Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and modulates the inflammatory immune response. Because HO-1 is up-regulated by NAD(P)H oxidase activators such as lipopolysaccharide and 12-O-tetradecanoylphorbol-13-acetate in monocytic cells, we investigated the gene regulation of HO-1 by the chemical NAD(P)H oxidase inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF). Unexpectedly, AEBSF induced endogenous gene expression and promoter activity of HO-1 in cell cultures of human and mouse monocytes. Inhibition of the phosphatidylinositol 3-kinase/protein kinase B (PKB) pathway by pharmacological inhibitors and cotransfection of an expression vector for a dominant negative mutant of PKB reduced the AEBSF-dependent induction of HO-1 gene transcription. Accordingly, overexpressed constitutively active PKB markedly up-regulated HO-1 promoter activity. AEBSF activated the mitogen-activated protein kinases (MAPK) JNK and p38. Inhibition of p38alpha and p38beta, but not that of JNK or p38gamma and p38delta, prevented the induction of HO-1 gene expression by AEBSF. p38 was stimulated by AEBSF in a PKB-dependent manner as demonstrated by a luciferase assay with a Gal4-CHOP fusion protein. Finally, AEBSF- and PKB-dependent induction of HO-1 promoter activity was reduced by simultaneous mutation of an E-box motif (-47/-42) and a cAMP response element/AP-1 element (-664/-657) of the proximal HO-1 gene promoter. Overexpression of the basic helix-loop-helix transcription factor USF2 and coactivator p300 enhanced the AEBSF-dependent response of the HO-1 promoter. The data suggest that the transcriptional induction of HO-1 gene expression by AEBSF is mediated via activation of a PKB, p38 MAPK signaling pathway.
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PMID:Heme oxygenase-1 gene activation by the NAD(P)H oxidase inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride via a protein kinase B, p38-dependent signaling pathway in monocytes. 1583 36

Transforming growth factor-beta1 (TGF-beta1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF-beta1 stimulation on freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF-beta1 initially promoted differentiation, with upregulated expression of smooth muscle contractile proteins. TGF-beta1 also induced expression of Nox4, the only NAD(P)H oxidase membrane homolog found in HPASMC, through a signaling pathway involving Smad 2/3 but not mitogen-activated protein (MAP) kinases. TGF-beta1 likewise increased production of reactive oxygen species (ROS), an effect significantly reduced by the NAD(P)H oxidase flavoprotein inhibitor diphenylene iodonium (DPI) and by Nox4 siRNAs. In the absence of TGF-beta1, Nox4 was present in freshly cultured cells but progressively lost with each passage in culture, paralleling a decrease in ROS production by HPASMC over time. At a later time point (72 h), TGF-beta1 promoted HPASMC proliferation in a manner partially inhibited by Nox4 small interfering RNA and dominant negative Smad 2/3, indicating that TGF-beta1 stimulates HPASMC growth in part by a redox-dependent mechanism mediated through induction of Nox4. HPASMC activation of the MAP kinases ERK1/2 was reduced by the NAD(P)H oxidase inhibitors DPI and 4-(2-aminoethyl)benzenesulfonyl fluoride, suggesting that TGF-beta1 may facilitate proliferation by upregulating Nox4 and ROS production, with transient oxidative inactivation of phosphatases and augmentation of growth signaling cascades. These findings suggest that Nox4 is the relevant Nox homolog in HPASMC. This is the first observation that TGF-beta1 regulates Nox4, with important implications for mechanisms of pulmonary vascular remodeling.
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PMID:Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. 1622 20