Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) is an important cytokine in immunity and inflammation and induces many cellular responses, including apoptosis and necrosis. TNF signaling enables the generation of superoxide in phagocytic and vascular cells through the activation of the NADPH oxidase Nox2/gp91. Here we show that TNF also activates the Nox1 NADPH oxidase in mouse fibroblasts when cells undergo necrosis. TNF treatment induces the formation of a signaling complex containing TRADD, RIP1, Nox1, and the small GTPase Rac1. TNF-treated RIP1-deficient fibroblasts fail to form such a complex, indicating that RIP1 is essential for Nox1 recruitment. Moreover, the prevention of TNF-induced superoxide generation with dominant-negative mutants of TRADD or Rac1, as well as knockdown of Nox1 using siRNA, inhibits necrosis. Thus our study suggests that activation of Nox1 through forming a complex with TNF signaling components plays a key role in TNF-induced necrotic cell death.
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PMID:TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. 1758 11

Necrosis is a caspase-independent cell death process involving the generation of reactive oxygen species (ROS). In a recent issue of Molecular Cell, Kim et al. (2007) reported on a novel TNF receptor 1 necrotic signaling complex inducing TRADD- and RIP1-dependent recruitment and activation of the ROS-generating Nox1 NADPH oxidase complex.
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PMID:NADPH oxidases: new players in TNF-induced necrotic cell death. 1756 Mar 73

Growing evidence suggests that NADPH oxidase (Nox)-derived reactive oxygen species (ROS) play important roles in regulating cytokine signaling. We have explored how TNF-alpha induction of Nox-dependent ROS influences NF-kappaB activation. Cellular stimulation by TNF-alpha induced NADPH-dependent superoxide production in the endosomal compartment, and this ROS was required for IKK-mediated activation of NF-kappaB. Inhibiting endocytosis reduced the ability of TNF-alpha to induce both NADPH-dependent endosomal superoxide and NF-kappaB, supporting the notion that redox-dependent signaling of the receptor occurs in the endosome. Molecular analyses demonstrated that endosomal H(2)O(2) was critical for the recruitment of TRAF2 to the TNFR1/TRADD complex after endocytosis. Studies using both Nox2 siRNA and Nox2-knockout primary fibroblasts indicated that Nox2 was critical for TNF-alpha-mediated induction of endosomal superoxide. Redox-active endosomes that form after TNF-alpha or IL-1 beta induction recruit several common proteins (Rac1, Nox2, p67(phox), SOD1), while also retaining specificity for ligand-activated receptor effectors. Our studies suggest that TNF-alpha and IL-1 beta signaling pathways both can use Nox2 to facilitate redox activation of their respective receptors at the endosomal level by promoting the redox-dependent recruitment of TRAFs. These studies help to explain how cellular compartmentalization of redox signals can be used to direct receptor activation from the plasma membrane.
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PMID:Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha. 1911 17