P53-DEPENDENT ELEVATION OF P21(WAF1) EXPRESSION BY UV-LIGHT IS MEDIATED THROUGH MESSENGER-RNA 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 enha nce cell survival. In this study, we examined the mechanisms contribut ing to the induction of p21(Waf1) by stress and its influence on the s urvival of cells subjected to short-wavelength UVC irradiation. UVC wa s found to elevate p21(Waf1) mRNA expression in mouse embryonal fibrob lasts (MEFs) and human colorectal carcinoma (RK0) cells in a p53-depen dent manner, The lack of p21(Waf1) induction in p53-deficient MEFs and RKO cells correlated with diminished cell survival following WC irrad iation. Unexpectedly, UVC treatment was also found to block the induct ion 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 r ather than increased transcription; in p53(-/-) MEFs, failure to eleva te p21(Waf1) after treatment with UVC appears to be due to their inabi lity to stabilize the p21(Waf1) transcripts, Treatment of the p53(-/-) MEFs with the protein tyrosine phosphatase inhibitor vanadate reverse d the WC-induced block on p21(Waf1) induction and resulted in their en hanced survival following irradiation. Thus, in cells bearing normal p 53, UVC augments p21(Waf1) expression by increasing tile half-life of p21(Waf1) mRNA; without p53, p21(Waf1) mRNA remains unstable after UVC , apparently due to a pathway involving tyrosine phosphatase activity.