and Paragon.
J Proteome Res 9: 6795-800.
Okser, S., Lehtimäki, T., Elo, L.L., Mononen, N., Peltonen, N.,
Kähönen, M., Juonala, M., Fan, Y.M., Hernesniemi, J.A., Laitinen,
T., Lyytikäinen, L.P., Rontu, R., Eklund, C., Hutri-Kähönen, N., Taittonen, L., Hurme, M., Viikari, J.S.A., Raitakari, O.T. and Aittokallio,
T. (2010).Genetic variants and their interactions in the prediction of
increased pre-clinical carotid atherosclerosis --The Cardiovascular
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Risk in Young Finns Study, PLoS Genet 6: e1001146.
Ahlfors, H., Limaye, A., Elo, L.L., Tuomela, S., Burute, M., Gottimukkala, K.V., Notani, D., Rasool, O., Galande, S. and Lahesmaa, R. (2010)
SATB1 dictates expression of multiple genes including IL-5 involved
in human T helper cell differentiation. Blood 116: 1443-1453.
Moulder, R., Lönnberg, T., Elo, L.L., Filén, J.J., Rainio, E., Corthals,
G., Orešic, M., Nyman, T.A., Aittokallio, T. and Lahesmaa, R. (2010)
Quantitative proteomics analysis of the nuclear fraction of human
CD4+ cells in the early phases of IL-4 induced Th2 differentiation,
Mol Cell Proteomics 9: 1937-1953.
Codrea, M.C., Hakala-Yatkin, M., Kårlund-Marttila, M., Nedbal,
L., Aittokallio, T., Nevalainen, O.S. and Tyystjärvi, E. (2010)
Mahalanobis distance screening of Arabidopsis mutants with
chlorophyll fluorescence, Photosynth Res 205: 273-283.
Talvinen, K., Tuikkala, J., Nykänen, M., Nieminen, A., Anttinen, J.,
Nevalainen, O.S., Hurme, S., Kuopio, T. and Kronqvist, P. (2010)
Altered expression of p120catenin predicts poor outcome in
invasive breast cancer. J Cancer Res Clin Oncol 136: 1377-1387.
Elo, L.L., Mykkänen, J., Järvenpää, H., Nikula, T., Simell, S.,
Aittokallio, T., Hyöty, H., Ilonen, J., Veijola, J., Simell, T., Knip, M.,
Simell, O. and Lahesmaa, R. (2010) Early suppression of immune
response pathways characterizes children with pre-diabetes in
genome-wide gene expression profiling, J Autoimmun 35: 70-76.
Eronen, V.P., Lindén, R.O., Lindroos, A., Kanerva, M. and Aittokallio
T. (2010) Genome-wide scoring of positive and negative epistasis
through decomposition of quantitative genetic interaction fitness
matrices, PLoS ONE 5: e11611.
Elo, L.L., Järvenpää, H., Tuomela, S., Raghav, S., Ahlfors, H.,
Laurila, K., Gupta, B., Lund, R.J., Tahvanainen, J., Hawkins, R.D.,
Orešic, M., Lähdesmäki, H., Rasool, O., Rao, K.V.S., Aittokallio, T.
and Lahesmaa, R. (2010) Genome-wide profiling of interleukin-4
and STAT6 transcription factor regulation of human Th2 cell
programming, Immunity 32: 852-862.
Piippo, M., Lietzén, N., Nevalainen, O.S., Salmi, J. and Nyman,
T.A. (2010) Pripper: prediction of caspase cleavage sites from
whole proteomes. BMC Bioinformatics 11: 320.
Aittokallio, T. (2010) Dealing with missing values in large-scale
studies - microarray data imputation and beyond, Invited Review,
Brief Bioinform 11: 253-264.
Korolainen, M.A., Nyman, T.A., Aittokallio, T. and Pirttilä, T. (2010)
An update on clinical proteomics in Alzheimer’s research, J Neurochem 112: 1386-1414.
Laajala, T.D., Raghav, S., Tuomela, S., Lahesmaa, R., Aittokallio,
T. and Elo, L.L. (2009) A practical comparison of methods for detecting transcription factor binding sites in ChIP-seq experiments.
BMC Genomics 10:618.
Clément-Ziza, M., Malabat, C., Weber, C., Moszer, I., Aittokallio, T.,
Letondal, C. and Rousseau, S. (2009) Genoscape: a Cytoscape
plug-in to automate the retrieval and integration of gene expression
data and molecular networks. Bioinformatics 25: 2617-2618.
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Hiissa, J., Elo, L.L., Huhtinen, K., Perheentupa, A., Poutanen, M.
and Aittokallio, T. (2009) Resampling reveals sample-level differential
expression in clinical genome-wide studies. OMICS 13: 381-396.
Elo, L.L., Hiissa, J., Tuimala, J., Kallio, A., Korpelainen, E. and
Aittokallio, T. (2009) Optimized detection of differential expression in
global profiling experiments: case studies in clinical transcriptomic
and quantitative proteomic datasets. Brief Bioinform 10: 547-555.
