Cancer remains one of the major health problems associated with aging, yet the role of the aging process in cancer remains to be determined. One approach to this problem is to study aging at the molecular level using cellular models of aging. In culture, normal human and rodent cells exhibit a finite life span at the end of which they cease proliferating, a process termed cellular senescence or cellular aging. Many cancer cells have escaped cellular senescence and can be grown indefinitely in culture, suggesting that alterations in cellular senescence are involved in the neoplastic evolution of cancer cells. An understanding of senescence at the cellular level may, therefore, provide insights into both the cancer process and the aging process. It has been shown that defects in the senescence program in cancer cells can be corrected by introduction of human chromosome 1 from normal cells into immortal cells. This finding suggests that senescence gene is located on this chromosome, and current attempts to isolate this gene and to understand its mechanism of action are in progress. In order to understand the mechanisms of growth arrest in senescence, we examined the RB protein in senescent cells. Senescent cells failed to phosphorylate the RB protein in response to serum. Since a central role for the P34(cdc2) protein kinase is postulated in control of the cell cycle and RB phosphorylation, we examined the status of this kinase in senescent cells and other growth-arrested cells. In senescent cells there was no p34(cdc2) protein synthesis and very little or no detectable cdc2 mRNA. In other growth-inhibited states, brought about by isoleucine deficiency in G1, by aphidicolin at G1/S, by etoposide in G2, or by colcemid in M-phase of the cell cycle, cdc2 mRNA was expressed at high levels. Following transfection of the human cdc2 gene with a constitutive promotor into hamster cells, expression of cdc2 mRNA failed to overcome the block to DNA synthesis in senescent cells. Taken together, these data support the concept that a chain of events leads to senescence, where p34(cdc2) kinase is one of the critical elements. However, other cell cycle controls are likely to also be affected.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES023003-01
Application #
3855884
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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