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 p21Waf1 by stress and its influence on the survival of cells subjected to short-wavelength UVC irradiation. UVC was found to elevate p21Waf1 mRNA expression in mouse embryonal fibroblasts (MEFs) and human colorectal carcinoma (RKO) cells in a p53-dependent manner. The lack of p21Waf1 induction in p53-deficient MEFs and RKO cells correlated with diminished cell survival following UVC irradiation. Unexpectedly, UVC treatment was also found to block the induction of p21Waf1 by various stress-inducing agents such as mimosine in the p53-deficient cells. Additional studies indicated that induction of p21Waf1 by UVC occurs primarily through enhanced mRNA stability rather than increased transcription; in p53-/- MEFs, failure to elevate p21Waf1 after treatment with UVC appears to be due to their inability to stabilize the p21Waf1 transcripts. Treatment of the p53-/- MEFs with the protein tyrosine phosphatase inhibitor vanadate reversed the UVC-induced block on p21Waf1 induction and resulted in their enhanced survival following irradiation. Thus, in cells bearing normal p53, UVC augments p21Waf1 expression by increasing the half-life of p21Waf1 mRNA; without p53, p21Waf1 mRNA remains unstable after UVC, apparently due to a pathway involving tyrosine phosphatase activity.
Gorospe
M
M
Laboratory of Biological Chemistry, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Wang
X
X
Holbrook
N J
NJ
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D014638:Vanadates / Q000378:metabolism* / Q000494:pharmacology
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D014638:Vanadates