Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts
1997; American Association for the Advancement of Science; Volume: 275; Issue: 5306 Linguagem: Inglês
10.1126/science.275.5306.1649
ISSN1095-9203
AutoresKaikobad Irani, Yong Xia, Jay L. Zweíer, Steven J. Sollott, Channing J. Der, Eric R. Fearon, Maitrayee Sundaresan, Toren Finkel, Pascal J. Goldschmidt‐Clermont,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoNIH 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 (·O 2 − ). ·O 2 − 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 ·O 2 − through one or more pathways involving a flavoprotein and Rac1. The implication of a reactive oxygen species, probably ·O 2 − , 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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