Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice

Nakano, Yoko; Longo-Guess, Chantal M.; Bergstrom, David E.; Nauseef, William M.; Jones, Sherri M.; Bánfi, Botond

doi:10.1172/jci33835

Cited by 83 publications

(110 citation statements)

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“…The phagocytosis and superoxide production is primary regulated by the cytochrome b- 245, (light) alpha subunit (also known as p 22 phox ), which is encoded by the gene CYBA. CYBA's mutation will cause the failure of phagocytosis and immune defects [50]. This observation supports our prediction that the immune phagocytosis and tumor suppressor gene CYBA might be associated with pancreatic cancer survival and tumor immune evasion.…”

Section: Resultssupporting

confidence: 86%

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Gong

Clarke

2014

BMC Systems Biology

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BackgroundRecent global genomic analyses identified 69 gene sets and 12 core signaling pathways genetically altered in pancreatic cancer, which is a highly malignant disease. A comprehensive understanding of the genetic signatures and signaling pathways that are directly correlated to pancreatic cancer survival will help cancer researchers to develop effective multi-gene targeted, personalized therapies for the pancreatic cancer patients at different stages. A previous work that applied a LASSO penalized regression method, which only considered individual genetic effects, identified 12 genes associated with pancreatic cancer survival.ResultsIn this work, we integrate pathway information into pancreatic cancer survival analysis. We introduce and apply a doubly regularized Cox regression model to identify both genes and signaling pathways related to pancreatic cancer survival.ConclusionsFour signaling pathways, including Ion transport, immune phagocytosis, TGFβ (spermatogenesis), regulation of DNA-dependent transcription pathways, and 15 genes within the four pathways are identified and verified to be directly correlated to pancreatic cancer survival. Our findings can help cancer researchers design new strategies for the early detection and diagnosis of pancreatic cancer.

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Section: Resultssupporting

confidence: 86%

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Gong

Clarke

2014

BMC Systems Biology

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“…This p22 phox (Y121H) mutation was correlated to a functional Nox2 and Nox3 deficiency, causing a CGD-like immune defect and a balance disorder due to lack of otoconia formation (24). This mutation is located in the putative second or fourth TM domain of p22 phox topology models (Fig.…”

Section: Analysis Of the P22mentioning

confidence: 98%

“…Murine neutrophils harboring the p22 phox (Y121H) mutation lack p22 phox expression and cannot generate a Nox2-dependent oxidative burst upon PMA stimulation (24 (Fig. 5D).…”

Section: Analysis Of the P22mentioning

confidence: 99%

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Mutational Analysis Reveals Distinct Features of the Nox4-p22 Complex

Löhneysen

Noack

Jesaitis

et al. 2008

Journal of Biological Chemistry

108

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The integral membrane protein p22phox forms a heterodimeric enzyme complex with NADPH oxidases (Noxs) and is required for their catalytic activity. Nox4, a Nox linked to cardiovascular disease, angiogenesis, and insulin signaling, is unique in its ability to produce hydrogen peroxide constitutively. To date, p22 phox constitutes the only identified regulatory component for Nox4 function. To delineate structural elements in p22 phox essential for formation and localization of the Nox4-p22 phox complex and its enzymatic function, truncation and point mutagenesis was used. Human lung carcinoma cells served as a heterologous expression system, since this cell type is p22 phox -deficient and promotes cell surface expression of the Nox4-p22 phox heterodimer. Expression of p22 phox truncation mutants indicates that the dual tryptophan motif contained in the N-terminal amino acids 6 -11 is essential, whereas the C terminus (amino acids 130 -195) is dispensable for Nox4 activity. Introduction of charged residues in domains predicted to be extracellular by topology modeling was mostly tolerated, whereas the exchange of amino acids in predicted membranespanning domains caused loss of function or showed distinct differences in p22 phox interaction with various Noxs. For example, the substitution of tyrosine 121 with histidine in p22 phox , which abolished Nox2 and Nox3 function in vivo, preserved Nox4 activity when expressed in lung cancer cells. Many of the examined p22 phox mutations inhibiting Nox1 to -3 maturation did not alter Nox4-p22 phox association, further accenting the differences between Noxs. These studies highlight the distinct interaction of the key regulatory p22 phox subunit with Nox4, a feature which could provide the basis for selective inhibitor development.The phagocyte NADPH oxidase consists of two membraneassociated subunits, the catalytic Nox2 (gp91 phox ) and the small subunit p22phox . Upon activation of the oxidase, several regulatory proteins in the cytosol undergo changes, such as incorporation of GTP or phosphorylation, leading to translocation and assembly of a multimeric oxidase complex at the membrane (1-3). This catalytically active complex shuttles electrons across the membrane in order to reduce molecular oxygen to superoxide. Although Nox2 contains the NADPH binding site, the flavin, and the heme groups required for accepting and transferring electrons, electron flow is also dependent on the presence of p22 phox as a focal point for oxidase assembly.

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“…phox and NOXO1 are essential for normal otoconium formation in the inner ear, and the absence of any of the three components results in vestibular dysfunction (34,37,51). Duox serves as the H 2 O 2 source in the thyroid that supports thyroid peroxidase-dependent iodination of thyroid hormone (38).…”

Section: Nox3-p22mentioning

confidence: 99%

Biological Roles for the NOX Family NADPH Oxidases

Nauseef

2008

Journal of Biological Chemistry

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283

225

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Linking the phagocyte defect in patients with chronic granulomatous disease (CGD) 2 with the biochemical basis for oxygen consumption by stimulated neutrophils (1) represented a seminal advance in understanding the molecular basis for a key component of innate immunity. In subsequent decades, the catalytic and regulatory elements of the "respiratory burst oxidase" were elucidated, tacitly assuming all along that the NADPH-dependent oxidase under study represented a system uniquely expressed in phagocytic cells and dedicated to generating relatively large amounts of reactive oxygen species (ROS) destined to destroy invading microbes. Development of more sensitive analytical systems for ROS detection revealed that some physiological and pathophysiological events in non-phagocytic cells were associated with ROS generation, although the subcellular source of oxidants remained uncertain. With the identification of mox1 in 1999 (2) as a homolog of gp91 phox , the catalytic component of the phagocyte oxidase, came the birth of the NADPH oxidase (NOX) protein family and the eventual identification of its seven members. With remarkable rapidity, many features of the structure, activity, cell biology, and physiology of the NOX proteins have been described, as summarized in several excellent and comprehensive recent reviews (3)(4)(5). This more circumscribed minireview provides an overview of the organizing features of the protein family, a summary of the physiology and pathophysiology in which NOX proteins participate (or might participate), and identification of some of the remaining unanswered questions in the field.

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Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice

Cited by 83 publications

References 49 publications

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Mutational Analysis Reveals Distinct Features of the Nox4-p22 Complex

Biological Roles for the NOX Family NADPH Oxidases

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