Roles of Akt and glycogen synthase kinase 3 beta in the ultraviolet B induction of cyclooxygenase-2 transcription in human keratinocytes

Ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) expression plays an im portant role in WE tumor promotion. We examined whether Akt and glycogen sy nthase kinase 3 beta (GSK-3 beta), components of the phosphatidylinositol 3 '-kinase pathway, are involved in UVB induction of COX-2 transcription. UVB caused Akt phosphorylation at both Thr-308 and Ser-473 that was inhibited by LY294002, a phosphatidylinositol 3'-kinase inhibitor. LY294002 also decr eased the expression of endogenous COX-2 protein and a luciferase construct driven by COX-2 promoter. Similarly, UVB caused phosphorylation of GSK-3 b eta (Ser-9) and presumably inactivation of GSK-3 beta. Inhibition of GSK-3 beta by lithium induced endogenous COX-2 protein expression and COX-2 promo ter activity. Finally, overexpression of a dominant-negative Akt mutant or wild-type GSK-3 beta suppressed UVB-mediated induction of COX-2 promoter. T hese studies suggest that inactivation of GSK-3 beta through activation of Akt plays an important role in the UVB induction of COX-2 transcription.