Merisaari, H., Parkkola, R., Alhoniemi, E., Teräs, M., Lehtonen, L.,
Haataja, L., Lapinleimu, H. and Nevalainen, O.S. (2009) Gaussian
mixture model-based segmentation of MR images taken from
premature infant brains. J Neurosci Methods 182: 110-122.
Salmi, J., Nyman, T.A., Nevalainen, O.S. and Aittokallio, T. (2009)
Filtering strategies for improving protein identification in highthroughput MS/MS studies. Proteomics 9: 848-860.
Laajala, E., Aittokallio T., Lahesmaa, R. and Elo, L.L. (2009) Probelevel estimation improves the detection of differential splicing in Affymetrix exon array studies. Genome Biol 10: R77.
Huhtinen, K., Suvitie, P., Hiissa, J., Junnila, J., Huvila, J., Kujari,
H., Setälä, M., Härkki, P., Jalkanen, J., Fraser, J., Mäkinen, J., Auranen, A., Poutanen, M. and Perheentupa, A. (2009) Serum HE4
concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer 100:1315-1319.
Aittokallio, T. (2009) Module finding approaches for protein interaction networks. In: Li, X.-L. and Ng, S.-K. (eds.) Biological Data Mining
in Protein Interaction Networks, Medical Information Science Series,
Chapter 18, pp. 335-353. IGI Global, Hershey, Pennsylvania, U.S.A.
From left to right: Johannes Tuikkala, Heidi Vähämaa, Laura Elo, Rolf Linden, Jussi
Salmi, Olli Nevalainen, Ville Koskinen, and Tero Aittokallio.
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ORGANISATION OF NEURONAL
SIGNALING PATHWAYS
Michael Courtney, Ph.D., Research manager, Professor of Cell
Signaling. Contact information: Molecular Signaling Laboratory,
Department of Neurobiology, A.I. Virtanen Institute,
University of Eastern Finland, P.O. Box1627,
Neulaniementie 2, FIN-70211Kuopio, Finland.
Biography:
Michael Courtney (b. 1967) graduated from University of Cambridge in 1988 (B.A.), and the University of Dundee in 1991(Ph.D).
Postdoctoral fellowships from the Royal Society, Wellcome Trust,
Academy of Finland and Sigrid Jusélius Foundation supported his
quantitative imaging development and application activities from
1992 in Prof. Karl Åkerman’s laboratory in Åbo Akademi, Turku.
After group leader positions at BTK from 1998, he was appointed
from 2000 to a position at the A.I. Virtanen Institute, Kuopio and
from 2006 to BTK. He has been affiliated with the Cell Imaging
Core since its inception, and established and is running the Multimodal Imaging Unit at Kuopio University. He was appointed to an
Academy of Finland Researcher post from 2003-2008, and Professor of Cell Signaling at the University of Kuopio from 2008.
Personnel:
Post-doctoral researchers: Franz Ho Ph.D., Peter Martinsson
Ph.D., Minna Tuittila, Ph.D, Olga Vergun Ph.D. Graduate students:
Lili Li, B.Sc., Xiaonan Liu, M.Sc., Maykel Lopez-Rodriguez M.Sc.,
Xijun Wang, M.Sc., Leena Yadav M.Sc. Undergraduate students:
Zoher Hoosenally
Neuronal cells possess a complex architecture consisting of multiple subcellular compartments. Disease states place cells under
stressful conditions. The p38 and JNK stress-activated protein
kinase pathways are widely accepted to play a significant role in
cell death in and outside the nervous system, and drugs directly
targeting stress activated protein kinases have been under development for many years. However, these pathways also contribute
to development, differentiation, and even survival and proliferation.
This suggests that direct stress-activated protein kinase inhibitors
may be of only limited use. In order to exploit the pathways for the
development of novel neuroprotective drugs, it will be necessary
to elucidate the mechanisms that organise these pathways into
pools with neurodegenerative or physiological functions within the
complex structure of neuronal cells. Only then can the neurodegenerative activities of the pathways be selectively eliminated. It
has been suggested that this may help reduce the neuronal death
that contributes to neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, increasingly major causes of death,
disability and socioeconomic impact in society. Previous studies
of the mammalian stress-activated MAPK pathway have revealed
the existence of a plethora of upstream regulators competent to
recruit this pathway. In particular, proteins with putative scaffolding actions have been found. Such components could in principle
have a number of effects on the associated upstream regulator,
including (i) to potentiate their ability to activate the pathway, (ii) to
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restrict accessibility to activators, (iii) to channel the downstream
consequence to select targets and (iv) to localise these properties
to specific compartments within a cell.
Our lab’s aim is to elucidate how neuronal cells compartmentalise the endogenous components of the stress-activated protein
kinase pathway and how specific stimuli recruit only select components of these pathways. To achieve this, we focus mainly on
3 areas: i) Signalling between post-synaptic density proteins and
neuronal stress-activated protein kinase pathways; ii) Small G-protein signaling pathways regulating stress-activated protein kinases
in neurons; iii) Development and implementation of approaches
to imaging of intracellular signaling pathways. The mechanisms
which maintain selective responsiveness to upstream stimuli and
restricted downstream consequences are anticipated to be a fruitful source of potential targets for future neuroprotective strategies.
