Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) stimulates migration of B cells and affects B cell immunoglobulin production. However, the molecular mechanisms by which MIP-1alpha modulates these biologic effects have not been completely defined. Previously, we demonstrated that treatment of B cells with MIP-1alpha induced the transcription factor, nuclear factor (NF)-kappaB, to bind to DNA, concomitant with the degradation of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB activation. Here, we report that MIP-1alpha treatment of tonsil B cells induced IkappaB gene expression that was dependent on MIP-1alpha-mediated activation of a pathway(s) involving NF-kappaB and phosphatidylinositol-3 kinase (PI3K). The NF-kappaB pathway is understood to be controlled in an autoregulatory fashion, so expression of IkappaB is thought to provide a means by which B cells modulate this pathway after stimulation with MIP-1alpha. Although the idea of NF-kappaB autoregulation is not novel, this is the first report to suggest the regulation of B cell gene expression by MIP-1alpha. In addition, we observed the activation of Jun N-terminal kinase (JNK) and p38 mitogenic-activated protein kinase (MAPK), but not extracellular signal-related kinase (ERK) in response to MIP-1alpha. Although p38 and NF-kappaB activity were both necessary for B cell migration, IkappaB gene expression was not affected by p38 inhibition, suggesting that p38 is involved in a separate MIP-1alpha-mediated signal transduction pathway.
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PMID:MIP-1alpha induces differential MAP kinase activation and IkappaB gene expression in human B lymphocytes. 1529 51

Aerobic cells adjust the expression of antioxidant enzymes to maintain reactive oxygen species within tolerable levels. In addition, phosphatidylinositol 3 kinase (PI3K) and its downstream protein kinase effector Akt adapt cells to survive in the presence of oxidative stress. Here we provide evidence for an association between these two defense systems via transcriptional regulation of Cu/Zn-superoxide dismutase (Cu/Zn-SOD). PC12 pheochromocytoma cells expressing active Akt1 exhibit lower ROS levels in response to hydrogen peroxide, as determined with the superoxide-sensitive probe hydroethidine. Transfection of constitutive or 4-hydroxytamoxifen-inducible versions of Akt1 results in higher messenger RNA and protein levels of Cu/Zn-SOD. Luciferase reporter constructs, carrying different length fragments of the human sod1 gene promoter, have identified a region between -552 and -355 that is targeted by PI3K and Akt and that contains a putative site of regulation by nuclear factor-kappaB (NF-kappaB). Nerve growth factor (NGF) and Akt augment the transactivating activity and produce higher nuclear levels of p65-NF-kappaB. Electrophoretic mobility shift assays indicate that the putative NF-kappaB regulatory sequence binds p65-NF-kappaB more efficiently in nuclear extracts from these cells. A dominant-negative mutant of IkappaBalpha further demonstrates that the PI3K/Akt axis targets the sod1 promoter at the level of the newly characterized NF-kappaB site. These results illustrate a new mechanism by which the PI3K/Akt pathway protects cells against oxidative stress, involving the upregulation of Cu/Zn-SOD gene expression, and the results identify NF-kappaB as a key mediator in the regulation of this gene.
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PMID:Regulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol 3 kinase/Akt pathway and nuclear factor-kappaB. 1531 58

Infection with lesion-derived Leishmania mexicana amastigotes inhibited LPS-induced IL-12 production by mouse bone marrow-derived macrophages. This effect was associated with expression of cysteine peptidase B (CPB) because amastigotes of CPB deletion mutants had limited ability to inhibit IL-12 production, whereas preincubation of cells with a CPB inhibitor, cathepsin inhibitor IV, was able to suppress the effect of wild-type amastigotes. Infection with wild-type amastigotes resulted in a time-dependent proteolytic degradation of IkappaBalpha and IkappaBbeta and the related protein NF-kappaB. This effect did not occur with amastigotes of CPB deletion mutants or wild-type promastigotes, which do not express detectable CPB. NF-kappaB DNA binding was also inhibited by amastigote infection, although nuclear translocation of cleaved fragments of p65 NF-kappaB was still observed. Cysteine peptidase inhibitors prevented IkappaBalpha, IkappaBbeta, and NF-kappaB degradation induced by amastigotes, and recombinant CPB2.8, an amastigote-specific isoenzyme of CPB, was shown to degrade GST-IkappaBalpha in vitro. LPS-mediated IkappaBalpha and IkappaBbeta degradation was not affected by these inhibitors, confirming that the site of degradation of IkappaBalpha, IkappaBbeta, and NF-kappaB by the amastigotes was not receptor-driven, proteosomal-mediated cleavage. Infection of bone marrow macrophages with amastigotes resulted in cleavage of JNK and ERK, but not p38 MAPK, whereas preincubation with a cysteine peptidase inhibitor prevented degradation of these proteins, but did not result in enhanced protein kinase activation. Collectively, our results suggest that the amastigote-specific cysteine peptidases of L. mexicana are central to the ability of the parasite to modulate signaling via NF-kappaB and consequently inhibit IL-12 production.
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PMID:Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway. 1532 92

