11408617

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1

Resveratrol, a phenolic compound found in grapes and other food products, prevents chemical-induced carcinogenesis in a number of animal models of cancers. To better understand its chemopreventive property, we examined effects of resveratrol on the activity of activator protein 1 (AP-1), a dimeric transcription factor that plays a critical role in the carcinogenesis and tumor transformation. Pretreatment of HeLa cells with resveratrol inhibited the transcription of AP-1 reporter gene by UVC and phorbol 12-myristate 13-acetate (PMA). Pretreatment with resveratrol also inhibited the activation of extracellular signal-regulated protein kinase 2 (ERK2), c-jun N-terminal kinase 1 (JNK1), and p38. Selectively blocking mitogen-activated protein kinase (MAPK) pathways by overexpression of dominant-negative mutants of kinases attenuated the AP-1 activation by PMA and UVC. Interestingly, resveratrol had little effect on the induction of AP-1 reporter gene by active Raf-1, MEKK1, or MKK6, suggesting that it inhibited MAPK pathways by targeting the signaling molecules upstream of Raf-1 or MEKK1. Indeed, incubation of resveratrol with the isolated c-Src protein tyrosine kinase and protein kinase C diminished their kinase activities. Furthermore, inhibition of protein tyrosine kinases and protein kinase C with their selective inhibitors impaired the activation of MAPKs as well as the induction of AP-1 activity by PMA and UVC. In addition, modulation of estrogen receptor activity with 17beta-estradiol had no effect on the inhibition of AP-1 by resveratrol. Taken together, these results suggest that the effects of resveratrol on AP-1 and MAPK pathways may involve the inhibition of both protein tyrosine kinases and protein kinase C.

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MEDLINE

0026-895X

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217-24

pubmed-meshheading:11408617-Anticarcinogenic Agents, pubmed-meshheading:11408617-Carcinogens, pubmed-meshheading:11408617-Drug Interactions, pubmed-meshheading:11408617-Enzyme Activation, pubmed-meshheading:11408617-HeLa Cells, pubmed-meshheading:11408617-Humans, pubmed-meshheading:11408617-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:11408617-Mitogen-Activated Protein Kinases, pubmed-meshheading:11408617-Phosphorylation, pubmed-meshheading:11408617-Protein Kinase C, pubmed-meshheading:11408617-Protein-Tyrosine Kinases, pubmed-meshheading:11408617-Receptors, Estrogen, pubmed-meshheading:11408617-Stilbenes, pubmed-meshheading:11408617-Tetradecanoylphorbol Acetate, pubmed-meshheading:11408617-Transcription Factor AP-1, pubmed-meshheading:11408617-Tyrosine, pubmed-meshheading:11408617-Ultraviolet Rays, pubmed-meshheading:11408617-p38 Mitogen-Activated Protein Kinases, pubmed-meshheading:11408617-src-Family Kinases

Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogen-activated protein kinase pathways.

Journal Article, Research Support, U.S. Gov't, P.H.S.