Research Group
Alexandros Pintzas, PhD, Molecular Biologist-Biochemist (Head)
Michael Roberts, PhD, Mol. Biologist (EU Post-doctoral Fellow)
Valantis Andreolas, PhD, Biochemist (Post-doctoral Fellow)
Ageliki Voulgari, PhD, Mol. Biologist (Post-doctoral Fellow)
Sophia Moumtzi, MPhil Cell Biology (PhD student)
Fotini Psachoulia, BSc Biology (PhD student)
Konstantinos Drosopoulos, BSc Mol. Biology (PhD student)
Ioannis Psarras, MSc, Human Genetics (Research Assistant)
Chrisa Mastora, BSc, Biology (Research Assistant)
Stella Voskou, diploma student of Biology
Ioannis Papadogiannakis, MD, part-time

Correspondence:
Alexandros Pintzas, PhD, Molecular Biologist-Biochemist (Head)
Research Professor
Address:
Laboratory of Signal Mediated Gene Expression
National Hellenic Research Foundation (N.H.R.F.)
Institute of Biological Research and Biotechnology (I.B.R.B.)
48 Vas. Constantinou Ave., 116 35 Athens, Greece
Tel: 30 210 7273753 (office), 30 210 7273745 (lab)
Fax: 30 210 7273755
e-mail: apint@eie.gr

Research objectives

The Laboratory of Signal Mediated Gene Expression is studying molecules which convert the mitotic signals into changes in gene expression and their regulatory mechanisms, in order to inhibit their deregulated activity in diseases, like cancer.
The activities of the Laboratory are focusing in the analysis of the function of transcription factors as well as global gene expression in physiological as compared to neoplastic cell. More specifically, studies concerning the mechanisms of regulation of jun/fos (AP-1), ets/SRF families of transcription factors and basal transcription factor families as well as the global expression of their target genes induced by membrane receptors and Ras oncoprotein are performed.

Cell systems in use
a) cell lines from different stages of human colorectal carcinogenesis.
Analysis of gene expression profile during tumour progression in this system is currently in process (Roberts et al., in preparation)
The interplay between oncogenic and apoptotic signals is under investigation utilizing TRAIL, a novel potential cancer therapeutic agent
Candidate genes to be involved in colon tumour progression have been identified by microarray analysis and their role is currently being validated.

b) cell lines derived from skin tumours in mice initiated by the chemical carcinogen DMBA and promoted by TPA. We found an important role of AP-1 in tumor progression of mouse epidermis, and have stressed the role of c-Jun, Fra-1 and ATF-2 factors in the process (Zoumpourlis et al. (2000), Oncogene 19, 4011-4021). In parallel studies, an important role of serum response factor (SRF) during the epithelial to mesenchymal transition during tumor progression of mouse epidermis has been shown. (Psichari et al. (2002). J. Biol. Chem. 277, 29490-29495).

Ras oncogenes are mutated at a high percentage in human tumours, like colon or lung. Recently, we have developed in the lab systems of conditional expression of ras genes in human and mouse cells in order to analyse early changes in signalling and gene expression events mediated by ras oncogene. Human cells expressing conditional forms of Ha-ras and K-ras are currently being used in order to monitor global gene expression profile mediated by ras and to potentially identify new important targets for intervention in (colorectal) cancer.
In our first study, we have observed a novel rapid and transient mechanism of ERK1/2 activation and nuclear translocation dependent on ras, that is phosphatase dependent (Plows et al. (2002), Biochem J. 362, 305-315).
We would like to develop exploitable in vitro chemoprevention cell systems, based on the home made inducible oncogene expression systems.

In parallel studies concerning mechanisms of transcriptional regulation by the c-Jun transcription factor, an important role of TAFII55 in this process has been revealed (Munz et al. (2003) J. Biol. Chem. 278, 21510-21516).

International collaborators

• Collaboration with research groups from UCSF Cancer Center, San Francisco, USA, in analysing signal transduction pathways in mouse carcinogenesis.
• Cooperative studies with IGBMC, Strasbourg , France and DKFZ, Heidelberg, Germany on the mechanisms of c-Jun interaction with basal trancriptional machinery.
• Cooperation with Czech Academy of Sciences, Prague on mechanisms of apoptosis induced by TRAIL

Applications and exploitations of Research

• In collaboration with Hospitals in Athens members of the lab currently performing collaborative studies on gene expression profile analysis (microarray) in human tumors.
• Collaboration with wine producing unions of Greece in the frame of Greek research programme in order to identify novel chemopreventing agents in grapes
  
  

Selected Current and Recent Awarded Research Grants

2004-2007: “Transcription complex dynamics controlling specific gene expression programs” EU- Fundamental Genomics Programme. funding for the lab: 450 kEuros

2004-2008: “Macromolecular assemblies involved in regulated gene expression: structural/functional characteristics, interplay and novel functions”, EU Transfer of Knowledge (TOK) Research Programme, funding for the lab: 250 kEuros

2004-2007: “TAF-Chromatin” EU Research Training Network (RTN) Programme. Participation of 7 labs from 6 countries. Funding for the lab: 370 kEuros.Funding for the lab: 370 kEuros

2004-2006: “Molecular mechanisms of tumour invasion and metastasis”, Research cooperation programme between Greece and USA. Funding for the lab: 60 kEuros

2002-2005: “Regulation of transcription and mRNA processing by oncogenic signals”, EU-IHP Research Programme. Funding: 228 kEuros

2003-2006: “RETRAIL - Alternative therapy for tumours” EU EUREKA Project. Funding 1.6 MEuros

2003-2006: “In vivo and in silico analysis of gene expression induced by Ras oncogene in cancer” , Greek Research Network PENED. Funding 140 kEuros

2000-2001: “Study mechanisms of transcriptional regulation by developing an in vitro transcription system in the context of reconstituted chromatin substrates”. Greek Research Network, Total funding 170 kEuros. Participation of 3 labs.

