Abstract
Reactive oxygen species (ROS) generated in some non-phagocytic cells are implicated in mitogenic signalling and cancer1,2,3,4,5,6. Many cancer cells show increased production of ROS7, and normal cells exposed to hydrogen peroxide or superoxide show increased proliferation8 and express growth-related genes9,10,11. ROS are generated in response to growth factors, and may affect cell growth2,3,12,13, for example in vascular smooth-muscle cells6,13,14,15. Increased ROS in Ras-transformed fibroblasts correlates with increased mitogenic rate16. Here we describe the cloning of mox1, which encodes a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase of phagocytes17,18, gp91phox. mox1 messenger RNA is expressed in colon, prostate, uterus and vascular smooth muscle, but not in peripheral blood leukocytes. In smooth-muscle cells, platelet-derived growth factor induces mox1 mRNA production, while antisense mox1 mRNA decreases superoxide generation and serum-stimulated growth. Overexpression of mox1 in NIH3T3 cells increases superoxide generation and cell growth. Cells expressing mox1 have a transformed appearance, show anchorage-independent growth and produce tumours in athymic mice. These data link ROS production by Mox1 to growth control in non-phagocytic cells.
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References
Jones,S. A., Hancock,J., Jones,O. T. G., Neubauer,A. & Topley,N. The expression of NADPH oxidase components in human glomerular mesangial cells: Detection of protein and mRNA for p47phox, p67phox, and p22phox. J. Am. Soc. Nephrol. 5, 1483–1491 (1995).
Matsubara,T. & Ziff,M. Increased superoxide anion release from human endothelial cells in response to cytokines. J. Immunol. 137, 3295–3298 (1986).
Meier,B. et al. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumor necrosis factor-α. Biochem. J. 263, 539–545 (1989).
Pagano,P. et al. Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: Enhancement by angiotensin II. Proc. Natl Acad. Sci. USA 94, 14483–14488 (1997).
Jones,S. et al. Expression of phagocyte NADPH oxidase components in human endothelial cells. Am. J. Physiol. 271, H1626 (1996).
Griendling,K. K., Minieri,C. A., Ollerenshaw,J. D. & Alexander,R. W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ. Res. 74, 1141–1148 (1994).
Szatrowski,T. P. & Nathan,C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991).
Burdon,R. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Rad. Biol. Med. 18, 775–794 (1995).
Crawford,D., Zbinden,I., Amstad,P. & Cerutti,P. Oxidant stress induces the proto-oncogenes c-fos and c-myc in mouse epidermal cells. Oncogene 3, 27–32 (1988).
Nose,K. et al. Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. Eur. J. Biochem. 201, 99–106 (1991).
Datta,R. et al. Involvement of reactive oxygen intermediates in the induction of c-jun gene transcription by ionizing radiation. Biochemistry 31, 8300–8306 (1992).
Bae,Y. S. et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. J. Biol. Chem. 272, 217–221 (1997).
Zafari,A. M. et al. Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 32, 488–495 (1998).
Wolin,M. S. Activated oxygen metabolites as regulators of vascular tone. Klin. Wochenschr. 69, 1046–1049 (1991).
Sundaresan,M., Zu-Xi,Y., Ferrans,V. J., Irani,K. & Finkel,T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).
Irani,K. et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275, 1649–1652 (1997).
Segal,A. W. & Shatwell,K. P. The NADPH oxidase of phagocytic leukocytes. Ann. NY Acad. Sci. 832, 215–222 (1997).
Royer-Pokora,B. et al. Cloning the gene for an inherited human disorder–chronic granulomatous disease–on the basis of its chromosomal location. Nature 322, 32–38 (1986).
Wallach,T. M. & Segal,A. W. Analysis of glycosylation sites on gp91phox, the flavocytochrome of the NADPH oxidase, by site-directed mutagenesis and translation in vitro. Biochem. J. 321, 583–3746 (1998).
Bjorgvinsdottir,H. Zhen,L. & Dinauer,M. Cloning of murine gp91phox cDNA and functional expression in a human X-linked chronic granulomatous disease cell line. Blood 87, 2005–2010 (1996).
Rotrosen,D. Yeung,C. L., Leto,T. L. & Malech,K. C. H. Cytochrome b558: The flavin-binding component of the phagocyte NADPH oxidase. Science 256, 1459–1462 (1992).
Segal,A. W. et al. Cytochrome b-245 is a flavocytochrome containing FAD and the NADPH-binding site of the microbicidal oxidase of phagocytes. Biochem. J. 284, 781–788 (1992).
Sumimoto,H. et al. Cytochrome b558, a component of the phagocyte NADPH oxidase, is a flavoprotein. Biochem. Biophys. Res. Commun. 186, 1368–1363 (1992).
Berk,B. C., Elder,E. & Mitsuka,M. Hypertrophy and hyperplasia cause differing effects on vascular smooth muscle cell Na+/H+ exchange and intracellular pH. J. Biol. Chem. 265, 19632–19637 (1990).
Gardner,P., Raineri,I., Epstein,L. & White,C. Superoxide radical and iron modulate aconitase activity in mammalian cells. J. Biol. Chem. 270, 13399–13405 (1995).
Fridovich,I. Superoxide anion radical (O*2-), superoxide dismutases, and related matters. J. Biol. Chem. 272, 18515–18517 (1997).
Gardner,P. R., Znguyen,D. H. & White,C. W. Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs. Proc. Natl Acad. Sci. USA 91, 12248–12252 (1994).
Flint,D. H. Initial kinetic and mechanistic characterization of Escherichia coli fumarase A. Arch. Biochem. Biophys. 311, 509–513 (1994).
Li,Y. et al. Validation of lucigenin (bis-N-methylacridinium) as a chemiluigenic probe for detecting superoxide anion radical production by enzymatic and cellular systems. J. Biol. Chem. 273, 2015–2023 (1998).
Acknowledgements
We thank D. Jones and D. Edmondson for discussions and technical advice; W. Sun for technical assistance; and D. Dillehay for the histological analysis. This work was supported by the NIH.
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Suh, YA., Arnold, R., Lassegue, B. et al. Cell transformation by the superoxide-generating oxidase Mox1. Nature 401, 79–82 (1999). https://doi.org/10.1038/43459
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DOI: https://doi.org/10.1038/43459
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