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Abstract
DNA-damaging agents signal to p53 through as yet unidentified posttranscriptional
mechanisms. Here we show that phosphorylation of human p53 at serine 15 occurs after
DNA damage and that this leads to reduced interaction of p53 with its negative regulator,
the oncoprotein MDM2, in vivo and in vitro. Furthermore, using purified DNA-dependent
protein kinase (DNA-PK), we demonstrate that phosphorylation of p53 at serines 15
and 37 impairs the ability of MDM2 to inhibit p53-dependent transactivation. We present
evidence that these effects are most likely due to a conformational change induced
upon phosphorylation of p53. Our studies provide a plausible mechanism by which the
induction of p53 can be modulated by DNA-PK (or other protein kinases with similar
specificity) in response to DNA damage.