Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase: effect on Mdm2 binding

Sakaguchi, Kazuyasu ; Saito, Shin'ichi ; Higashimoto, Yuichiro ; Roy, Siddhartha ; Anderson, Carl W. ; Appella, Ettore (2000) Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase: effect on Mdm2 binding Journal of Biological Chemistry, 275 (13). pp. 9278-9283. ISSN 0021-9258

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Official URL: http://www.jbc.org/content/275/13/9278.short

Related URL: http://dx.doi.org/10.1074/jbc.275.13.9278

Abstract

The p53 tumor suppressor protein is stabilized in response to ionizing radiation and accumulates in the nucleus. Stabilization is thought to involve disruption of the interaction between the p53 protein and Mdm2, which targets p53 for degradation. Here we show that the direct association between a p53 N-terminal peptide and Mdm2 is disrupted by phosphorylation of the peptide on Thr18 but not by phosphorylation at other N-terminal sites, including Ser15 and Ser37. Thr18 was phosphorylated in vitro by casein kinase (CK1); this process required the prior phosphorylation of Ser15. Thr18 was phosphorylated in vivo in response to DNA damage, and such phosphorylation required Ser15. Our results suggest that stabilization of p53 after ionizing radiation may result, in part, from an inhibition of Mdm2 binding through a phosphorylation-phosphorylation cascade involving DNA damage-activated phosphorylation of p53 Ser15 followed by phosphorylation of Thr18.

Item Type:Article
Source:Copyright of this article belongs to The American Society for Biochemistry and Molecular Biology.
ID Code:43185
Deposited On:10 Jun 2011 07:39
Last Modified:18 May 2016 00:16

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