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

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.

Pubmed ID: 19196987


  • Xia Y
  • Padre RC
  • De Mendoza TH
  • Bottero V
  • Tergaonkar VB
  • Verma IM


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 24, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI048034

Mesh Terms

  • Animals
  • Base Sequence
  • DNA Primers
  • Hydrolysis
  • I-kappa B Kinase
  • Mice
  • Peptide Mapping
  • Phosphorylation
  • Protein Binding
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Ubiquitination
  • beta-Transducin Repeat-Containing Proteins