Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 8, Pages 2629-2634Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812256106
Keywords
beta-TrCP1; DNA damage; IKK2; p53 stability
Categories
Funding
- National Institutes of Health
- Lustgarten Foundation
- Leducq Foundation
- Ellison Medical Foundation
- H.N. and Frances C. Berger Foundation
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Functional inactivation of p53 and constitutive activation of the NF-kappa B pathway has been associated with several human cancers. In this study, we show that I kappa B kinase 2 (IKK2/IKK beta), which is critical for NF-kappa B 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.
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