Thus we also utilise the information gleaned from studies of neuronal signaling mechanisms to develop and evaluate novel neuroprotective molecules in cooperation with collaborating partners from
both the pharmaceutical industry and from academia.
While pursuing these scientific goals, we also implement imaging
methodologies. We adapt and establish the use of a wide range
of FRET-based probes of cell signaling and multiparameter imaging methods. These allow spatiotemporal measurement of several
pathways simultaneously in the same cells. We established facilities
(physically located within Biocentre Kuopio, www.uef.fi/aivi/muic)
to make available to all researchers both live cell high High-Content
Analysis (HCA) and as TIR-FRET and TIR-FRAP techniques.
Westerlund, N., Zdrojewska, J., Padzik, A. Komulainen, E., Björkblom, B., Rannikko E., Tararuk, T., Garcia-Frigola, C., Sandholm,
J. Nguyen, L., Kallunki, T. Courtney, M.J., Coffey, E.T. (2011) Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit
and neuronal migration rate. Nat. Neurosci. 14:305-13.
Yang H., Courtney, M.J., Martinsson, P., Manahan-Vaughan, D.
(2011) LTD is enhanced, depotentiation is inhibited and LTP is unaffected by the application of a selective JNK inhibitor to the hippocampus of freely behaving rats. Eur. J. Neurosci., in press.
Waetzig, V., Wacker, U., Haeusgen, W., Björkblom, B., Courtney,
M.J., Coffey, E.T. and Herdegen, T. (2009) Concurrent protective
and destructive signaling of JNK2 in neuroblastoma cells. Cell Signal. 21, 873-80
Hellwig, C.T., Kohler, B.F., Lehtivarjo A.-K., Dussmann, H., Courtney, M.J., Prehn, J.H. and Rehm, M. (2008) Real-time analysis of
TRAIL/ CHX-induced caspase activities during apoptosis initiation.
J. Biol. Chem. 283, 21676-85.
Björkblom, B., Vainio, J.C., Hongisto, V., Herdegen, T., Courtney,
M.J. and Coffey, E.T. (2008) All JNKs can kill but nuclear localization is critical for neuronal death. J. Biol. Chem. 283, 19704-19713.
Hongisto, V., Vainio, J.C., Thompson, R., Courtney, M.J. and Coffey, E.T. (2008) The Wnt pool of GSK-3b is critical for trophic deprivation induced neuronal death. Mol. Cell. Biol. 28, 1515-1527.
Total Internal Reflection methods exploit the spatially
restricted evanescent wave formed at the interface between media of different refractive indices, thereby surpassing the classical diffraction limits. These methods are ideally suited to measure signaling events and protein turnover at protein complexes in the plasma-membrane proximal zones of living cells, such as the neuronal postsynaptic density.
The live-cell HCA unit is interfaced with an automated incu-
bator and is suitable for high-throughput studies. This is a nationally unique Biocentre Finland (BF) infrastructure plat-
form supported by two BF networks. Our group has estab-
lished a number of assays permitting application of HCA methods to primary cultured neurons and, most recently, an in vivo model. More details can be found via the links at www.uef.fi/aivi/muic.
Westerlund, N., Zdrojewska, J., Courtney, M.J. and Coffey, E.T.
(2008) SCG10 as a molecular effector of JNK1: Implications for the
therapeutic targeting of JNK in nerve regeneration. Expert Opin.
Ther. Targets, 12, 1-13.
Funding:
The Academy of Finland, The EU 6th framework STREP “STRESSPROTECT”, the EU 7th framework project “MEMOLOAD”, The
Sigrid Juselius Foundation, The University of Eastern Finland, The
Drug Discovery Graduate School and The Molecular Medicine
Graduate School.
Björkblom, B., Östman, N., Hongisto, V., Komarovski, V., Filén, J.,
Nyman, T.A., Kallunki, T., Courtney, M.J. and Coffey, E.T. (2005)
Constitutively active cytoplasmic JNK1 is a dominant regulator of
dendritic architecture; role of MAP2 as an effector. J. Neurosci. 25,
6350-6361.
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Collaborators:
Eleanor Coffey and Tassos Papageorgiou (BTK, Åbo Akademi and
University of Turku), Christophe Bonny (University of Lausanne and
Xigen Pharma AG), Denise Manahan-Vaughan (University of Bochum), Mark Spaller (Brown University, Providence, RI), Olli Pentikäinen (University of Jyväskylä), Antti Poso (University of Eastern
Finland) and Anita Truttman (CHUV, Lausanne University Hospital).
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Semenova, M.M., Mäki-Hokkonen, A.M.J., Cao, J., Komarovski,
V., Forsberg, K.M., Koistinaho, M. Coffey E.T. and Courtney, M.J.
(2007) Rho mediates calcium-dependent activation of p38α and
subsequent excitotoxic cell death. Nat. Neurosci. 10, 436-443.
