Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

gamma-Glutamyl transpeptidase (GGT) catalyzes the transfer of the glutamyl moiety from glutathione, and glutathione S-conjugates to acceptors to form another amide or to water to produce free glutamate. Functionally, GGT plays important roles in glutathione homeostasis and mercapturic acid metabolism. The expression of GGT is increased as an adaptive response upon the exposure of oxidative stress. The underlying mechanism of this, however, is nebulous, as GGT gene structure is complex and its transcription is usually controlled by multiple promoters that generate several subtypes of GGT mRNAs. Studies reveal that signaling pathways such as Ras, ERK, p38MAPK, and PI3K are involved in the induction of GGT gene expression in response to oxidative stress. Thus, not surprisingly, induction of GGT mRNA subtypes and the involvement of multiple signaling pathways vary depending on cell type and stimuli.
Am J Respir Cell Mol Biol 2009 Nov
PMID:Redox regulation of gamma-glutamyl transpeptidase. 1968 7

Recent studies have discovered changes in the insulin-/IGF1 signaling affecting glucose metabolism and the molecular pathogenesis of human hepatocellular cancer. Insulin/IGF1 receptor mediates its intracellular effects by recruitment of one out of the four different insulin receptor substrates (IRS). To investigate mechanisms of IRS2 expression, we analyzed transcriptional regulation of IRS2 in human HepG2 cells. We identified a region 688 bp upstream of the translation start codon responsible for approximately 90% of basal human IRS2 promoter activity in HepG2 cells, and confirmed binding of specificity protein 1 (also called Sp1 transcription factor, SP1) and nuclear factor 1 (NFI) in this region. Mutation of both SP1 and NFI binding sites or inhibition of extracellular signal regulated kinase (ERK) suppressed IRS2 promoter activity almost completely, revealing a major role of MAP kinases (MAPK) for IRS2 transcription. Activating this cascade with oxidative stress increased IRS2 promoter activity and endogenous IRS2 expression substantially. IRS2 promoter activity rose even more after additional inhibition of p38MAPK indicating an inhibitory effect of p38MAPK on ERK mediated IRS2 transcription. Activation of the MAPK pathway using interleukin 1, beta (IL1B) increased IRS2 promoter activity similar to oxidative stress. In contrast IL1B decreases and inhibition of the MAPK pathway increases IRS1 promoter activity revealing opposed effects of IL1B and ERK on the expression of different IRS proteins. In conclusion we discovered a specific region (-688 to -611 bp) in the IRS2 promoter essential for basal promoter activity and oxidative stress induced transcription depending on ERK activation and SP1 and NFI binding in human hepatocytes.
J Mol Endocrinol 2010 Feb
PMID:Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells. 1975 87

Extracellular signal-regulated kinases (ERKs) or mitogen-activated protein kinases (MAPKs) are involved in cellular proliferation, differentiation, migration, and gene expression. The MAPK family includes ERK1/2, c-Jun NH(2)-terminal kinases 1, 2, and 3, p38MAPK alpha, beta, gamma, and -delta, and ERK5 as conventional MAPKs and ERK3, ERK4 NLK, and ERK7 as atypical MAPKs. Like other MAPKs, ERK5 is activated by variety of stimuli, including growth factors, G-protein-coupled receptor (GPCR) agonists, cytokines, and stress. However, the signaling pathway leading to ERK5 activation is not well understood compared with the other conventional MAPKs. For example, the pharmacological reagents that induce second messenger cAMP and Ca(2+) downstream of GPCRs do not activate ERK5 in neuronal cells. In addition, conflicting results have come from studies examining the involvement of small G-proteins in ERK5 activation by growth factors, and the details of the signaling pathway remain controversial. In addition, the physiological roles of ERK5 in neuronal cells have not been clarified. One reason was the lack of a selective ERK5 pharmacological inhibitor until the novel selective MEK5/ERK5 inhibitors BIX02188 and BIX02189 (Biochem Biophys Res Commun 377:120-125, 2008) reported last year. Another reason is that the use of interfering mutants is limited in neuronal cells because the transfection efficiency is low. Despite these difficulties, recent studies suggest that ERK5 mediates the promotion of neuronal survival and neuronal differentiation in vitro and in vivo. In this review, the signaling pathway leading to ERK5 activation through heterotrimeric and small G-proteins and the physiological roles of ERK5 in neuronal cells are summarized and discussed.
Mol Pharmacol 2010 Jan
PMID:The signaling pathway leading to extracellular signal-regulated kinase 5 (ERK5) activation via G-proteins and ERK5-dependent neurotrophic effects. 1985 97

