p53-dependent elevation of p21Waf1 expression by UV light is mediated through mRNA stabilization and involves a vanadate-sensitive regulatory system

Exposure of mammalian cells to adverse stimuli triggers the expression of numerous stress response genes, many of which are presumed to enhance cell survival. In this study, we examined the mechanisms contributing to the induction of p21(Waf1) by stress and its influence on the survival of cells subjected to short-wavelength UVC irradiation. UVC was found to elevate p21(Waf1) mRNA expression in mouse embryonal fibroblasts (MEFs) and human colorectal carcinoma (RK0) cells in a p53-dependent manner, The lack of p21(Waf1) induction in p53-deficient MEFs and RKO cells correlated with diminished cell survival following WC irradiation. Unexpectedly, UVC treatment was also found to block the induction of p21(Waf1) by various stress-inducing agents such as mimosine in the p53-deficient cells, Additional studies indicated that induction of p21(Waf1) by UVC occurs primarily through enhanced mRNA stability rather than increased transcription; in p53(-/-) MEFs, failure to elevate p21(Waf1) after treatment with UVC appears to be due to their inability to stabilize the p21(Waf1) transcripts, Treatment of the p53(-/-) MEFs with the protein tyrosine phosphatase inhibitor vanadate reversed the WC-induced block on p21(Waf1) induction and resulted in their enhanced survival following irradiation. Thus, in cells bearing normal p53, UVC augments p21(Waf1) expression by increasing the half-life of p21(Waf1) mRNA; without p53, p21(Waf1) mRNA remains unstable after UVC, apparently due to a pathway involving tyrosine phosphatase activity.