Journal Article

Ras mutation promotes p53 activation and apoptosis of skin keratinocytes

Yunfeng Zhao, Luksana Chaiswing, Vasudevan Bakthavatchalu, Terry D. Oberley and Daret K. St. Clair

in Carcinogenesis

Volume 27, issue 8, pages 1692-1698
ISSN: 0143-3334
Published online April 2006 | e-ISSN: 1460-2180 | DOI:
Ras mutation promotes p53 activation and apoptosis of skin keratinocytes

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Previous studies in our laboratory demonstrated that 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) treatment induced apoptosis and mitochondrial translocation of the tumor suppressor p53 in a mouse skin carcinogenesis model, suggesting that oncogenic versus cell death signaling involve a common mediator. Mutational activation of oncogenic Ras is an early event and has been demonstrated to play a critical role in skin carcinogenesis. A malignant skin keratinocyte cell line (308), which carries a H-ras mutation at codon 61, showed elevated p53 levels, increased caspase 3 activity and enhanced apoptosis after TPA treatment. In contrast, the non-malignant counterpart (C50) showed undetectable levels of p53 and less apoptosis than 308 cells similarly treated. Inhibition of NADPH-oxidase (NOX) by diphenyleneiodonium suppressed p53 activation and apoptosis in 308 cells, linking Ras mutation to NOX-induced p53 activation, which was further supported by the finding that siRNA to Rac1 inhibited p53 activation after TPA treatment. Application of DPI to DMBA-initiated skin tissue significantly blocked TPA-mediated increased p53 levels and reduced apoptosis in skin epidermal tissues. Taken together, our results suggest that NOX bridges oncogenic activation and p53 mitochondrial translocation to apoptosis in the multistage chemical-induced skin carcinogenesis model.

Journal Article.  3943 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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