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.
Highlights
The tumor suppressor protein p53 plays a central role in mediating stress and DNA damage-induced growth arrest and apoptosis [1]
We have examined the effect of protein kinase C (PKC) ␦ on p53 protein and gene expression and report that PKC ␦ is required for the basal transcription of the p53 gene
We show that pretreatment of cells with TPA or treatment with rottlerin results in the inhibition of basal p53 transcription
Summary
The tumor suppressor protein p53 plays a central role in mediating stress and DNA damage-induced growth arrest and apoptosis [1]. The tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) promotes tumor formation in a variety of mice and tissue culture models, and this has been associated with the down-regulation of protein kinase C (PKC) [7]. We demonstrated that the tumor-promoting activities of TPA are mediated at least in part by down-regulating PKC ␦ (9 –12). Increasing evidence suggests that PKC ␦ is a player in DNA damage response pathways. We have examined the effect of PKC ␦ on p53 protein and gene expression and report that PKC ␦ is required for the basal transcription of the p53 gene These results are discussed in the context of the tumor promotion by phorbol esters
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