p85 Regulates p53 K370 Accetylation and Transactivity and Contributes to UVB -induced Apoptosis

摘要

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 p85 ,the regulatory subunit of PI-3K,plays a critical role in mediating pS3 acetylation and promoter-specific transactivation in the UVB response. Depletion of p85 in mouse embryonic fibroblasts (MEFs) 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, p85 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 pS3 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 p85 is a novel regulator of p53-mediated response under certain stress conditions,and targeting the p85-dependent p53 pathway may be promising for cancer therapy.