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p53 is a major component of the transcriptional and apoptotic program regulated by PI 3‐kinase/Akt/GSK3 signaling
Author(s) -
NAYAK GAURI,
COOPER GEOFFREY
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.604.7
Subject(s) - cyclin dependent kinase 4 , protein kinase b , gsk 3 , map kinase kinase kinase , kinase , microbiology and biotechnology , ask1 , biology , cyclin dependent kinase 9 , microphthalmia associated transcription factor , signal transduction , cyclin dependent kinase 2 , transcription factor , protein kinase a , biochemistry , gene
The phosphatidylinositol (PI) 3‐kinase/Akt signaling pathway plays a prominent role in cell survival and proliferation, in part by regulating gene expression at the transcriptional level. Global expression profiling combined with computational and experimental analysis previously identified FOXOs and the E‐box‐binding transcription factors MITF and USF1 as key targets that lead to the induction of proapoptotic and cell cycle arrest genes in response to inhibition of PI 3‐kinase. In this study, we investigated the role of p53 downstream of PI 3‐kinase signaling by analyzing the effects of PI 3‐kinase inhibition in Rat‐1 cells and Rat‐1 cells expressing dominant‐negative p53 mutant. Dominant‐negative p53 expression conferred partial resistance to apoptosis induced by PI 3‐kinase inhibition and p53, along with FOXO, MITF and USF1, contributed to gene induction in response to PI 3‐kinase inhibition. Activation of p53 was mediated by phosphorylation of the histone acetyltransferase Tip60 by glycogen synthase kinase (GSK) 3, leading to activation of p53 by acetylation. Many of the genes targeted by p53 were also targeted by FOXO and the E‐box‐binding transcription factors, indicating that p53 functions coordinately with these factors to regulate gene expression. Current studies are focused on analyzing the effect of PI‐3 kinase inhibition on transformed cell lines with hyperactive PI‐3 kinase activity.