NADPH oxidase, which produces superoxide, is an important bactericidal product of neutrophils and critically important in host defense. The oxidase complex includes cytochrome b559 which is a heterodimer of p22phox and gp91phox as well as cytosolic proteins (p47phox, p67phox and Rax1/2 which assemble into the oxidase upon activation. Although expression of the oxidase has been thought to be myeloid specific, new evidence indicates that similar proteins and oxidase activity occur in other cell types. In this regard, the applicants have recently cloned the gene NOH-1 which encodes a gp91phox homologue expressed in non-myeloid cells, especially colonic epithelium. The predicted protein has conserved sites for binding of heme, FAD and NADPH and appears to be able to generate superoxide. This suggests the existence of a family of mammalian plasma membrane flavo-heme oxidoreductases which may share, with phagocyte NADPH oxidase, similar biochemical and molecular mechanisms but exhibit tissue-specific function, regulation and roles in the host defense system. To explore this prospect, the specific aims of the present grant are to: (1) characterize the biochemical features and molecular mechanisms of the oxidoreductase activity of gp91phox and the homologous NOH-1, as well as define cofactors, substrates, structural requirements and mechanisms of enzyme activation, (2) determine the possible role of NOH-1 as an antimicrobial host defense system in colon epithelium and (3) examine the regulation of expression of NADPH oxidase genes, with an emphasis on the molecular bases for specificity of expression in myeloid vs. non-myeloid tissues and the response to inflammatory stimuli and cell maturation.
| El Jamali, Amina; Valente, Anthony J; Clark, Robert A (2010) Regulation of phagocyte NADPH oxidase by hydrogen peroxide through a Ca(2+)/c-Abl signaling pathway. Free Radic Biol Med 48:798-810 |
| Lambeth, J David; Krause, Karl-Heinz; Clark, Robert A (2008) NOX enzymes as novel targets for drug development. Semin Immunopathol 30:339-63 |
| El Jamali, Amina; Valente, Anthony J; Lechleiter, James D et al. (2008) Novel redox-dependent regulation of NOX5 by the tyrosine kinase c-Abl. Free Radic Biol Med 44:868-81 |
| Valente, Anthony J; Zhou, Qing; Lu, Zhenhua et al. (2008) Regulation of NOX1 expression by GATA, HNF-1alpha, and Cdx transcription factors. Free Radic Biol Med 44:430-43 |
| Qin, Bin; Cartier, Laetitia; Dubois-Dauphin, Michel et al. (2006) A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol Aging 27:1577-87 |
| He, Weijing; Qiang, Mei; Ma, Wuqiong et al. (2006) Development of a synthetic promoter for macrophage gene therapy. Hum Gene Ther 17:949-59 |
| Banfi, Botond; Malgrange, Brigitte; Knisz, Judit et al. (2004) NOX3, a superoxide-generating NADPH oxidase of the inner ear. J Biol Chem 279:46065-72 |
| Banfi, Botond; Tirone, Fabiana; Durussel, Isabelle et al. (2004) Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5). J Biol Chem 279:18583-91 |
| Banfi, Botond; Clark, Robert A; Steger, Klaus et al. (2003) Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J Biol Chem 278:3510-3 |
| Li, Sen-Lin; Valente, Anthony J; Qiang, Mei et al. (2002) Multiple PU.1 sites cooperate in the regulation of p40(phox) transcription during granulocytic differentiation of myeloid cells. Blood 99:4578-87 |
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