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Carcinogenesis Advance Access originally published online on April 12, 2006
Carcinogenesis 2006 27(8):1692-1698; doi:10.1093/carcin/bgl037
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ras mutation promotes p53 activation and apoptosis of skin keratinocytes

Yunfeng Zhao1,5, Luksana Chaiswing2,4, Vasudevan Bakthavatchalu1, Terry D. Oberley2,3 and Daret K. St. Clair1,*

1 Graduate Center for Toxicology, University of Kentucky Lexington, KY 40536, USA
2 Department of Pathology, University of Wisconsin Madison, WI 53705, USA
3 VA Hospital, University of Wisconsin Madison, WI 53705, USA
4 Faculty of Medical Technology, Mahidol University Bangkok, Thailand 10700
5 Department of Pharmacology, Toxicology & Neuroscience, LSU Health Science Center Shreveport, LA 71103, USA

*To whom correspondence should be addressed. Tel: +1 859 257 3956; Fax: +1 859 323 1059; Email: dstcl00{at}pop.uky.edu

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.


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