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 apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional 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 apoptosis through phosphorylation of p53 at serine 15.
The Hormel Institute, University of Minnesota, Austin 55912, USA.
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D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077185:Resveratrol; D012694:Serine / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D016588:Anticarcinogenic Agents; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D000077185:Resveratrol