The factors that cause cancer to be a major health problem of the elderly are unknown. We are addressing this problem by studying aging at the molecular level using cellular models. We have shown that defects in the senescence program in tumor cells is corrected by introduction of specific normal human chromosomes, including chromosomes 1,2, and 3. We are cloning these putative senescence genes by combining several approaches including radiation reduction hybrids, TAR cloning, subtractive hybridization, and cDNA microarray analysis. We have shown that one of these putative senescence genes functionally acts to suppress the enzyme, telomerase, is localized to chromosome 3. We have shown that the suppression of telomerase activity is due to down-regulation of the expression of the hTERT component of the telomerase enzyme complex. This down-regulation occurs at the level of the RNA. We have cloned the hTERT promoter and are currently examining elements that interact with the candidate gene on chromosome 3 in addition to conducting extensive analysis of the methylation and acetylation of this promoter. Our work indicates that c-myc is an important regulator of telomerase in some cells. Finally, we are also testing a candidate cDNA, hHic5, which was cloned by our laboratory from senescent keratinocytes, for its ability to function as an important gene involved in cell growth and differentiation. We have found that hic5 binds to the int-6 gene. Expression of hic5 and int6 are inversely proportional in most tumor lines examined and therefore indicate that these genes may function in an important pathway for tumorigenesis. - telomerase repressor, cell cycle, immortalization, cancer, tumor viruses
