Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts

Kaikobad Irani, Yong Xia, Jay L. Zweier, Steven J. Sollott, Channing J. Der, Eric R. Fearon, Maitrayee Sundaresan, Toren Finkel, Pascal J. Goldschmidt-Clermont

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Abstract

NIH 3T3 fibroblasts stably transformed with a constitutively active isoform of p21(Ras), H-Ras(V12) (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-Ras(V12) 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-Ras(V12)-transformed cells. Thus, H-Ras(V12)-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.

Original languageEnglish (US)
Pages (from-to)1649-1652
Number of pages4
JournalScience
Volume275
Issue number5306
DOIs
StatePublished - Mar 14 1997

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    Irani, K., Xia, Y., Zweier, J. L., Sollott, S. J., Der, C. J., Fearon, E. R., Sundaresan, M., Finkel, T., & Goldschmidt-Clermont, P. J. (1997). Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science, 275(5306), 1649-1652. https://doi.org/10.1126/science.275.5306.1649