Tararuk, T., Östman N., Li, W., Björkblom, B., Padzik, A., Zdrojewska, J., Hongisto, V., Herdegen, T., Konopka, W., Courtney M.J. and
Coffey, E.T. (2006) JNK1 phosphorylation of SCG10 determines
microtubule dynamics and axodendritic length. J. Cell Biol. 173,
265-277.
Cao, J., Viholainen, J.I., Dart, C., Warwick, H.K., Leyland, M.L. and
Courtney, M.J. (2005) The nNOS-PSD95 interface - a target for inhibition of excitotoxic p38 stress-activated protein kinase activation
and cell death. J. Cell Biol. 168, 117-126.
Cao, J., Semenova, M.M., Solovyan, V.T., Han, J., Coffey, E.T and
Courtney, M.J. (2004) Distinct requirements for p38a and JNK
stress-activated protein kinases in different forms of apoptotic neuronal death. J. Biol. Chem. 279, 35903-35913.
93
Solovyan, V.T., Bezvenyuk, Z., Salminen, A., Austin, C.A. and
Courtney M.J. (2002) The role of topoisomerase II beta in the excision of DNA loop domains during apoptosis. J. Biol. Chem. 277,
21458-21467.
Coffey, E.T., Smiciene, G., Hongisto, V., Cao, J., Brecht, S., Herdegen, T. and Courtney, M.J. 2002) JNK2/3 is specifically activated
by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. J. Neurosci. 22, 43354345.
Coffey, E.T., Hongisto, V., Davis, R.J., Dickens, M. and Courtney,
M.J. (2000) Dual Roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. J. Neurosci.
20, 7602-7613.
Courtney, M.J., Åkerman, K.E.O. and Coffey, E.T. (1997)
Neurotrophins protect cultured cerebellar granule neurons against
the early phase of cell death by a two-component mechanism. J.
Neurosci. 17, 4201-4211.
BIOENERGY GROUP
http://www.btk.fi/research/affiliated-groups/
jones-patrik-bioenergy-group/
Patrik R. Jones, Ph.D., Principal Investigator, University of Turku,
Centre for Biotechnology, Turku BioCity, Tykistökatu 6B, 4krs,
20520, Turku. Tel.:+358-2-333-7913. E-mail: [email protected].
Biography:
Patrik Jones (b. 1968) completed his undergraduate degree in Agricultural Sciences (Oenology, Honours) at the University of Adelaide and obtained his Ph.D. (2001) from the University of Adelaide,
Australia, and the Royal Veterinary and Agricultural University of
Copenhagen, Denmark, on the topic of plant natural product metabolism. Before commencing his current position in Turku in 2008,
he held a position as JSPS-funded post-doctoral fellow (20012002, plant natural product metabolism) at Chiba University, Japan; Research Chemist (2003-2004, wine chemistry and sensory
perception) at the Australian Wine Research Institute in Adelaide,
Australia; Research Director (2005-2008, microbial metabolic engineering and renewable fuel production) at Fujirebio Inc. (100%
for-profit), Tokyo, Japan.
Personnel:
Undergraduate students: Sanna Peltonen, Linda Vuorijoki, Hariharan Dapandani, Melak Weldengodguad
Visiting students: Danilo Corredu, Artur Tallihärm
Graduate students: Jari Kämäräinen, Veronica Carbonell, Andras
Pasztor
Researchers: Fernando Guerrero, M. Kalim Akhtar
Coordinator: Yumi Otani
We target the interface between fundamental and applied sciences by studying fundamental questions of applied importance. In
most cases, we wish to answer or obtain insight about outstanding
questions and issues which are important for current and theoretical biological energy conversion processes. The laboratory currently has two main lines of research:
(1) Fundamental understanding for improving fermentative
and photobiological H2-production. Topics include iron sulfur
cluster metabolism and NADP(H)-homeostasis. The subjects are
studied with a combination of computational and experimental
methodologies, with a focus on key reactions and/or the entire
metabolism of the cell (systems biology).
(2) Pathway engineering for synthesis of transport fuels.
We engineer a tiny fraction of the metabolism of model hosts in
order to (a) introduce biofuel-pathways that do not exist in nature
and (b) modify host metabolism to favor those pathways. The
engineering is aided by computational flux balance analysis and
development of engineering tools.
Funding:
European Research Council, EU FP7, Tekes
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Akhtar, M.K. and Jones, P.R. (2009) Construction of a synthetic YdbK-dependent pyruvate:H2 pathway in Escherichia coli BL21(DE3).
Metabolic Engineering 11, 139-147.
COMPUTATIONAL SYSTEMS
BIOLOGY
Veit, A., Akhtar, K.M., Mizutani, T., Jones P.R. (2008) Constructing and testing the thermodynamic limits of synthetic NAD(P)
H:H2Pathways. Microbial Biotechnology 1, 382-394.
http://users.ics.tkk.fi/harrila/research/
Akhtar, K.M., and Jones P.R. (2008) Deletion of iscR stimulates
recombinant clostridial Fe-Fe hydrogenase activity and H2accumulation in Escherichia coli BL21(DE3). Applied Microbiology and
Biotechnology 78(5), 853-862.
