Involvement of c-jun NH(2)-terminal kinases in resveratrol-induced activation of p53 and apoptosis.
Resveratrol, a constituent of grapes and other foods, is one of the most promising agents for cancer prevention. In a previous study, we showed that the antitumor activity of resveratrol occurs through extracellular signal-regulated protein kinases (ERKs) and p38 kinase-mediated p53 activation. In this study, we also determined that c-jun NH(2)-terminal kinases (JNKs) are involved in resveratrol-induced p53 activation and induction of apoptosis. In the JB6 mouse epidermal cell line, resveratrol activated JNKs dose-dependently within a dose range of 10-40 microM, the same dosage responsible for the inhibition of tumor promoter-induced cell transformation. Stable expression of a dominant negative mutant of JNK1 or disruption of the Jnk1 or Jnk2 gene markedly inhibited resveratrol-induced p53-dependent transcription activity and induction of apoptosis. Furthermore, resveratrol-activated JNKs were shown to phosphorylate p53 in vitro, but this activity was repressed in the cells expressing a dominant negative mutant of JNK1 or in Jnk1 or Jnk2 knockout (Jnk1(-/-) or Jnk2(-/-)) cells. These data suggested that JNKs act as mediators of resveratrol-induced activation of p53 and apoptosis, which may occur partially through p53 phosphorylation.
She
Qing-Bai
QB
The Hormel Institute, University of Minnesota, Austin 55912, USA.
Huang
Chuanshu
C
Zhang
Yiguo
Y
Dong
Zigang
Z
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D053938:DNA Fragmentation; D004817:Epidermis; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection
D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; D013267:Stilbenes; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol