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v‐Ha‐ ras mitogenic signaling through superoxide and derived reactive oxygen species
Author(s) -
Yang JiQin,
Buettner Garry R.,
Domann Frederick E.,
Li Qiang,
Engelhardt John F.,
Weydert Christine Darby,
Oberley Larry W.
Publication year - 2002
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.10037
Subject(s) - superoxide , superoxide dismutase , biology , reactive oxygen species , transfection , microbiology and biotechnology , plating efficiency , oncogene , cell growth , signal transduction , catalase , cancer research , biochemistry , cell , cell cycle , enzyme , gene
The ras proto‐oncogene is frequently mutated in human tumors and functions to constitutively stimulate signal transduction cascades, resulting in unchecked proliferation and malignant transformation. In certain cells, superoxide functions as a signal‐transduction messenger, mediating the downstream effects of ras and rac. We demonstrated previously that v‐Ha ‐ras –transfected rat kidney epithelial cells (RECs) overproduced superoxide anion and that this superoxide production was mediated by ras. In the present study, we further demonstrated that v‐Ha ‐ras overexpression transformed immortal nonmalignant RECs into malignant cancer cells; v‐Ha ‐ras –transfected cells formed clones in soft agar, had high plating efficiency, and formed tumors in nude mice. Our data suggest that superoxide radical plays a role in ras‐induced transformation; modulation of intracellular superoxide level by overexpression of manganese‐containing superoxide dismutase or copper‐ and zinc‐containing superoxide dismutase inhibited ras‐induced transformation, as evidenced by in vitro studies of plating efficiency and by in vivo studies of tumor formation in nude mice. Overexpression of catalase (CAT) alone was found to have little effect on tumor cell growth, but overexpression of glutathione peroxidase 1 (GPx1) completely suppressed tumor cell growth in nude mice. This finding suggests that peroxides removed by GPx1, but not by CAT, are also involved in ras‐induced transformation. © 2002 Wiley‐Liss, Inc.