title: NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91phox in the regulated production of superoxide by phagocytes.
abstract: Reactive oxygen species (ROS) serve several physiological functions; in some settings they act in host defense, while in others they function in cellular signaling or in biosynthetic reactions. We studied the expression and function of a recently described source of ROS, NAD(P)H oxidase 1 or Nox1, which has been associated with cell proliferation. In situ hybridization in mouse colon revealed high Nox1 expression within the lower two-thirds of colon crypts, where epithelial cells undergo proliferation and differentiation. Human multitumor tissue array analysis confirmed colon-specific Nox1 expression, predominantly in differentiated epithelial tumors. Differentiation of Caco2 and HT29 cells with 1alpha,25-dihydroxyvitamin D(3) or IFN-gamma enhances Nox1 expression and decreases cell proliferation, suggesting that Nox1 does not function as a mitogenic oxidase in colon epithelial cells. Transduction with retrovirus encoding Nox1 restored activation and differentiation-dependent superoxide production in gp91(phox)-deficient PLB-985 cells, indicating close functional similarities to the phagocyte oxidase (phox). Furthermore, coexpression of cytosolic components, p47(phox) and p67(phox), augments Nox1 activity in reconstituted K562 cells. Finally, Nox1 partially restores superoxide production in neutrophils differentiating ex vivo from gp91(phox)-deficient CD34(+) peripheral blood-derived stem cells derived from patients with X-linked chronic granulomatous disease. These studies demonstrate a significant functional homology (cofactor-dependent and activation-regulated superoxide production) between Nox1 and its closest homologue, gp91(phox), suggesting that targeted up-regulation of Nox1 expression in phagocytic cells could provide a novel approach in the molecular treatment of chronic granulomatous disease.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Miklós
authors.initials: M
authors.lastname: Geiszt
authors.forename: Kristen
authors.initials: K
authors.lastname: Lekstrom
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brenner
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Raya
authors.initials: R
authors.lastname: Dana
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Leto
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006105:Granulomatous Disease, Chronic / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology; D019073:HT29 Cells; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010586:Phagocytes / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D016372:RNA, Antisense / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D008562:Membrane Glycoproteins; D016372:RNA, Antisense; D013481:Superoxides; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse