The role of glycogen synthase kinase 3β in the transformation of epidermal cells

Cuiling Ma, Jian Wang, Ying Gao, Tian Wen Gao, Gang Chen, Kimberly A. Bower, Mohammed Odetallah, Min Ding, Zunji Ke, Jia Luo

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Glycogen synthase kinase 3β (GSK3β) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3β 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 GSK3β 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 GSK3β than JB6 P+ cells; JB7 cells, the transformed derivatives of JB6, had the least amount of GSK3β. The activity of GSK3β 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 GSK3β activation significantly stimulated activator protein-1 (AP-1) activity. Overexpression of wild-type (WT) and S9A mutant GSK3β 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) GSK3β, in contrast, potentiated anchorage-independent growth and drastically enhanced in vivo tumorigenicity. Together, these results indicate that GSK3β plays an important role in skin tumorigenesis.

Original languageEnglish
Pages (from-to)7756-7764
Number of pages9
JournalCancer Research
Volume67
Issue number16
DOIs
StatePublished - Aug 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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