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. We are cloning this putative senescence gene by several approaches including radiation reduction hybrids, genetic suppressor element technology, and PCR differential display. 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 maybe caused by the inhibition of Rb-kinases (such as cdk4 and cdk6) by elevation of p21 and p16. The hypophosphorylation of Rb allows the formation of Rb-E2F complexes. In addition, two new E2F complexes containing the p21 protein are also found in senescent cells. These complexes most likely negatively regulate genes that are required for entry into DNA synthesis, and hence play an important role in the maintenance of the senescent phenotype. We are continuing to investigate the function of these complexes in several cellular systems, and how loss of their expression may influence the cancer process. 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 teomlerase is not an absolute requirement for senescence. We are investigating these 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 #
1Z01ES023003-06
Application #
2574318
Study Section
Special Emphasis Panel (LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1996
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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