Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation - PubMed (original) (raw)
. 2003 Oct 10;278(41):39527-33.
doi: 10.1074/jbc.M304423200. Epub 2003 Jul 30.
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- PMID: 12890678
- DOI: 10.1074/jbc.M304423200
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Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation
Kai Chen et al. J Biol Chem. 2003.
Free article
Abstract
Phosphorylation of the p53 tumor suppressor protein is a critical event in the up-regulation and activation of p53 during cellular stress. In this study, we characterized the signaling pathway linking oxidative stress to p53 through the platelet-derived growth factor beta (PDGF beta) receptor and the ataxia telangiectasia mutated (ATM) kinase. In response to H2O2, we observed phosphorylation of p53 specifically at serine 15, but not serine 9, 20, or 392. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the p53 target p21CIP/WAF. We found that H2O2 induced phosphorylation of the PDGF beta receptor and increased ATM kinase activity, two events integral to p53 activation as either AG1433 (a PDGF beta receptor inhibitor) or caffeine (an ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Similarly, p53 activation by H2O2 was inhibited by kinase-inactive forms of the PDGF beta receptor or ATM. Inhibition of ATM kinase had no effect on H2O2-induced PDGF beta receptor tyrosine phosphorylation, whereas PDGF beta receptor suppression with RNA interference impaired H2O2-induced ATM activation, indicating that ATM lies downstream to the PDGF beta receptor in this signaling cascade. Functionally, inhibition of the PDGF beta receptor abrogated the inhibition of cell proliferation, and promotion of apoptosis due to H2O2 treatment. Thus, these data link PDGF beta receptor transactivation to H2O2-induced p53 phosphorylation and suggest a functional role for growth factor receptors in modulation of p53 function.
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