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Sestrins, Novel Targets of Ras Oncoproteins and the p53 Tumor-Suppressor, Regulate Antioxidant Defense, Genetic Stability, Cell Motility, Angiogenesis, and Tumor Growth
Summary: Boris Kopnin studies mechanisms of genetic instability induced by Ras and p53 oncogenes and asbestos exposure.
Mutations of RAS oncogenes and the p53 tumor suppressor are frequently observed in a variety of human tumors. We have found that dysfunctions of Ras and/or p53 proteins lead to decreased expression of sestrin family genes, which encode essential modulators of peroxiredoxins. Peroxiredoxins are abundant enzymes that catalyze the decomposition of hydrogen peroxide in the nucleus and in some other cell compartments. Inhibition of PA26/ sestrin-1, Hi95/sestrin-2, and/or sestrin-3 expression by corresponding si-RNAs was accompanied by a significant increase in the content of reactive oxygen species followed by (1) induction of DNA oxidation and chromosome breaks/ recombinations; (2) enhancement of Ras-induced morphological changes and stimulation of cell motility; and (3) activation of the HIF1-VEGF pathway, stimulation of tumor angiogenesis, and acceleration of tumor growth in vivo. The antioxidant N-acetyl-L-cysteine (NAC) abolished the effects caused by anti-sestrin si-RNAs. In addition, treatment with NAC significantly inhibited the mutagenic effects of Ras and p53 dysfunctions. Taken together, our results suggest an important role for sestrin gene deregulation in mediating the oncogenic effects of Ras and/or p53 mutations.
Abstract from 2005 International Research Scholars Meeting
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