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Replicative senescence in human uroepithelial cells
J A Puthenveettil1, M S Burger, C A Reznikoff
1University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA.
Advances in Experimental Medicine and Biology
|December 22, 1999
Summary
Elevated p16INK4a, not p53 or p21WAF1, drives replicative senescence in human urothelial cells (HUCs). This clarifies the tumor suppressor role of p16INK4a in bladder cancer.
Area of Science:
- Cell Biology
- Oncology
- Urology
Background:
- Normal human urothelial cells (HUCs) exhibit replicative senescence.
- Previous work indicated elevated p16INK4a in senescent HUCs, suggesting its role in this process.
Purpose of the Study:
- To further characterize the senescent state in HUCs.
- To investigate the roles of cell cycle proteins p53, p21WAF1, pRb, and cyclin D1 in HUC senescence.
Main Methods:
- HUCs were cultured from ureteral mucosa explants.
- Senescence was identified by senescence-associated beta-galactosidase activity (SA-beta-gal).
- Cell cycle distribution, c-fos induction, and protein levels (p53, p21WAF1, p16INK4a, cyclin D1, PAI-1) were analyzed.
Main Results:
- Senescent HUCs were arrested at G1/S and lacked c-fos induction.
- Elevated p16INK4a was confirmed in senescent HUCs.
- Unlike fibroblasts, senescent HUCs did not show elevated p53 or p21WAF1, nor elevated PAI-1.
Conclusions:
- p16INK4a elevation, not p53 or p21WAF1, is critical for HUC replicative senescence.
- These findings support p16INK4a's tumor suppressor function and its relevance in bladder tumors with p16INK4a or pRb loss.