Akhtar, K.M., and Jones P.R. (2008) Constructing a synthetic hydFhydE-hydG-hydA operon for engineering biohydrogen production.
Analytical Biochemistry 373(1), 170-172.
Park, M.-O., Mizutani, T., Jones. P.R. (2007) Glyceraldehyde3phosphate:ferredoxin oxidoreductase from Methanococcus maripaludis. Journal of Bacteriology 189(20), 7281-7289.
Jones, P.R. (2008) Improving fermentative biomass-derived
H2production by engineering microbial metabolism. International
Journal of Hydrogen Energy 33, 5122-5130.
Harri Lähdesmäki, D.Sc. (Tech), Prof. (pro term).
Affiliated group leader: Turku Centre for Biotechnology
Contact information: Aalto University School of Science,
Department of Information and Computer Science,
PO Box 15400, FI-00076 Aalto, Finland.
We use computational techniques to model and understand molecular regulatory mechanisms and their role in health and disease.
We focus on developing statistical modeling and machine learning methods to understand transcriptional, post-transcriptional
and epigenetic regulatory mechanisms, protein signaling pathways, and effects of mutations on regulatory mechanisms. We
also develop methods for biological sequence analysis, combining
heterogeneous biological information sources and analyzing highthroughput measurement data, such as deep-sequencing and microarray measurements. Research projects are carried out in close
collaboration with experimental groups, and we collaborate on molecular immunology, stem cell, cancer and type 1 diabetes systems
biology research projects. Ongoing research topics include:
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•
•
•
•
•
•
Modeling gene expression regulation by transcription
factors, chromatin structure and epigenetic modifications
Modeling molecular dynamics; signaling pathways and gene
regulatory networks
Alternative splicing detection
Molecular systems immunology Statistical modeling for high-throughput data
Systems approaches in Type 1 diabetes and cancer
research
Machine learning and computational statistics,
with applications to molecular biology
Funding:
Academy of Finland, EU FP7, EraSysBio+, Emil Aaltonen
Foundation, FICS and TISE graduate schools.
From left to right, front row: Patrik Jones , Fernando Guerrero, Danilo Correddu,
back row: Linda Vuorijoki, Francy El Souki, Eva Fredriksson-Lidsele,
Sanna Peltonen, Veronica Carbonell, Hariharan Dapandani, Melak Weldenegodguad,
András Pásztor, Jari Kämäräinen.
Erkkilä, T., Lehmusvaara, S., Ruusuvuori, P., Visakorpi, T.,
Shmulevich, I. and Lähdesmäki, H., Probabilistic analysis of gene
expression measurements from heterogeneous tissues,
Bioinformatics, Vol. 26, No. 20, pp. 2571-2577, 2010.
Elo, L. L., Järvenpää, H., Tuomela, S., Raghav, S., Ahlfors, H.,
Laurila, K., Gupta, B., Lund, R. J., Tahvanainen, J., Hawkins, D.,
Oresic, M., Lähdesmäki, H., Rasool, O., Rao, K. V., Aittokallio, T. and
Lahesmaa, R., Genome-wide Profiling of Interleukin-4 and STAT6
Transcription Factor Regulation of Human Th2 Cell Programming,
Immunity, Vol. 32, No. 6, pp. 727-862, 2010.
Aho, T., Almusa, H., Matilainen, J., Larjo, A., Ruusuvuori, P., Aho,
K.-L., Wilhelm, T., Lähdesmäki, H., Beyer, A., Harju, M., Chowdhury,
96
97
S., Leinonen, K, Roos, C. and Yli-Harja, O., Reconstruction and
validation of RefRec: a global model for the yeast molecular
interaction network, PLoS ONE, 5(5):e10662, 2010.
Dai, X. and Lähdesmäki, H., Novel data fusion method and
exploration of multiple information sources for transcription factor
target gene prediction, EURASIP Journal on Advances in Signal
Processing, Special issue on Genomic Signal Processing, Vol.
2010, Article ID 235795, 2010.
Laurila, K. and Lähdesmäki, H., A protein-protein interaction guided
method for competitive transcription factor binding improves target
predictions, Nucleic Acids Research, Vol. 37, No. 22, e146, 2009.
Äijö, T. and Lähdesmäki, H., Learning gene regulatory networks
from gene expression measurements using non-parametric
molecular kinetics, Bioinformatics, Vol. 25, No. 22, pp. 2937-2944,
2009.
Laurila, K. and Lähdesmäki, H., Systematic analysis of diseaserelated regulatory mutation classes reveals distinct effects on
transcription factor binding, In Silico Biology, Vol. 9, 0018, 2009.
Dai, X., Erkkilä, T., Yli-Harja, O. and Lähdesmäki, H., A joint mixture
model for clustering genes from Gaussian and beta distributed
data, BMC Bioinformatics 10:165, 2009.
