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 a putative senescence gene that 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 have examined elements that interact with E-box elements 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 while c-myc is an important regulator of telomerase in some cells other factors are more likely to be critical in our renal cell carcinoma model.
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