CELL SENESCENCE, CARCINOGENESIS, AND AGING

导致癌症的因素是老年人的一个主要健康问题

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 the X. We are cloning the putative ovarian cancer senescence gene in the Xq25 region. Senescent cells are ir- reversibly 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 hypophos- phorylation of the Rb protein may be involved because this allows the formation of Rb-E2F complexes. In addition, two new E2F complexes contain- ing the p21 protein are also found in senescent cells. It is hypothesized that these complexes are involved in the negative regulation of genes required for the G1 to S-phase transition, and hence play an important role in the maintenance of the senescent arrest. We are continuing to investigate the function of these p21-E2F complexes. In separate studies,we have demonstrated that protein phosphatases may serve as negative growth regulators and mediators of cellular senescence. We are investigating this hypothesis by examining phosphatase levels as cells age, and by over- expressing various subunits of protein phosphatases and observing their effect on cell growth. 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. We are investigating these species differences to resolve these issues.