Dai, X., Lähdesmäki, H. and Yli-Harja, O., A stratified beta-Gaussian
mixture model for clustering genes with multiple data sources,
International Journal on Advances in Life Sciences, Vol. 1, No. 1,
pp. 14-25, 2009.
Nykter, M., Lähdesmäki, H., Rust, A. G., Thorsson, V. and
Shmulevich, I., A data integration framework for prediction of
transcription factor targets: a BCL6 case study, Annals of the New
York Academy of Sciences, Vol. 1158, pp. 205-214, 2009.
Lähdesmäki, H., Rust, A. G. and Shmulevich, I., Probabilistic
inference of transcription factor binding from multiple data sources,
PLoS ONE, Vol. 3, No. 3, e1820, 2008.
Lähdesmäki, H. and Shmulevich, I., Learning the structure of
dynamic Bayesian networks from time series and steady state
measurements, Machine Learning, Vol. 71, No. 2-3, pp. 185-217,
2008.
Liu, W., Lähdesmäki, H., Dougherty, E. R. and Shmulevich, I.,
Inference of Boolean networks using sensitivity regularization,
EURASIP Journal on Bioinformatics and Systems Biology, Vol.
2008, Article ID 780541, 12 pages, 2008.
Ahdesmäki, M., Lähdesmäki, H., Gracey, A., Shmulevich, I. and
Yli-Harja O., Robust regression for periodicity detection in nonuniformly sampled time-course gene expression data, BMC
Bioinformatics, 8:233, 2007.
PUBLICATIONS
Ph.D. theses 2010
1. Ahlfors, Helena: Interleukin-4 induced leukocyte differentiation.
University of Turku, p. 145
2. Ahlskog, Johanna: Regulation of heat shock transcription
factors by ubiquitin and ubiquitin-like modifiers. Åbo Akademi
University, p. 139
3. Blomster, Henri: Cellular regulation of SUMO modification by
alternative targeting mechanisms. Åbo Akademi University, p.
145
4. Filén, Sanna: ATF3 and GIMAP family proteins 1 and 4 in
human T helper cell differentiation. Åbo Akademi University, p.
145
5. Kouvonen, Petri: Simplified sample handling in mass
spectrometry based protein research. University of Turku,
p.106
6. Kukkonen-Macchi, Anu: Functional characterization of proteins
required for mitotic progression and the spindle assembly
checkpoint. University of Turku, p. 96
7. Pallari, Hanna-Mari: Dynamic interplay between the
intermediate filament protein nestin and Cyclin-dependent
kinase 5. Åbo Akademi University, p. 111
8. Peuhu, Emilia: Lethal Weapons - Novel approaches for
receptor-targeted cancer cell elimination. Åbo Akademi
University, p. 179
9. Sandqvist, Anton: HSF1-HSF2 heterotrimerization as a
transcriptional switch and miR-18 mediated regulation of
HSF2. Åbo Akademi University, p.140
10. Tahvanainen, Johanna: New mechanisms regulating human
Th1 and Th2 cell differentiation. University of Turku, p. 175
11. Tiikkainen, Pekka: Study of ligand-based virtual screening
tools in computer-aided drug design. University of Turku, p. 98
12. Toivonen, Raine: Targeting adenoviral gene therapy vectors to
HNSCC and heart. University of Turku, p. 103
13. Tuomi, Saara: The integrin tail: A tail of motility and division.
University of Turku, p.166
14. Vuoriluoto, Karoliina: Anchor or accelerate – a study on cancer
cell adhesion and mobility. University of Turku, p.162
Publications 2010
1. Aittokallio, T. 2010. Dealing with missing values in large-scale
studies – microarray data imputation and beyond. Briefings in
Bioinformatics, 11: 253-264.
2. Ahlfors H., Limaye A., Elo L.L., Tuomela S., Burute M.,
Gottimukkala K.V., Notani D., Rasool O., Galande S., Lahesmaa
R. 2010. SATB1 dictates expression of multiple genes including
IL-5 involved in human T helper cell differentiation. Blood,
116(9):1443-1453.
3. Ahlskog J.K., Björk J.K., Elsing A.N., Aspelin C., Kallio M.,
Roos-Mattjus P., Sistonen L. 2010. Anaphase-promoting
complex/cyclosome participates in the acute response to
protein-damaging stress. Mol. Cell. Biol., 30(24):5608-5620.
4. Axarli I., Georgiadou C., Dhavala P., Papageorgiou A.C., Labrou
98
99
N.E. 2010. Investigation of the role of conserved residues
Ser13, Asn48 and Pro49 in the catalytic mechanism of the
tau class glutathione transferase from Glycine max. Biochim.
Biophys. Acta, 1804(4):662-667.
5. Björk J.K., Sandqvist A., Elsing A.N., Kotaja N., Sistonen L.
2010. miR-18, a member of Oncomir-1, targets heat shock
transcription factor 2 in spermatogenesis. Development,
137(19):3177-3184.
6. Björk J.K., Sistonen L. 2010. Regulation of the members of the
mammalian heat shock factor family. FEBS J., 277(20):41264139.
