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

Details

• Personal Author:
  Bower KA ; Chen G ; Ding M ; Gao TW ; Gao Y ; Ke Z ; Luo J ; Ma C ; Odetallah M ; Wang J
• Description:
  Glycogen synthase kinase 30 (GSK3 beta) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3 beta 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 GSK3 beta 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 GSK3 beta than JB6 P+ cells; JB7 cells, the transformed derivatives of JB6, had the least amount of GSK3 beta. The activity of GSK3 beta is negatively regulated by its phosphorylation at Ser(9). 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 (Pl3K)/Akt and protein kinase C (PKC) pathways. Inhibition of GSK3 beta activation significantly stimulated activator protein-1 (AP-1) activity. Overexpression of wild-type (WT) and S9A mutant GSK3 beta in JB6 P+ cells suppressed EGF and TPA-mediated anchorage-independent growth in soft agar and turnorigenicity in nude mice. Overexpression of a kinase-deficient (K85R) GSK3 beta, in contrast, potentiated anchorage-independent growth and drastically enhanced in vivo turnorigenicity. Together, these results indicate that GSW plays an important role in skin tumorigenesis. [Description provided by NIOSH]
• Subjects:
  Carcinogens Chemistry Chemistry, Analytic Hypersensitivity Neoplasms Occupational Health Safety Skin Skin Absorption Skin Diseases
• Keywords:
  Analytical-chemistry Analytical-Method Analytical-methods Analytical-processes Cancer-rates Carcinogenesis Carcinogenicity Carcinomas Cell-alteration Cell-metabolism Cell-transformation Cellular-structures Chemical-hypersensitivity Chemical-properties Chemical-synthesis Skin-absorption Skin-cancer Skin-disorders Skin-infections Skin-sensitivity Skin-tumors Statistical-analysis Tumor-inhibition Tumorigenesis Tumorigens

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• ISSN:
  0008-5472
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  67
• Issue:
  16
• NIOSHTIC Number:
  nn:20032598
• Citation:
  Cancer Res 2007 Aug; 67(16):7756-7764
• Contact Point Address:
  Jia Luo, Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, P.O. Box 9177, Morgantown, WV 26506
• Email:
  jluo@hsc.wvu.edu
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Cancer Research
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6ac8f40b540945ab98c8f4a5cb2b8a80ecf7b813446b93f9f03d9b6086c2332b87f52ca9c5d5191bdb2ce211b1612c1b018a98b07c8e9899199c1ede7395b8f2
• Download URL:
  https://stacks.cdc.gov/view/cdc/186514/cdc_186514_DS1.pdf
• File Type:
  [PDF - 9.90 MB ]