Enteroaggregative Escherichia coli (EAEC) is emerging as a cause of acute and persistent diarrhea in developing countries. An important feature of EAEC pathogenesis is the induction of profound inflammatory response in the intestinal epithelium. In this article, we have shown that EAEC-induced activation of mitogen-activated protein kinases (MAPK) (ERK-1/2, JNK and p38MAPK) in cultured human intestinal epithelial cells (INT-407) leads to the induction of DNA-binding activity of NF-kappaB and AP-1, resulting in IL-8 production. Plasmid-cured EAEC could also activate the MAPK and the transcription factors leading to IL-8 secretion, but to a lesser extent than that of wild-type EAEC. Further, pretreatment of these cells with the highly specific MEK inhibitor (PD 098059), the JNK inhibitor (SP 600125), and the p38MAPK inhibitor (SB 203580) resulted in inhibition of the IL-8 secretion by EAEC (wild type as well as plasmid cured)-infected INT-407 cells. These findings demonstrate that the inflammatory response induced by EAEC may be due to the specific stimulation of MAPK signaling pathways leading to nuclear responses. To our knowledge, this is the first article regarding the detailed mechanism of IL-8 secretion from the EAEC-infected human intestinal epithelial cell line.
Mol Cell Biochem 2010 Apr
PMID:Enteroaggregative Escherichia coli infection induces IL-8 production via activation of mitogen-activated protein kinases and the transcription factors NF-kappaB and AP-1 in INT-407 cells. 1989 47

Present study investigates the role of Mycobacterium leprae (M. leprae) antigens on TCR- and TCR/CD28-induced signalling leading to T-cell activation and further correlates these early biochemical events with T-cell anergy, as prevailed in advanced stages of leprosy. We observed that both whole cell lystae (WCL) and soluble fraction of M. leprae sonicate (MLSA) not only inhibited TCR, thapsigargin and ionomycin induced calcium fluxes by diminishing the opening of calcium channels, but also TCR- or TCR/CD28-induced proximal signalling events like phosphorylation of Zap-70 and protein kinase-C (PKC) activity. Study of TCR- and TCR/CD28-induced downstream signals revealed that M. leprae antigens curtail phosphorylation of both Erk1/2 and p38MAPK, consequently altering terminal signalling events like reduced binding of NFAT on IL-2 promoter and transcription of IL-2 gene, diminished expression of activation markers (CD25 and CD69). Furthermore, M. leprae fractions significantly inhibited IL-2 secretion and T-cell blastogenesis in healthy individuals. Altogether, results suggest that M. leprae interferes with TCR/CD28-induced upstream as well as downstream signalling events resulting in reduced IL-2 production and thus inhibition in T-cell proliferation, which might be responsible for T-cell unresponsiveness leading to stage of immunosuppression and consequently, for the progression of disease.
Mol Immunol 2010 Feb
PMID:Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy. 2001 78

Mitogen-activated protein kinases (MAPKs) are a superfamily of cytoplasmic serine/threonine kinases that transduce many types of extracellular stimuli into cellular responses. p38MAPK is a member of this family with its active form in a diphosphorylated state (p38MAPKdiP). Two strong anti-p38MAPKdiP immunoreactive bands (apparent molecular weight 38 and 34 kDa) were detected by Western blotting in cultured astrocytes. Using a specific antibody and employing immunoprecipitation procedures and SELDI-TOF analysis, the 34 kDa band was found to correspond to Mxi2, a splice variant of p38MAPK; cultured astrocytes therefore express Mxi2. Separate protein extractions of different subcellular fractions, and fluorescent immunovisualisation employing confocal microscopy, showed Mxi2 to have a non-nuclear, cytosolic distribution in the studied cells. ERK1/2, protein whose intracellular distribution is influenced by Mxi2, showed the same cytoplasmic pattern than Mxi2.
J Mol Histol 2009 Oct
PMID:Astrocytes express Mxi2, a splice isoform of p38MAPK. 2004 36

