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The Superoxide-Generating Oxidase Nox1 Is Functionally Required for Ras Oncogene Transformation

¹ Department of Molecular Biology and Biochemistry, Shinshu University School of Medicine, Matsumoto, Nagano, Japan, and ² Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia

The activated Ras oncogene can transform various mammalian cells and has been implicated in development of a high population of malignant human tumors. Recent studies suggest that generation of reactive oxygen species such as superoxide and H₂O₂ is involved in cell transformation by the activated Ras. However, the nature of an oxidase participating in Ras-transformation is presently unknown. Here, we report that Ras oncogene up-regulates the expression of Nox1, a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase, via the mitogen-activated protein kinase kinase-mitogen-activated protein kinase pathway, and that small interfering RNAs designed to target Nox1 mRNA effectively blocks the Ras transformed phenotypes including anchorage-independent growth, morphological changes, and production of tumors in athymic mice. Therefore, we propose that increased reactive oxygen species generation by Ras-induced Nox1 is required for oncogenic Ras transformation.

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