7. Blom T., Bergelin N., Meinander A., Löf C., Slotte J.P.,
Eriksson J.E., Törnquist K. 2010. An autocrine sphingosine-1phosphate signaling loop enhances NF-kappaB-activation and
survival. BMC Cell Biol., 11:45.
8. Blomster H.A., Imanishi S.Y., Siimes J., Kastu J., Morrice
N.A., Eriksson J.E., Sistonen L. 2010. In vivo identification of
sumoylation sites by a signature tag and cysteine-targeted
affinity purification. J. Biol. Chem., 285(25):19324-19329.
9. Das D., Lanner F., Main H., Andersson E.R., Bergmann O.,
Sahlgren C., Heldring N., Hermanson O., Hansson E.M.,
Lendahl U. 2010. Notch induces cyclin-D1-dependent
proliferation during a specific temporal window of neural
differentiation in ES cells. Dev. Biol., 15;348(2):153-166.
10. de Thonel A., Ferraris S.E., Pallari H.M., Imanishi S.Y., Kochin
V., Hosokawa T., Hisanaga S., Sahlgren C., Eriksson J.E.
2010. Protein kinase Czeta regulates Cdk5/p25 signaling
during myogenesis. Mol. Biol. Cell, 21(8):1423-1434.
11. Diamandis E.P., Hudson T., Kallioniemi O., Liu E.T., López-Otín
C. 2010. Cancer Genomes. Clin. Chem., 6 (11):1660-1664
12. Dias J.D., Guse K., Nokisalmi P., Eriksson M., Chen
D.T., Diaconu I., Tenhunen M., Liikanen I., Grénman R.,
Savontaus M., Pesonen S., Cerullo V., Hemminki A. 2010.
Multimodal approach using oncolytic adenovirus, cetuximab,
chemotherapy and radiotherapy in HNSCC low passage
tumour cell cultures. Eur. J. Cancer, 46(3):625-635.
13. do Carmo Costa M., Bajanca F., Rodrigues A.J., Tomé R.J.,
Corthals G., Macedo-Ribeiro S., Paulson H.L., Logarinho
E., Maciel P. 2010. Ataxin-3 plays a role in mouse myogenic
differentiation through regulation of integrin subunit levels.
PLoS One, 5(7):e11728.
14. Elo L.L., Järvenpää H., Tuomela S., Raghav S., Ahlfors H.,
Laurila K., Gupta B., Lund R.J., Tahvanainen J., Hawkins R.D.,
Oresic M., Lähdesmäki H., Rasool O., Rao K.V., Aittokallio T.,
Lahesmaa R. 2010. Genome-wide profiling of interleukin-4
and STAT6 transcription factor regulation of human Th2 cell
programming. Immunity, 32(6):852-862.
15. Elo L.L., Mykkänen J., Nikula T., Järvenpää H., Simell S.,
Aittokallio T., Hyöty H., Ilonen J., Veijola R., Simell T., Knip M.,
Simell O., Lahesmaa R. 2010. Early suppression of immune
response pathways characterizes children with prediabetes
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in genome-wide gene expression profiling. J. Autoimmun.,
35(1):70-76.
16. Filén S., Ylikoski E., Tripathi S., West A., Björkman M., Nyström
J., Ahlfors H., Coffey E., Rao K.V., Rasool O., Lahesmaa R.
2010. Activating transcription factor 3 is a positive regulator
of human IFNG gene expression. J. Immunol., 184(9):49904999.
17. Filén S., Lahesmaa R. GIMAP Proteins in T-Lymphocytes.
2010. Journal of Signal Transduction. Volume 2010, Article ID
268589
18. Gupta S., Iljin K., Sara H., Mpindi J.P., Mirtti T., Vainio P.,
Rantala J., Alanen K., Nees M., Kallioniemi O. 2010. FZD4
as a mediator of ERG oncogene-induced WNT signaling and
epithelial-to-mesenchymal transition in human prostate cancer
cells. Cancer Res., 70(17):6735-6745.
19. Haikarainen T., Tsou C.C., Wu J.J, Papageorgiou A.C.
Structural characterization and biological implications of di-zink
binding in the ferroxidase center of Strepococcus pyogenes
Dpr. Biochem. Biophys. Res. Comm., 398:361-365.
20. Haikarainen T., Papageorgiou A.C. 2010. Dps-like proteins:
Structural and functional insights into a versatile protein family.
Cell. Mol. Life Sci., 67:341-251
21. Heikkinen P.T., Nummela M., Jokilehto T., Grenman R., Kähäri
V.-M., Jaakkola P.M. 2010. Hypoxic conversion of SMAD7
function from an inhibitor into a promoter of cell invasion.
Cancer Res., 70(14):5984-5993.
22. Heikkinen P.T., Nummela M., Leivonen S.K., Westermarck J.,
Hill C.S., Kähäri V.-M., Jaakkola P.M. 2010. Hypoxia activated
Smad3-spesific dephosphorylation by PP2A. J Biol. Chem.,
285(6):3740-3749.
