p85α mediates p53 K370 acetylation by p300 and regulates its promoter-specific transactivity in the cellular UVB response.
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.
Nelson Institute of Environmental Medicine, Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA. lunsong@yahoo.com
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D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D016158:Genes, p53 / Q000528:radiation effects; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation / Q000528:radiation effects*; D014466:Ultraviolet Rays
D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D058543:Class Ia Phosphatidylinositol 3-Kinase