CELL SENESCENCE, CARCINOGENESIS, AND AGING

工作总结：癌症是导致健康的主要因素

Summary of Work: 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 chromosome 1. In addition we have shown that another putative senescence gene, that functionally acts to suppress the enzyme, telomerase, is localized to chromosome 3. We are cloning these putative senescence genes by several approaches including radiation reduction hybrids, genetic suppressor element technology, and PCR differential display. We are also testing a candidate cDNA, limZ, which was cloned by our laboratory from senescent keratinocytes, for its ability to function as a senescence gene. Senescent cells are irreversibly arrested and fail to enter into DNA synthesis upon serum stimulation. Current efforts are involved in investigating the mechanism responsible for the arrest. We have shown that the permanent hypophosphorylation of the Rb protein is most likely due to the inhibition of the cdk4 and cdk6 kinase complexes by elevation of the inhibitor, p16. We are continuing this work by investigating the mechanism that results in the elevation of p16. In addition, we are investigating the function of these complexes in several cellular systems and have been comparing the mechanism of senescence arrest in fibroblasts versus epithelial cells. 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.