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Received for publication March 22, 2004.
Revised June 25, 2004.
Accepted for publication June 29, 2004.
-B
Activation of the inducible transcription factor NF-
B (Nuclear Factor -B) occurs in cells exposed to oxidative stress, and the serine/threonine kinase PKD (protein kinase D) is critical for signal relay to NF-B. We have recently delineated two coordinated events which control PKD activation in response to oxidative stress, phosphorylation at Tyr463 by the tyrosine kinase Abl, and phosphorylation at the activation loop Ser738/Ser742 by the PKC isoform PKC
. The result is fully active PKD which controls NF-B activation through the IKK complex. Here, we investigate the mechanism by which PKD controls IKK/NF-B activation. Resveratrol, a potent anti-oxidant, blocks both PKD activation and NF-B induction. Specifically, resveratrol blocked PKD activation loop phosphorylation and activity, and this was due to a specific inhibition of the Ser738/Ser742 kinase, PKC. Conversely, resveratrol did not affect Abl kinase activity and had no effect on Tyr463 phosphorylation. Moreover, we show that the mechanism by which resveratrol inhibits NF-B is by blocking the translocation of PKD to the IKK complex, specifically by inhibiting Ser738/Ser742 phosphorylation. We therefore propose that rather than acting as an anti-oxidant, resveratrol specifically blocks oxidative stress-dependent NF-B activation by interfering with PKD phosphorylation and association with the IKK complex.
Key words:
Protein Kinase C, NFkappaB, Oxidative stress/antioxidants, Oxidative stress
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