Ras mutation promotes p53 activation and apoptosis of skin keratinocytes

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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1692-1698
Number of pages7
JournalCarcinogenesis
Volume27
Issue number8
DOIs
StatePublished - Aug 2006

Bibliographical note

Funding Information:
The authors wish to thank Ms Jimie Swanlund for technical assistance. This work was supported by NIH grants CA 73599, CA 73599-S1 and AG-08938. L.C. is partially supported by the Thailand Research Fund under the Golden Jubilee Program. This work was also partially supported by the use of resources and facilities of William S. Middleton Veteran Administration Hospital, Madison, WI 53705, USA.

ASJC Scopus subject areas

  • Cancer Research

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