In the present study, we investigated the effects of millimeter wave treatment on the activation of the p38MAPK signaling pathway in the process of NO-induced apoptosis in chondrocytes. Cartilage was isolated from the knee joint of SD rats and used to establish cultured primary chondrocytes. After identification using in situ staining of type II collagen, the passage 2 chondrocytes were incubated with or without sodium nitroprussiate (SNP) to induce apoptosis and treated with a millimeter wave for various times. The apoptosis of chondrocytes was detected using immunofluorescence, an MTT assay, and Annexin V-FITC labeling followed by fluorescence-activated cell sorting (FACS). The activity of caspase-3 was measured using colorimeters, and the levels of p38 and p53 were also detected using RT-PCR and Western blotting. After treatment with SNP, the OD values of the experimental groups were significantly lower than the control group (P<0.01). The 24-h interference of a millimeter wave significantly prevented apoptosis (P<0.01) and showed a dose dependency, and an identical trend of apoptosis was noted with normal cell number counting (P<0.01) and FACS (P<0.01). Consistently, the caspase 3 activity showed a reverse trend, with the highest activity in the experimental group receiving no millimeter wave treatment (P<0.01). The mRNA expression of p38 and p53 and the protein levels of phosphorylated p38 and p53 showed a similar trend (P<0.01) to that of caspase 3 activity. In conclusion, millimeter wave treatment inhibits the SNP-induced apoptosis of chondrocytes through the p38MAPK pathway.
Int J Mol Med 2010 Mar
PMID:Millimeter wave treatment inhibits NO-induced apoptosis of chondrocytes through the p38MAPK pathway. 2012 44

Cutaneous and ocular injuries caused by sulfur mustard (SM; bis-(2-chloroethyl) sulfide) are characterized by severe inflammation and death of exposed cells. Given the known roles of p38MAPK and NF-kappaB in inflammatory cytokine production, and the known roles of NF-kappaB and p53 in cell fate, these pathways are of particular interest in the study of SM injury. In this study, we utilized inhibitory RNA (RNAi) targeted against p38 alpha, the p50 subunit of NF-kappaB, or p53 to characterize their role in SM-induced inflammation and cell death in normal human epidermal keratinocytes (NHEK). Analysis of culture supernatant from 200 microM SM-exposed cells showed that inflammatory cytokine production was inhibited by p38 alpha RNAi but not by NF-kappaB p50 RNAi. These findings further support a critical role for p38 in SM-induced inflammatory cytokine production in NHEK and suggest that NF-kappaB may not play a role in the SM-induced inflammatory response of this cell type. Inhibition of NF-kappaB by p50 RNAi did, however, partially inhibit SM-induced cell death, suggesting a role for NF-kappaB in SM-induced apoptosis or necrosis. Interestingly, inhibition of p53 by RNAi potentiated SM-induced cell death, suggesting that the role of p53 in SM injury, may be complex and not simply prodeath.
J Biochem Mol Toxicol
PMID:Sulfur mustard induced cytokine production and cell death: investigating the potential roles of the p38, p53, and NF-kappaB signaling pathways with RNA interference. 2014 54

Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.
Mol Syst Biol 2010
PMID:Feedback between p21 and reactive oxygen production is necessary for cell senescence. 2016 Jul 8

Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH)2D3 increases cytosolic Ca2+ concentration and transiently activates RhoA and its effector the Rho-associated coiled-kinase (ROCK), and later p38MAPK-MSK. We found that the inhibition of ROCK signaling by Y27632 or that of MSK by Ro318220 prevent the formation of epithelioid islands of SW480-ADH cells by 1,25(OH)2D3 and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH)2D3 24-hydroxylase (CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH)2D3. Moreover, 1,25(OH)2D3 does not promote the localization of the tight junction protein occludin at the plasma membrane in cells expressing a dominant negative RhoA (N19-RhoA). In addition, 1,25(OH)2D3 specifically increases the level of the cysteine protease-inhibitor cystatin D, whereas that of cystatin SN is unaffected. The increase of cystatin D protein caused by 1,25(OH)2D3 is abrogated in N19-RhoA cells. Thus, activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH)2D3 in colon cancer cells.
J Steroid Biochem Mol Biol 2010 Jul
PMID:The effects of 1,25-dihydroxyvitamin D3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling. 2022 87


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