TY - JOUR
T1 - Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts
AU - Irani, Kaikobad
AU - Xia, Yong
AU - Zweier, Jay L.
AU - Sollott, Steven J.
AU - Der, Channing J.
AU - Fearon, Eric R.
AU - Sundaresan, Maitrayee
AU - Finkel, Toren
AU - Goldschmidt-Clermont, Pascal J.
PY - 1997/3/14
Y1 - 1997/3/14
N2 - 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.
AB - 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.
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U2 - 10.1126/science.275.5306.1649
DO - 10.1126/science.275.5306.1649
M3 - Article
C2 - 9054359
AN - SCOPUS:0030980641
SN - 0036-8075
VL - 275
SP - 1649
EP - 1652
JO - Science
JF - Science
IS - 5306
ER -