Inhibition of human p53 basal transcription by down-regulation of protein kinase Cdelta

Abstract

In response to DNA damage, signal transduction pathways are activated that result in the increase of p53 protein levels, leading to either growth arrest or apoptosis. Protein kinase C (PKC) delta has been implicated as a tumor suppressor that is down-regulated by tumor-promoting phorbol esters in both mouse skin and cell culture models. We report here that the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate prevents DNA damage-induced up-regulation of p53 by down-regulating PKC delta. Regulation of p53 in response to stress most commonly occurs by preventing ubiquitination and degradation of the p53 protein. Surprisingly, suppression of p53 expression by inhibition of PKC delta was caused by the inhibition of p53 synthesis, not increased degradation of p53 protein. Inhibiting PKC delta blocked both basal transcription of the human p53 gene and initiation of transcription from the human p53 promoter. Therefore, the tumor-suppressing effects of PKC delta are mediated at least in part through activating p53 transcription.