23. Härmä V., Virtanen J., Mäkelä R., Happonen A., Mpindi J.P.,
Knuuttila M., Kohonen P., Lötjönen J., Kallioniemi O., Nees M.
2010. A comprehensive panel of three-dimensional models
for studies of prostate cancer growth, invasion and drug
responses. PLoS One, 5(5):e10431.
24. Ivaska J, Heino J. 2010. Interplay between cell adhesion and
growth factor receptors: from the plasma membrane to the
endosomes. Cell Tissue Res., 339(1):111-120.
25. Jaakkola U., Kakko, T., Seppälä H., Vainio-Jylhä E., Vahlberg T.,
Raitakari OT., Kallio J. 2010: The Leu7Pro polymorphism of the
signal peptide of neuropeptide Y (NPY) gene is associated with
increased levels of inflammatory markers preceding vascular
complications in patients with type 2 diabetes. Microvasc.
Res., 80(3):433-439.
26. Jokilehto T., Högel H., Heikkinen P., Rantanen K., Elenius
K., Sundström J., Jaakkola P.M. 2010. Retention of prolyl
hydroxylase PHD2 in the cytoplasm prevents PHD2-induced
anchorage-independent carcinoma cell growth. Exp. Cell
Res., 316(7):1169-1178.
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27. Jokilehto T., Jaakkola P.M. 2010. The role of HIF prolyl
hydroxylases in tumour growth. J. Cell Mol. Med., 14(4):758770.
28. Kankare M., Salminen T., Laiho A., Vesala L., Hoikkala A. 2010.
Changes in gene expression linked with adult reproductive
diapause in a northern malt fly species: a candidate gene
microarray study. BMC Ecol., 10:3.
29. Kerosuo L., Fox H., Perälä N., Ahlqvist K., Suomalainen A.,
Westermarck J., Sariola H., Wartiovaara K. 2010. CIP2A
increases self-renewal and is linked to Myc in neural progenitor
cells. Differentiation, 80(1):68-77.
30. Korolainen M.A., Nyman T.A., Aittokallio T., Pirttilä T. 2010.
An update on clinical proteomics in Alzheimer’s research. J
Neurochem., 112(6):1386-1414
31. Labrou N.E., Papageorgiou A.C., Avramis V.I. 2010.
Structure-function relationships and clinical applications of
L-asparaginases. Curr. Med. Chem., 17(20):2183-2195.
32. Main H., Lee K.L., Yang H., Haapa-Paananen S., Edgren
H., Jin S., Sahlgren C., Kallioniemi O., Poellinger L., Lim B.,
Lendahl U. 2010. Interactions between Notch- and hypoxiainduced transcriptomes in embryonic stem cells. Exp. Cell
Res., 316(9):1610-1624.
33. Matlawska-Wasowska K, Finn R, Mustel A, O’Byrne CP, Baird
AW, Coffey ET, Boyd A. The Vibrio parahaemolyticus Type III
Secretion Systems manipulate host cell MAPK for critical steps
in pathogenesis. BMC Microbiol., 2010 Dec 30;10:329.
34. Mattila E, Marttila H, Sahlberg N, Kohonen P, Tähtinen S,
Halonen P, Perälä M, Ivaska J. 2010. Inhibition of receptor
tyrosine kinase signalling by small molecule agonist of T-cell
protein tyrosine phosphatase. BMC Cancer, 10:7.
35. McDonnell L.A., Corthals G.L., Willems S.M., van Remoortere
A., van Zeijl R.J., Deelder A.M. 2010. Peptide and protein
imaging mass spectrometry in cancer research. J. Proteomics,
73(10):1921-1944.
36. Medina-Aunon J.A., Paradela A., Macht M., Thiele H., Corthals
G., Albar J.P. 2010. Protein Information and Knowledge
Extractor: Discovering biological information from proteomics
data. Proteomics, 10(18):3262-3271.
37. Melissis S.C., Papageorgiou A.C., Labrou N.E., Clonis Y.D.
2010. Purification of M-MLVH- RT on a 9-aminoethyladenine(1,6-diamine-hexane)-triazine selected from a combinatorial
library of dNTP-mimetic ligands. J. Chromatogr. Sci., 48(6):496502.
38. Moulder R., Lönnberg T., Elo L.L., Filén J.J., Rainio E., Corthals
G., Oresic M., Nyman T.A., Aittokallio T., Lahesmaa R. 2010.
Quantitative proteomics analysis of the nuclear fraction of
human CD4+ cells in the early phases of IL-4-induced Th2
differentiation. Mol. Cell Proteomics, 9(9):1937-1953.
39. Nevo J, Mai A, Tuomi S, Pellinen T, Pentikäinen OT, Heikkilä
P, Lundin J, Joensuu H, Bono P, Ivaska J. 2010. Mammaryderived growth inhibitor (MDGI) interacts with integrin
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α-subunits and suppresses integrin activity and invasion.
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Phd DEFENCES
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LIFE OUTSIDE THE LAB
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Report 2010 - Turku Centre for Biotechnology

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