The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation.
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 H(2)O(2) 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.
Mitsushita
Junji
J
Department of Molecular Biology and Biochemistry, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
Lambeth
J David
JD
Kamata
Tohru
T
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D041681:NIH 3T3 Cells; D009861:Onium Compounds / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D013481:Superoxides / Q000378:metabolism*
D009861:Onium Compounds; D034741:RNA, Small Interfering; D013481:Superoxides; C007517:diphenyleneiodonium; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human