P85α mediates p53 K370 acetylation by p300 and regulates its promoter-specific transactivity in the cellular UVB response

L. Song, M. Gao, W. Dong, M. Hu, J. Li, X. Shi, Y. Hao, Y. Li, C. Huang

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Inducible acetylation of p53 at lysine residues has a great impact on regulating the transactivation of this protein, which is associated with cell growth arrest and/or apoptosis under various stress conditions. However, the factor(s) for regulating p53 acetylation remains largely unknown. In the current study, we have shown that p85α, the regulatory subunit of phosphatidylinositol-3-kinase, has a critical role in mediating p53 acetylation and promoter-specific transactivation in the ultraviolet B (UVB) response. Depletion of p85α in mouse embryonic fibroblasts significantly impairs UVB-induced apoptosis, as well as p53 transactivation and acetylation at Lys370 (Lys373 of human p53); however, the accumulation, nuclear translocation and phosphorylation of p53 are not affected. Interestingly, p85α binds to p300, promotes the p300-p53 interaction and the subsequent recruitment of the p53/p300 complex to the promoter region of the specific p53 target gene in response to UVB irradiation. Moreover, ablation of p53 acetylation at Lys370 by site-directed mutagenesis dramatically suppresses UVB-induced expression of the specific p53-responsive gene as well as cell apoptosis. Therefore, we conclude that p85α is a novel regulator of p53-mediated response under certain stress conditions, and targeting the p85α-dependent p53 pathway may be promising for cancer therapy.

Original languageEnglish
Pages (from-to)1360-1371
Number of pages12
JournalOncogene
Volume30
Issue number11
DOIs
StatePublished - Mar 17 2011

Bibliographical note

Funding Information:
We appreciate the technical help from Dr Dan Liu and the helpful discussion provided by Dr Ailing Li. This project is partially supported by NIH/NCI CA112557, CA119028-05S110, NIH/NIEHS ES010344 and ES012451 (to Dr C Huang); and National Natural Science Foundation of China No. 30871277, 30970594, Beijing Natural Science Foundation 5092022 and 5102035 and the National Key Research and Development Programs on Fundamental Sciences (973 Project) 2011CB503803 (to Dr L Song).

Keywords

  • UVB radiation
  • acetylation
  • p300
  • p53
  • p85α

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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