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Final Activity Report Summary - TELOMERASE (Identification and functional assessment of genes specifically involved in hTERT regulation)

Telomerase, an enzymatic complex responsible for the maintenance of telomeres, is significantly expressed in 90% of cancer cells and apparently absent in normal somatic cells. Expression of the protein component of this telomerase complex, human Telomerase Reverse Transcriptase( hTERT), seems to be the limiting factor for telomerase activity, and plays a fundamental role in cellular immortalisation. The knowledge of the factors and mechanisms controlling hTERT gene expression is highly significant to understand the telomerase re-activation process, a key step during tumourogenesis in human cancers. At this date, only few transcriptional factors able to bind the promoter of hTERT gene have been described in the scientific literature and their genuine contribution in telomerase regulation has not been demonstrated yet. Moreover, published data from different laboratories indicate that important relevant transcription factors have not yet been identified. Thus, the factors and mechanisms controlling the hTERT transcription still remain to be elucidated during physiological processes.

This project, funded by a Marie Curie EIF during two years (University of Bergen, Norway), has allowed the identification of eight transcription factors rapidly induced by retinoids (vitamin A derivatives) and potentially important in telomerase regulation. These eight transcription factors, early-induced by retinoic acid, have been identified by a microarray approach (DNA biochips) and their expression confirmed with different techniques of biochemistry and molecular biology. Our goal is now to assess the contribution of these eight candidate genes in telomerase regulation leukemic cells, by studying the consequence of their over-expression and/or specific invalidation (by RNA interference). All the molecular and cellular tools required for the functional study of these candidate genes have been developed in the perspective of my reintegration in France (also granted by a European contract) were the project will be continued. These genes could act as tumour suppressors and could have potential applications in clinical oncology (diagnostics, prognostic and therapeutics).

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