Tang Q, Gonzales M, Inoue H, Bowden G T
Department of Radiation Oncology, Arizona Cancer Center, The University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
Cancer Res. 2001 Jun 1;61(11):4329-32.
Ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) expression plays an important role in UVB tumor promotion. We examined whether Akt and glycogen synthase kinase 3beta (GSK-3beta), 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 decreased the expression of endogenous COX-2 protein and a luciferase construct driven by COX-2 promoter. Similarly, UVB caused phosphorylation of GSK-3beta (Ser-9) and presumably inactivation of GSK-3beta. Inhibition of GSK-3beta by lithium induced endogenous COX-2 protein expression and COX-2 promoter activity. Finally, overexpression of a dominant-negative Akt mutant or wild-type GSK-3beta suppressed UVB-mediated induction of COX-2 promoter. These studies suggest that inactivation of GSK-3beta through activation of Akt plays an important role in the UVB induction of COX-2 transcription.
紫外线B(UVB)诱导的环氧化酶-2(COX-2)表达在UVB促进肿瘤过程中起重要作用。我们研究了磷脂酰肌醇3'-激酶途径的组成部分Akt和糖原合酶激酶3β(GSK-3β)是否参与UVB诱导的COX-2转录。UVB导致Akt在Thr-308和Ser-473位点磷酸化,这被磷脂酰肌醇3'-激酶抑制剂LY294002所抑制。LY294002还降低了内源性COX-2蛋白的表达以及由COX-2启动子驱动的荧光素酶构建体的表达。同样,UVB导致GSK-3β(Ser-9)磷酸化,并推测使GSK-3β失活。锂对GSK-3β的抑制诱导了内源性COX-2蛋白表达和COX-2启动子活性。最后,显性负性Akt突变体或野生型GSK-3β的过表达抑制了UVB介导的COX-2启动子诱导。这些研究表明,通过激活Akt使GSK-3β失活在UVB诱导的COX-2转录中起重要作用。