Scope: Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants, including the regulation of transcription. Here, we have analyzed the impact of resveratrol on the activity of the transcription factor activator protein-1 (AP-1).
Methods and results: Using a chromosomally embedded AP-1-responsive reporter gene, we show that the AP-1 activity was significantly elevated in resveratrol-treated 293 human embryonic kidney and HepG2 hepatoma cells. The 12-O-tetradecanoylphorbol-13-acetate-responsive element, a binding site for c-Jun and c-Fos, was identified as resveratrol-responsive element. Expression of c-Jun and c-Fos, two proteins that constitute AP-1, is upregulated in resveratrol-stimulated HEK293 cells. On the transcriptional level, c-Jun and the ternary complex factor Elk-1 are essential for the activation of AP-1 in resveratrol-treated cells. In addition, mitogen-activated protein kinases and protein kinase C are required to connect resveratrol stimulation with enhanced AP-1 controlled transcription. Finally, we show that resveratrol increased the activities of the AP-1 responsive cyclin D1 and tumor necrosis factor α promoters.
Conclusion: Resveratrol regulates gene transcription via activation of stimulus-regulated protein kinases and the stimulus-responsive AP-1 transcription factors. The fact that resveratrol regulates AP-1 activity may explain many of the pleiotropic intracellular alterations induced by resveratrol.
Keywords: AP-1; Elk-1; MKP-1; Resveratrol; Transcription; c-Fos; c-Jun.
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