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 and 2.We are cloning these putative senescence genes by combining several approaches including radiation reduction hybrids, TAR cloning, and subtractive hybridization. In addition we have shown that another 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. Currently we are analyzing the hTERT promoter for elements that interact with the candidate gene on chromosome 3. 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. Finally, work from other labs suggests that reactivation of telomerase occurs with a high frequency in cells undergoing immortalization. We have found, however, that telomerase activity is low in senescent human fibroblasts but is maintained in senescent hamster fibroblasts. This difference is interesting, because it may account for the difference between species and their immortalization rate, or may indicate that downregulation of telomerase is not an absolute requirement for senescence. In addition, it has been shown that exposure to oxidative damage may influence the rate of telomere shortening and cellular lifespan. We are investigating telomerase activity and accumulation of oxidative damage in rodent versus human species differences to resolve these issues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES023003-08
Application #
6106615
Study Section
Special Emphasis Panel (LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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