Research Group

Apoptosis group
Eftychia Oikonomou, PhD, Cancer Biology (Post-doctoral Fellow)
Konstantinos Drosopoulos, BSc Mol. Biology (PhD student)
Fotini Psachoulia, BSc Biology (PhD student)

Functional genomics group
Toby Joyce, PhD, Mol. Biology (EU Marie Curie Post-doctoral Fellow)
Beata Madziar, PhD, Cell Biology (EU Marie Curie Post-doctoral Fellow)
Eleni Makrodouli, MSc, Biology (PhD student)
Sophia Moumtzi, MPhil Cell Biology (PhD student)

Transcription group
Valantis Andreolas, PhD, Biochemistry (Post-doctoral Fellow)
Ignacio Mazon Pelaez, PhD, Genetics (EU Marie Curie Post-doctoral Fellow)
Ageliki Voulgari, PhD, Mol. Biology (Post-doctoral Fellow)
Margarita Kalogeropoulou, MSc, Genetics (EU Marie Curie PhD student)

Correspondence:
Dr Alexandros Pintzas, Research Professor

Address:
Laboratory of Signal Mediated Gene Expression, Head
Institute of Biological Research and Biotechnology (I.B.R.B.)
National Hellenic Research Foundation (N.H.R.F.)
48 Vas. Constantinou Ave., 116 35 Athens, Greece
Tel: +302107273753, +302107273745
Fax: +302107273755
e-mail: apint

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 on the interplay between oncogenic and apoptotic signals and its exploitation towards the development of novel anti-cancer agents. Analysis of the function of transcription factors as well as global gene expression in physiological as compared to neoplastic cell is also performed.

Recent Highlights

a. Identification of novel important genes in colon cancer cells by microarray analysis
b. Analysis of oncogenic mutations which sensitise tumour cells to the apoptotic agent TRAIL, a potential novel cancer therapeutic
c. Identification of novel important interactions in transcriptional regulation

''Gene expression profile analysis in colon cancer cell lines''

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., Int. J. Cancer, 2006 ) Candidate genes to be involved in colon tumour progression have been identified by microarray analysis and their role is currently being validated.
The interplay between oncogenic ras and apoptotic signals induced by TRAIL, a novel potential cancer therapeutic agent has been analysed using human colon cell lines as a model. Oncogenic forms of ras oncogenes sensitise human colon cells to TRAIL induced apoptosis by upregulating TRAIL receptors DR4 and DR5 through a MEK-dependent pathway (Drosopoulos et al. , J. Biol. Chem., 2005).

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., Oncogene, 2000; Papassava et al. Cancer Res., 2004). 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. , J. Biol. Chem. 2002)

c) Our goal is the development of exploitable in vitro chemoprevention cell systems, based on the home made inducible oncogene expression systems.

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. 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. Biochem J., 2002)

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. J. Biol. Chem. , 2003).

International collaborators

• Cooperative studies with IGBMC, Strasbourg , France on the role of components of basal trancriptional machinery in tumour progression
• Cooperation with Czech Academy of Sciences, Prague, Czech Republic on mechanisms of apoptosis induced by TRAIL
• Cooperation with Medical School, Turin University on microarray analysis of oncogenic pathways

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 tumours.
• 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 (1996-2006)
TOTAL budget for the lab: > 3.000 kEuros

2006-2009 : Resistant determinants and sensitisation of solid tumor cells to death receptor related therapies: combination of TRAIL with other therapeutic molecules. EU Combating Cancer Programme. Total funding 2.345 kEuros , for the lab: 589 kEuros (co-ordinator)

2006-2009: Functional oncogenomics: a powerful tool towards diagnosis and treatment of diagnosis and treatment of human colorectal cancer. Greek Research Network PENED. Funding 235 kEuros (co-ordinator)

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

2004-2008: "TAF-Chromatin" EU Research Training Network (RTN) Programme. Participation of 7 labs from 6 countries.
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 (co-ordinator)

2003-2006: "In vivo and in silico analysis of gene expression induced by Ras oncogene in cancer" , Greek Research Network PENED.
Funding 140 kEuros (co-ordinator)

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

Selected recent publications

Drosopoulos, C and Pintzas, A. (2006). Targeted therapy in cancer: the recent players meet the usual suspects. Submitted.

Moumtzi, S., Roberts, M.L. , Frillingos, S., Fotsis, T., and Pintzas, A. (2006). Induction of early oncogenic Ras action in HEK-293 cells leads to growth inhibition in parallel with partial transformation: association with novel genes identified by expression profiling. Submitted.

Oikonomou, E. and Pintzas, A. (2006). Cancer Genetics of Sporadic Colorectal Cancer: BRAF and PI3KCA Mutations, their Impact on Signalling and Novel Targeted Therapies. Anticancer Res. 26, 1077-1084 (Review).

Roberts, M., Drosopoulos, K., Vasileiou, I., Stricker, M., Taoufik E., Maercker, C., Guialis, A., Alexis, M. and Pintzas, A. (2006). Microarray analysis of the differential transformation mediated by kirsten and harvey ras oncogenes in a human colon adenocarcinoma cell line. Int. J. Cancer. 118, 616-627.

Drosopoulos, C., Roberts , M., Cermak, L., Sasazuki , T., Shirasawa, S., Andera L. and Pintzas, A. (2005). Oncogenic Ras transformation sensitizes human colon cancer cells to TRAIL induced apoptosis by upregulating DR4 and DR5 receptors through a MEK dependent pathway. J. Biol. Chem. 280, 22856-22867.

Papassava P., Gorgoulis V.G., Papaevangeliou D., Vlahopoulos S., van Dam H. and Zoumpourlis V. (2004). Overexpression of activating transcription factor-2 is required for tumor growth and progression in mouse skin tumors (2004). Cancer Res. 64, 8573-8584.

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.

Psichari, E., 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 K.D., Gorgoulis V., Papavassiliou A.G., Zoumpourlis V.K. (2002). The progression in the mouse skin carcinogenesis model correlates with ERK1/2 signaling. Mol Med. 8, 624-637.

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., Pintzas, A., Moutsatsou, P. and Katsanakis, K. (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 levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis 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. In: "Molecular mechanisms of signal transduction", pp 57-62, J. Bos (Ed.), IOS Press.