Ras mutation promotes p53 activation and apoptosis of skin keratinocytes

Carcinogenesis
Yunfeng ZhaoDaret St Clair

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 resu...Continue Reading

Citations

Sep 21, 2010·Pigment Cell & Melanoma Research·Tamara TerzianNeil F Box
Oct 19, 2011·Journal of Signal Transduction·Delira Robbins, Yunfeng Zhao
Jan 25, 2011·Expert Opinion on Therapeutic Targets·Ghulam Mohammad, Renu A Kowluru
Jan 24, 2007·Physiological Reviews·Karen Bedard, Karl-Heinz Krause
Jun 17, 2008·Prostaglandins & Other Lipid Mediators·Raymond L KongerJeffrey B Travers
Sep 22, 2010·Pathology·Sowmya SharmaC Soon Lee

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