RT Journal Article
SR Electronic
T1 Resveratrol Inhibits Phorbol Ester and UV-Induced Activator Protein 1 Activation by Interfering with Mitogen-Activated Protein Kinase Pathways
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 217
OP 224
DO 10.1124/mol.60.1.217
VO 60
IS 1
A1 Rong Yu
A1 Vidya Hebbar
A1 Daniel W. Kim
A1 Sandhya Mandlekar
A1 John M. Pezzuto
A1 Ah-Ng Tony Kong
YR 2001
UL http://molpharm.aspetjournals.org/content/60/1/217.abstract
AB 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 17β-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. EGFepidermal growth factorPMAphorbol 12-myristate 13-acetateMAPKmitogen-activated protein kinaseERKextracellular signal-regulated protein kinaseJNKc-Jun N-terminal kinasePTKprotein tyrosine kinasePKCprotein kinase CE217β-estradiolMBPmyelin basic proteinTBSTTris-buffered saline/Tween 20AP-1activator protein 1ERestrogen receptorATF2activating transcription factor 2