Success Story Greek Scientists Find Way to Weaken Cancer Cells (Reuters, 1/3/2004)

Discussion in TV show
Genes and ageing

Research objectives:

The Programme of ''Molecular and Cellular Ageing'' focuses on the genetic and environmental factors that are linked to human ageing and longevity. By using functional genomics approaches several genes have been cloned which associate with both cellular senescence and longevity; in addition, it has been shown that most of them represent ageing biomarkers. Detailed studies on one of the isolated genes (ApoJ/Clusterin) have revealed that ApoJ is directly implicated in cell survival signals and, moreover, its expression is linked with the appearance of age-related diseases, such as diabetes type II or coronary heart disease. In parallel the general biochemical mechanisms that relate to ageing are also studied, for example, the telomeres shortening and the function of the proteasome. Emphasis is given to the molecular understanding of the impaired function of the proteasome during ageing as well as the identification of the biochemical pathways of its activation. Finally the Programme possesses a collection of samples (PBMC, skin fibroblasts) of donors of different ages, including healthy centenarians. These samples are employed to study agents that either accelerate (e.g. pollutants) or delay (e.g. anti-oxidants) the cellular ageing process as well as to identify gene variants that are linked with longevity in the Hellenic population.

Current Awarded Research Grants:

A. European union:
1. ''Molecular mechanisms of senescence and ageing''. Project: QLRT (2001-2004). Total budget: 2.150.510 Euros, lab budget: 547.914 Euros.
2. ''Functional genomics and proteomics in human molecular gerontology and geriatrics: development of ad hoc microarray, diagnostic applications and molecular screening''. Project: QLRT (2002-2005). Total budget: 2.495.051 Euros, lab budget: 818.927 Euros.
3. ''Nutritional Zinc, oxidative stress and immunosenescence: biochemical, genetic and lifestyle implications for healthy ageing''. Project: FQS/STREP (2004-2007). Total budget: 4.010.942 Euros, lab budget: 324.000 Euros.
4. ''Genetics of healthy ageing''. Project: GBH/Integrated Project (2004-2009). Total budget: 7.867.010 Euros, lab budget: 452.346 Euros.

B. Hellenic General Secretariat of Research & Technology:
5. ''Study of the secretion of plants anti-oxidants and their biological action''. Project: PENED (2002-2005). Total budget: 176.083 Euros.
6. ''Molecular mechanisms of hypoxia: activation and function of the transcription factor HIF-1''. Project: PENED (2002-2005). Total budget: 187.821 Euros.

Selected Recent Articles:

1. E.S. Gonos, J.S. Burns, G.R. Mazars, A. Kobrna, T.E.W. Riley, S.C. Barnet, G. Zafarana, R. Ludwig, Z. Ikram, AJ. Powell and P.S. Jat (1996) Rat embryo fibroblasts immortalized with SV40 large T antigen undergo senescence upon its inactivation. Mol. Cell Biol. 16, 5127-5138.
2. E.S. Gonos, A. Derventzi, M. Kveiborg, G. Agiostratidou, M. Kassem, B.F.C. Clark, P.S. Jat and S.I.S. Rattan (1998) Cloning and identification of genes that associate with mammalian replicative senescence. Exp. Cell Res. 240, 66-74.
3. C. Mondello, C. Petropoulou, D. Monti, E.S. Gonos, C. Franceschi and F. Nuzzo (1999) Telomere length in fibroblasts and blood cells from healthy centenarians. Exp. Cell Res. 248, 234-242.
4. A.J. Powell, A.J. Darmon, E.S. Gonos, E.W.F. Lam, K.W.C. Peden and P.S. Jat (1999) Different functions are required for initiation and maintenance of immortalization of rat embryo fibroblasts by SV40 T antigen. Oncogene 18, 7343-7350.
5. P. Dumont, M. Burton, Q.M. Chen, E.S. Gonos, C. Frippiat, J.B. Mazarati, F. Eliaers, J. Remacle and O. Toussaint (2000) Induction of replicative senescence biomarkers by sublethal successive oxidative stresses in normal human fibroblasts. Free Rad. Biol. Med. 28, 361-373.
6. E.S. Gonos (2000) Genetics of ageing: lessons from centenarians. Exp. Gerontol. 35, 15-21.
7. N. Chondrogianni, I. Petropoulos, C. Franceschi, B. Friguet and E.S. Gonos (2000) Fibroblast cultures from healthy centenarians have an active proteasome. Exp. Gerontol. 35, 721-728.
8. C. Petropoulou, I.P. Trougakos, E. Kolettas, O. Toussaint and E.S. Gonos (2001) Clusterin/Apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasts. FEBS Lett. 509, 287-297.
9. M. Barradas, E.S. Gonos, Z. Zebedee, E. Kolettas, C. Petropoulou, M. Dolores-Delgado, J. Leon, E. Hara and M. Serrano (2002) Identification of a candidate tumor suppressor gene specifically activated during ras-induced senescence. Exp. Cell Res. 273, 127-137.
10. I.P. Trougakos, M. Poulakou, M. Stathatos, A. Chalikia, A. Melidonis and E.S. Gonos (2002) Serum levels of the senescence biomarker Clusterin/Apolipoprotein J increase significantly in diabetes type II and during development of coronary heart disease or at myocardial infarction. Exp. Gerontol. 37, 1175-1187.
11. N. Chondrogianni, F.L.L. Stratford, I.P. Trougakos, B. Friguet, A.J. Rivett and E.S. Gonos (2003) Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. J. Biol. Chem. 278, 28026-28037.
12. I.P. Trougakos, A. So, B. Jansen, M.E. Gleave and E.S. Gonos (2004) Silencing expression of the Clusterin/Apolipoprotein J gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability and cell sensitization to genotoxic and oxidative stress. Cancer Res., in press.