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Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2629-34. doi: 10.1073/pnas.0812256106. Epub 2009 Feb 5.

Phosphorylation of p53 by IkappaB kinase 2 promotes its degradation by beta-TrCP.

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  • 1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Abstract

Functional inactivation of p53 and constitutive activation of the NF-kappaB pathway has been associated with several human cancers. In this study, we show that IkappaB kinase 2 (IKK2/IKKbeta), which is critical for NF-kappaB activation, also phosphorylates p53. Phosphorylation of p53 at serines 362 and 366 by IKK2 leads to its recruitment to and ubiquitination by beta-TrCP1. Degradation of ubiquitinated p53 is independent of Mdm2, because it occurs in both wild-type and Mdm2(-/-) cells. SiRNA-mediated reduction in the levels of beta-TrCP1 and other members of the SCF(beta-TrCP1)E3 ubiquitin ligase complex or overexpression of a dominant negative form of beta-TrCP1 enhances p53 stability. Substitutions at Ser-362 and 366 of p53 by alanines (p53 AA) result in reduced phosphorylation of p53 by IKK2, decreased association with beta-TrCP1, and thus increased stability of p53 and expression of p53 target genes such as p21, altering the G1 phase of the cell cycle. Our results identify IKK2 and beta-TrCP1 as novel regulators of the p53 pathway and suggest that blocking of IKK2 and beta-TrCP1 could be a means of regulating p53 stability and thereby modulating its biological activity.

PMID:
19196987
[PubMed - indexed for MEDLINE]
PMCID:
PMC2650315
Free PMC Article

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