Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transglutaminase 2 (TGase 2) expression is increased in inflammatory diseases. We demonstrated previously that inhibitors of TGase 2 reduce nitric oxide (NO) generation in a lipopolysaccharide (LPS)-treated microglial cell line. However, the precise mechanism by which TGase 2 promotes inflammation remains unclear. We found that TGase 2 activates the transcriptional activator nuclear factor (NF)-kappaB and thereby enhances LPS-induced expression of inducible nitric-oxide synthase. TGase 2 activates NF-kappaB via a novel pathway. Rather than stimulating phosphorylation and degradation of the inhibitory subunit alpha of NF-kappaB (I-kappaBalpha), TGase2 induces its polymerization. This polymerization results in dissociation of NF-kappaB and its translocation to the nucleus, where it is capable of up-regulating a host of inflammatory genes, including inducible nitric-oxide synthase and tumor necrosis factor alpha (TNF-alpha). Indeed, TGase inhibitors prevent depletion of monomeric I-kappaBalpha in the cytosol of cells overexpressing TGase 2. In an LPS-induced rat brain injury model, TGase inhibitors significantly reduced TNF-alpha synthesis. The findings are consistent with a model in which LPS-induced NF-kappaB activation is the result of phosphorylation of I-kappaBalpha by I-kappaB kinase as well as I-kappaBalpha polymerization by TGase 2. Safe and stable TGase2 inhibitors may be effective agents in diseases associated with inflammation.
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PMID:Transglutaminase 2 induces nuclear factor-kappaB activation via a novel pathway in BV-2 microglia. 1547 61

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with l-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.
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PMID:Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. 1655 42