Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Celecoxib (CE) is a nonsteroidal anti-inflammatory drug (NSAID) that is a specific inhibitor of cyclooxygenase 2 (COX2). It is indicated for a variety of chronic inflammatory conditions, including rheumatoid arthritis. Over the last few years, adverse cardiovascular effects and increased risk for heart attacks have been associated with this drug. In addition, evidence is emerging for COX2-independent molecular targets. CE has been shown to induce apoptosis in various cancer cells lines through a COX2-independent mechanism that seems to involve inactivation of protein kinase Akt and inhibition of endoplasmic reticulum (ER) Ca2+ ATPase. In this study, we show that both CE and an analog devoid of COX2 inhibitory activity [1-(4-sulfamoyl phenyl)-3-trifluoromethyl-5-(4-trifluoromethylphenyl)pyrazole, CEA] inhibit the secretion of the dimeric interleukin-12 (IL-12) alphabeta and beta2 forms with identical IC50 values of 20 and 30 microM, respectively, whereas no such effect was seen with rofecoxib. Reverse transcription-polymerase chain reaction analysis showed that this inhibition was not due to a blockage of transcription of the alpha- and beta-chain expression cassettes. Secretion of the beta monomer form was less strongly inhibited, suggestive for a mechanism primarily targeting dimer assembly in the ER. Analysis of intracellular fractions revealed that both CE and CEA increased the association of IL-12 with calreticulin, an endoplasmic reticulum-resident chaperone involved in the retention of misfolded cargo proteins while blocking interaction with ERp44. Our findings reveal a previously undescribed effect of celecoxib on oligomer protein folding and assembly in the endoplasmic reticulum and ensuing secretion and suggest that celecoxib-driven alteration of the secretome may be involved in some of its clinical side effects.
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PMID:Celecoxib inhibits interleukin-12 alphabeta and beta2 folding and secretion by a novel COX2-independent mechanism involving chaperones of the endoplasmic reticulum. 1646 90

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I(Ca,L)) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 +/- 2 ms; control, 257 +/- 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 +/- 2 ms; control, 305 +/- 2 ms, P < 0.05). I(Ca,L) density was significantly reduced in myocytes from the LPS group (-3.2 +/- 0.8 pA/pF) compared with that of control myocytes (-6.7 +/- 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I(Ca,L) in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I(Ca,L) density. This effect was reversed by ADM-(22-52). The G(i) protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I(Ca,L). The results suggest a COX-2-involved PKA-dependent switch from G(s) coupled to PTX-sensitive G(i) coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I(Ca,L) in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.
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PMID:The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway. 1776 82

Bordetella pertussis causes a profound inflammatory response in lungs of infected individuals. The adenylate cyclase toxin (ACT) of B. pertussis is a potent enzyme that converts cytosolic ATP into cAMP, and is required for virulence in vivo. During infection, secreted ACT binds to macrophages utilizing the beta2 integrin, Mac-1 (CR3, CD11b/CD18), and subsequent intoxication by ACT inhibits essential antibacterial activities of macrophages. Additionally, Mac-1 has been reported to be a co-receptor for TLR4 required for the full induction of some LPS-responsive genes, including pro-inflammatory cyclooxygenase 2 (COX-2). We have examined the effect of ACT on COX-2 expression in HEK293T cells expressing Mac-1 and in murine macrophages. We report that ACT induces COX-2 in a manner that absolutely requires the catalytic activity of this enzyme and Mac-1 expression dramatically enhanced the sensitivity of cells to ACT-dependent COX-2 induction. The mechanism of COX-2 induction by ACT utilizes the cAMP-PKA-CREB-dependent pathway. Finally, ACT and TLR2 or TLR4 act synergistically to increase COX-2 expression. These data suggest that ACT contributes significantly to the inflammatory response induced by B. pertussis infection by augmenting COX-2 expression and provides evidence against the concept that ACT functions exclusively via its inhibitory effects on phagocytic leucocytes.
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PMID:Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase-2 (COX-2) in murine macrophages and is facilitated by ACT interaction with CD11b/CD18 (Mac-1). 1792 97

