Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apo ptosis. In this study, we have elucidated the potential signaling component s underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated ex tacellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kina ses (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. St able expression of a dominant negative mutant of ERK2 or p38 kinase or thei r respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mut ant of JNK1 had no effect on the phosphorylation. Most importantly, ERKs an d p38 kinase formed a complex with p53 after treatment with resveratrol. St rikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphor ylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells wi th PD98059 or SB202190 or stable expression of a dominant negative mutant o f ERE;2 or p38 kinase impaired resveratrol-induced p53-dependent transcript ional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apopt osis through phosphorylation of p53 at serine 15.