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The Role of Glycogen Synthase Kinase 3ß in the Transformation of Epidermal Cells

¹ Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center; ² National Institute for Occupational Safety and Health, Morgantown, West Virginia; Departments of ³ Dermatology and ⁴ Obstetrics and Gynecology, Xijing Hospital, Xian, P.R. China; and ⁵ Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China

Requests for reprints: Jia Luo, West Virginia University School of Medicine, P.O. Box 9177, Morgantown, WV 26506. Phone: 304-293-7208; Fax: 304-293-7823; E-mail: jluo{at}hsc.wvu.edu.

Glycogen synthase kinase 3ß (GSK3ß) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3ß was drastically down-regulated in human cutaneous squamous cell carcinomas and basal cell carcinomas. Due to its negative regulation of many oncogenic proteins, we hypothesized that GSK3ß may function as a tumor suppressor during the neoplastic transformation of epidermal cells. We tested this hypothesis using an in vitro model system, JB6 mouse epidermal cells. In response to epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA), the promotion-sensitive JB6 P+ cells initiate neoplastic transformation, whereas the promotion-resistant JB6 P– cells do not. JB6 P– cells expressed much higher levels of GSK3ß than JB6 P+ cells; JB7 cells, the transformed derivatives of JB6, had the least amount of GSK3ß. The activity of GSK3ß is negatively regulated by its phosphorylation at Ser⁹. EGF and TPA induced strong Ser⁹ phoshorylation in JB6 P+ cells, but phosphorylation was seen at a much lesser extent in JB6 P– cells. EGF and TPA-stimulated Ser⁹ phosphorylation was mediated by phosphoinositide-3-kinase (PI3K)/Akt and protein kinase C (PKC) pathways. Inhibition of GSK3ß activation significantly stimulated activator protein-1 (AP-1) activity. Overexpression of wild-type (WT) and S9A mutant GSK3ß in JB6 P+ cells suppressed EGF and TPA-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient (K85R) GSK3ß, in contrast, potentiated anchorage-independent growth and drastically enhanced in vivo tumorigenicity. Together, these results indicate that GSK3ß plays an important role in skin tumorigenesis. [Cancer Res 2007;67(16):7756–64]

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