To clarify the mechanisms of diarrheal disease induced by Aeromonas sobria, we examined whether prostaglandin E2 (PGE2) was involved in the intestinal secretory action of A. sobria hemolysin by use of a mouse intestinal loop model. The amount of PGE2 in jejunal fluid and the fluid accumulation ratio were directly related to the dose of hemolysin. The increase over time in the level of PGE2 was similar to that of the accumulated fluid. In addition, hemolysin-induced fluid secretion and PGE2 synthesis were inhibited by the selective cyclooxygenase 2 (COX-2) inhibitor NS-398 but not the COX-1 inhibitor SC-560. Western blot analysis revealed that hemolysin increased the COX-2 protein levels but reduced the COX-1 protein levels in mouse intestinal mucosa in vivo. These results suggest that PGE2 functions as an important mediator of diarrhea caused by hemolysin and that PGE2 is produced primarily through a COX-2-dependent mechanism. Subsequently, we examined the relationship between PGE2, cyclic AMP (cAMP), and cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels in mouse intestinal mucosa exposed to hemolysin. Hemolysin increased the levels of cAMP in the intestinal mucosa. NS-398 inhibited the increase in cAMP production, but SC-560 did not. In addition, H-89, a cAMP-dependent protein kinase A (PKA) inhibitor, and glibenclamide, a CFTR inhibitor, inhibited fluid accumulation. Taken together, these results indicate that hemolysin activates PGE2 production via COX-2 and that PGE2 stimulates cAMP production. cAMP then activates PKA, which in turn stimulates CFTR Cl- channels and finally leads to fluid accumulation in the intestines.
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PMID:Fluid secretion caused by aerolysin-like hemolysin of Aeromonas sobria in the intestines is due to stimulation of production of prostaglandin E2 via cyclooxygenase 2 by intestinal cells. 1808 11

The mRNA stabilizing factor HuR is involved in the posttranscriptional regulation of many genes, including that coding for cyclooxygenase 2 (COX-2). Employing RNA interference technology and actinomycin D experiments, we demonstrate that in human mesangial cells (hMC) the amplification of cytokine-induced COX-2 by angiotensin II (AngII) occurs via a HuR-mediated increase of mRNA stability. Using COX-2 promoter constructs with different portions of the 3' untranslated region of COX-2, we found that the increase in COX-2 mRNA stability is attributable to a distal class III type of AU-rich element (ARE). Likewise, the RNA immunoprecipitation assay showed AngII-induced binding of HuR to this ARE. Using the RNA pulldown assay, we demonstrate that the AngII-caused HuR assembly with COX-2 mRNA is found in free and cytoskeleton-bound polysomes indicative of an active RNP complex. Mechanistically, the increased HuR binding to COX-2-ARE by AngII is accompanied by increased nucleocytoplasmic HuR shuttling and depends on protein kinase Cdelta (PKCdelta), which physically interacts with nuclear HuR, thereby promoting its phosphorylation. Mapping of phosphorylation sites identified serines 221 and 318 as critical target sites for PKCdelta-triggered HuR phosphorylation and AngII-induced HuR export to the cytoplasm. Posttranslational modification of HuR by PKCdelta represents an important novel mode of HuR activation implied in renal COX-2 regulation.
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PMID:Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. 1828 62

Cathelicidin (hCAP-18/LL-37) and beta-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms.
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PMID:Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells. 1871 21

Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Coumarins have attracted intense interest in recent years because of their diverse pharmacological activities. This study examines the antioxidant coumarin 7,8-diacetoxy-4-methylcoumarin (DAMC) and its thiocoumarin derivative 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) for their effect on human non-small cell lung cancer A549 cells. Here we show that both DAMC and DAMTC not only inhibited cell proliferation, but also induced apoptosis with an IC(50) of 160 microg/ml as confirmed by morphological examination, annexin-V assay and flow cytometric analysis. Interestingly, it was observed that these two coumarin compounds exhibited little cytotoxicity towards peripheral blood mononuclear cells but induced apoptosis in malignant cells. DAMC/DAMTC treatment also resulted in pronounced release of apoptogenic cytochrome c from mitochondria to cytosol, alteration of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspase-9 and caspase-3. Although an increase in the levels of reactive oxygen species (ROS) was observed, pre-treatment with antioxidant showed no protective effect against DAMC/DAMTC-induced apoptosis. Results of present study suggest that downregulation of Bcl-xl, Cox-2 and mitogen activated protein kinase pathway and upregulation of p53, Akt and NF-kappaB pathway are involved in the underlying molecular mechanism of apoptosis induction by DAMC and DAMTC in A549 cells.
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PMID:Apoptogenic effect of 7,8-diacetoxy-4-methylcoumarin and 7,8-diacetoxy-4-methylthiocoumarin in human lung adenocarcinoma cell line: role of NF-kappaB, Akt, ROS and MAP kinase pathway. 1906 72

