Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts

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Science  14 Mar 1997:
Vol. 275, Issue 5306, pp. 1649-1652
DOI: 10.1126/science.275.5306.1649

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NIH 3T3 fibroblasts stably transformed with a constitutively active isoform of p21Ras, H-RasV12 (v-H-Ras or EJ-Ras), produced large amounts of the reactive oxygen species superoxide (·O2). ·O2 production was suppressed by the expression of dominant negative isoforms of Ras or Rac1, as well as by treatment with a farnesyltransferase inhibitor or with diphenylene iodonium, a flavoprotein inhibitor. The mitogenic activity of cells expressing H-RasV12 was inhibited by treatment with the chemical antioxidant N-acetyl-L-cysteine. Mitogen-activated protein kinase (MAPK) activity was decreased and c-Jun N-terminal kinase (JNK) was not activated in H-RasV12-transformed cells. Thus, H-RasV12-induced transformation can lead to the production of ·O2 through one or more pathways involving a flavoprotein and Rac1. The implication of a reactive oxygen species, probably ·O2, as a mediator of Ras-induced cell cycle progression independent of MAPK and JNK suggests a possible mechanism for the effects of antioxidants against Ras-induced cellular transformation.

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