1996-2001: “The AP-1 transcription factor”, EU-TMR Research Network. Participation of 7 labs from 6 EU countries. Funding for the lab: 220 kEuros.

1996-2000: “Cell signalling in development and disease”, EU-TMR Research Network. Participation of 9 labs from 7 EU countries. Funding for the lab: 55 kEuros

Participation in the Biomedical Applications Unit of IBRB-
International collaborators

• In collaboration with Hospitals in Athens members of the lab currently performing collaborative studies on gene expression profile analysis (microarray) in human tumors.
• Collaboration with research groups from UCSF Cancer Center, San Francisco, USA, in analysing signal transduction pathways in mouse carcinogenesis.
• Cooperative studies with IGBMC, Strasbourg , France and DKFZ, Heidelberg, Germany on the mechanisms of c-Jun interaction with basal trancriptional machinery.
• Cooperation with Czech Academy of Sciences, Prague on mechanisms of apoptosis induced by TRAIL

Selected recent publications

• Munz, C., Psichari, E., Mandilis, D., Lavigne, A.-C., Spiliotaki, M., Oehler, T., Davidson, I., Tora, L., Angel, P. and Pintzas, A. (2003). TAF7 (TAFII55) plays a role in the transcription activation by c-Jun. J. Biol. Chem. 278, 21510-21516.
• Pintzas, A. (2003). Signal regulated gene expression mediated by transcription factors-members of AP-1 and ets/SRF family members: pathways for potential therapeutic intervention. In: “Chemical probes in biology”, Kluwer Academic Pub., M. Schneider (Ed.), pp 35-38.
• Roberts, M., Tarik, E., Drosopoulos, K., Alexis, M., Guialis, A. and Pintzas, A. (2004). K- and H-ras oncogenes induce differential transformation properties of in human colon cells, analysed by gene expression profile. In preparation.
• Psichari, H., Balmain, A., Plows, D. , Zoumpourlis, V. and Pintzas, A. (2002). High activity of serum response factor in the mesenchymal transition of epithelial tumor cells is regulated by RhoA signaling. J. Biol. Chem. 277, 29490-29495.
• Plows, D., Briassouli, P., Owen, C., Zoumpourlis, V., Garrett, M. and Pintzas, A. (2002). Ecdysone-inducible expression of oncogenic Ha-Ras in NIH3T3 cells leads to transient nuclear localisation of activated ERK regulated by MKP-1 phosphatase. Biochem J. 362, 305-315.
• Cermak, L., Simova, S., Pintzas, A., Horejsi, V. and Andera, L. (2002). Molecular mechanisms involved in CD43-mediated apoptosis of TF-1 cells: roles of transcription, Daxx expression and adhesion molecules. J. Biol. Chem. 277, 7955-7961.
• Katsanakis KD, Gorgoulis V, Papavassiliou A and Zoumpourlis V. (2002) .The progression in the mouse skin carcinogenesis model is dependent on ERK1/2 signaling. Molecular Med 8, 624-637.
• Pintzas, A. (2003). Signal regulated gene expression mediated by transcription factors-members of AP-1 and ets/SRF family members: pathways for potential therapeutic intervention. “Chemical probes in biology”, M. Schneider (Ed.), IOS Press. In press.
• Papathoma, A., Zoumpourlis, V., Balmain, A. and Pintzas A. (2001). Role of matrix metalloproteinase-9 in progression of mouse skin carcinogenesis. Mol. Carcinogenesis 31, 74-82.
• Zoumpourlis, V., Papassava, P., Papathoma, A., Sekeris, K., Katsanakis, K., Psihari, H. and Pintzas, A. (2001). AP-1 transcription factor and steroid hormone receptors in multistage mouse skin carcinogenesis. Epith. Klin. Farmakol. Farmakokin. 15, 123-128.
• Zoumpourlis, V., Papassava, P., Linardopoulos, S., Gillespie, D., Balmain, A. and Pintzas, A. (2000). High expression of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogeneis model. Oncogene 19, 4011-4021.
• Papathoma, A., Petraki, C., Grigorakis, A., Papakonstantinou, H., Karavana, V. Stefanakis, S., Sotsiou, F. and Pintzas, A. (2000). Prognostic significance of matrix metalloproteinases 2 and 9 in bladder cancer. Anticancer Research 20, 2009-2014.
• Pintzas, A., Zoumpourlis, V. and Plows, D. (2000). Regulation of components of AP-1 transcription factor by early and late Ras signals. “Molecular mechanisms of signal transduction”, pp 57-62, J. Bos (Ed.), IOS Press.