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Loss of the hSNF5 Gene Concomitantly Inactivates p21^CIP/WAF1 and p16^INK4a Activity Associated with Replicative Senescence in A204 Rhabdoid Tumor Cells

¹ Department of Pathology and Laboratory Medicine and ² University of North Carolina-Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Bernard E. Weissman, Room 32-048, University of North Carolina-Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7295. Phone: 919-966-7533; Fax: 919-966-9673; E-mail: bernard_weissman{at}med.unc.edu.

hSNF5, the smallest member of the SWI/SNF chromatin remodeling complex, is lost in most malignant rhabdoid tumors (MRT). In MRT cell lines, reexpression of hSNF5 induces G₁ cell cycle arrest, elevated p16^INK4a, and activated replicative senescence markers, such as ß-galactosidase (ß-Gal) and plasminogen activator inhibitor-1. To compare the replicative senescence caused by hSNF5 in A204 cells to normal cellular senescence, we examined the activation of both p16^INK4a and p21^CIP/WAF1. Analogous to normal cellular senescence, both p16^INK4a and p21^CIP/WAF1 were up-regulated following hSNF5 restoration. Furthermore, we found that hSNF5 bound the p16^INK4a and p21^CIP/WAF1 promoters, suggesting that it directly regulates transcription of these genes. Using p16^INK4a RNA interference, we showed its requirement for the replicative senescence caused by hSNF5 but not the growth arrest. Instead, p21^CIP/WAF1 remained activated by hSNF5 in the absence of high p16^INK4a expression, apparently causing the growth arrest in A204. Interestingly, we also found that, in the absence of p16^INK4a, reexpression of hSNF5 also increased protein levels of a second cyclin-dependent kinase (CDK) inhibitor, p18^INK4c. However, our data show that lack of hSNF5 does not abrogate cellular responsiveness to DNA damage or growth-inhibitory factors. In summary, our studies suggest that hSNF5 loss may influence the regulation of multiple CDK inhibitors involved in replicative senescence.

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