TCDD (dioxin) induces a rapid inflammatory response from 3T3-L1 adipocytes as judged by prominent induction of the mRNA expression of prostaglandin-endperoxide synthase 2 (Cox-2) along with other inflammation markers within 1 h. This action of TCDD is clearly antagonized by cell pretreatment with AACOCF3 (an inhibitor of cPLA2), nifedipine (a Ca(2+) channel blocker), or 3'-methyl-4'-nitroflavone (MNF), an antagonist of the Ah receptor (AhR), suggesting the possible involvement of the nongenomic pathway of action of TCDD as shown previously in MCF10A cells [Dong, B., and Matsumura, F. (2008) Mol. Pharmacol. 74 (1), 255-263]. This early inflammatory action of TCDD is clearly different from that mediated by its classical action pathway in that the former is mediated by protein kinases such as PKC, PKA, and tyrosine kinases, but not by ARNT. Furthermore, the former is not blocked by two "DRE-decoy" treatments. Such an inflammatory effect of TCDD on 3T3-L1 adipocyes persists at least for 5 days, when the affected adipocytes exhibit significant reduction in their adipocyte characteristics. To assess the cause for the long-lasting influence of this nongenomic action of TCDD, we tested the effects of AACOCF3, exogenous arachidonic acid (AA), and H89 (an inhibitor of PKA) on the 5 day action of TCDD. These agents clearly antagonized all the long-term actions of TCDD except that on CYP1A1 induction, indicating that the influence of the nongenomic action of TCDD lasts a long time in this cell material. One of the major factors mediating its long-lasting effects has been identified to be PKA.
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PMID:Significance of the nongenomic, inflammatory pathway in mediating the toxic action of TCDD to induce rapid and long-term cellular responses in 3T3-L1 adipocytes. 1906 10

Embryo-induced signaling pathways are considered to be important for initiation and sustenance of pregnancy. However many of these pathways remain to be deciphered in primates. In the present study, differential display RT-PCR was used to identify genes or gene fragments that are differentially expressed in endometrium of bonnet monkeys (Macaca radiata) on Day 6 of pregnancy. Of several fragments found to be differentially expressed, a fragment of 567 base pair (named GG1) was characterized in detail. GG1 was highly represented in endometrium of pregnant animals compared with that of nonpregnant animals. Sequencing analysis revealed homology of this fragment to exons 7, 8, 9, and 10 and surprisingly to intron 6 of cAMP-dependent protein kinase A (PKA) regulatory type I alpha (tissue-specific extinguisher 1) (PRKAR1A). The increased expression of this fragment in gestational endometrium was confirmed by quantitative PCR studies. Two transcripts of 3.0 kilobase (kb) and 1.5 kb were detected in Northern blot probed with labeled GG1. Protein expressions of alpha regulatory (PRKAR1A) and alpha catalytic (PRKCA) subunits of PKA were also higher in gestational endometrium compared with that in nongestational endometrium. Further in vitro studies using human endometrial explants demonstrated regulation of PRKAR1A (or GG1) and prostaglandin-endoperoxide synthase 2 or cyclooxygenase 2 (PTGS2) by estradiol. This is the first study to date on the differential expression of PKA in primate endometrium during early pregnancy and its in vitro regulation by estradiol.
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PMID:Expression of endometrial protein kinase a during early pregnancy in bonnet monkeys (Macaca radiata). 1968 37

The active form of the serine/threonine kinase cRaf-1 is upregulated postmortem in the brains of Alzheimer's disease (AD) patients and in transgenic mouse models of AD pathology. The persistent activation of cRaf-1 can activate the proinflammatory factor NFkappaB and consequently, upregulate the expression of several of its downstream factors such as the amyloid precursor protein (APP), Cox-2 and iNOS. These factors have been found upregulated in numerous neurodegenerative conditions including AD, epilepsy, brain trauma, and psychological stress. The Raf kinase inhibitors, GW5074 and ZM336372, are neuroprotective against many different neurotoxic insults in vitro, including the Abeta peptide, glutamate and glutathione depletion. Recently, we have reported that the multi-kinase and potent Raf inhibitor sorafenib reversed memory impairment and reduced the expression of APP, Cox-2, and iNOS in the brain of the transgenic mouse model of AD, APPswe. Similar improvement of behavioral outcome was attained after acute treatment with GW5074 in a mouse model of Huntington's disease. Several Raf inhibitors have been developed to treat aggressive forms of cancer showing an upregulation of Raf kinases. These Raf inhibitors offer a great promise as therapeutic tools against neurological disorders. The negative and positive aspects of these inhibitors as anti-neurodegenerative agents are discussed.
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PMID:Raf inhibitors as therapeutic agents against neurodegenerative diseases. 2020 22


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