We demonstrated previously that 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), an activator of soluble guanylate cyclase (sGC), induces cyclooxygenase-2 (COX-2) expression via cGMP- and p44/42 mitogen-activated protein kinase-dependent pathways in human pulmonary epithelial A549 cells. In this study, we explore the role of Ras, phosphoinositide-3-OH-kinase (PI3K), Akt, and transcription factor nuclear factor-kappaB (NF-kappaB) in YC-1-induced COX-2 expression in A549 cells. A Ras inhibitor (manumycin A), a PI3K inhibitor (wortmannin), an Akt inhibitor (1l-6-Hydroxymethyl-chiro-inositol2-[(R)-2-O-methyl-3-O-octadecylcarbonate]), and an NF-kappaB inhibitor [pyrrolidine dithiocarbamate (PDTC)] all reduced YC-1-induced COX-2 expression. The YC-1-induced increase in COX activity was also blocked by manumycin A, wortmannin, PDTC, and the dominant-negative mutants for Ras (RasN17), Akt (Akt DN), and IkappaBalpha (IkappaBalphaM). The YC-1-induced increase in Ras activity was inhibited by an sGC inhibitor [1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ)], a protein kinase G (PKG) inhibitor [1-oxo-9.12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823)], and manumycin A. YC-1-induced Akt activation was also inhibited by ODQ, KT-5823, manumycin A, and wortmannin. YC-1 caused the formation of an NF-kappaB-specific DNA-protein complex and an increase in kappaB-luciferase activity. YC-1-induced kappaB-luciferase activity was inhibited by ODQ, KT-5823, manumycin A, wortmannin, an Akt inhibitor, PDTC, RasN17, Akt DN, and IkappaBalphaM. Likewise, YC-1-induced IKKalpha/beta activation was inhibited by ODQ, KT-5823, manumycin A, wortmannin, and an Akt inhibitor. Furthermore, YC-1-induced COX-2 promoter activity was inhibited by manumycin A, RasN17, Akt DN, PDTC, and IkappaBalphaM. Taken together, these results indicate that YC-1 might activate the sGC/cGMP/PKG pathway to induce Ras and PI3K/Akt activation, which in turn initiates IKKalpha/beta and NF-kappaB activation and finally induces COX-2 expression in A549 cells.
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PMID:YC-1-induced cyclooxygenase-2 expression is mediated by cGMP-dependent activations of Ras, phosphoinositide-3-OH-kinase, Akt, and nuclear factor-kappaB in human pulmonary epithelial cells. 1532 48

The mechanism by which the tumour product proteolysis-inducing factor (PIF) induced increased expression of the ubiquitin-proteasome proteolytic pathway was studied in C2C12 murine myotubes. PIF directly increased total protein breakdown at concentrations between 4 and 16 nM, and the effect was attenuated by eicosapentaenoic acid (EPA) and the 12/15-lipoxygenase inhibitor 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504). PIF induced an increased expression of mRNA for proteasome alpha (C2) and beta (C5) subunits over the same concentration range as that inducing protein degradation and with a maximal effect 4 h after PIF addition. The effect was attenuated by both EPA and CV-6504, suggesting the role of a lipoxygenase metabolite in the increased gene transcription. 15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE], an intermediate in intracellular signalling by PIF was shown to activate protein kinase Calpha(PKC) over the same concentration range as that inducing proteasome expression and both effects were attenuated by calphostin C, a highly specific inhibitor of PKC. 15(S)-HETE induced phosphorylation and degradation of IkappaBalpha at the same concentrations as those inducing 20S proteasome expression, and this effect was attenuated by calphostin C, suggesting the mediation of PKC. These results suggest potential control points in proteasome activation that could be useful for therapeutic intervention.
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PMID:Signalling pathways in the induction of proteasome expression by proteolysis-inducing factor in murine myotubes. 1545 Oct 26

In this study, we investigated the signaling pathways involved in bradykinin (BK)-induced NF-kappaB activation and cyclooxygenase-2 (COX-2) expression in human airway epithelial cells (A549). BK caused concentration- and time-dependent increase in COX-2 expression, which was attenuated by a selective B2 BK receptor antagonist (HOE140), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), an NF-kappaB inhibitor (pyrrolidine dithiocarbate), and an IkappaB protease inhibitor (L-1-tosylamido-2-phenylethyl chloromethyl ketone). The B1 BK receptor antagonist (Lys-(Leu8)des-Arg9-BK) had no effect on COX-2 induction by BK. BK-induced increase in COX-2-luciferase activity was inhibited by cells transfected with the kappaB site deletion of COX-2 construct. BK-induced Ras activation was inhibited by manumycin A. Raf-1 phosphorylation at Ser338 by BK was inhibited by manumycin A and GW 5074. BK-induced ERK activation was inhibited by HOE140, manumycin A, GW 5074, and PD 098059. Stimulation of cells with BK activated IkappaB kinase alphabeta (IKKalphabeta), IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 and p50 translocation from the cytosol to the nucleus, the formation of an NF-kappaB-specific DNA-protein complex, and kappaB-luciferase activity. BK-mediated increase in IKKalphabeta activity and formation of the NF-kappaB-specific DNA-protein complex were inhibited by HOE140, a Ras dominant-negative mutant (RasN17), manumycin A, GW 5074, and PD 098059. Our results demonstrated for the first time that BK, acting through B2 BK receptor, induces activation of the Ras/Raf-1/ERK pathway, which in turn initiates IKKalphabeta and NF-kappaB activation, and ultimately induces COX-2 expression in human airway epithelial cell line (A549).
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PMID:Bradykinin B2 receptor mediates NF-kappaB activation and cyclooxygenase-2 expression via the Ras/Raf-1/ERK pathway in human airway epithelial cells. 1547 67

In HSV-1 (herpes simplex virus 1)-infected cells, the U(L)41 gene product carried with the virion has been shown to mediate the degradation of mRNA, leading to the shut-off of cellular protein synthesis. Analysis of the RNAs accumulating in cells infected with HSV-1 revealed the accumulation of RNAs encoding numerous cellular proteins both associated with and independent of activation of the NF-kappaB (nuclear factor kappaB) pathway. Studies on the activation of NF-kappaB and the expression and fate of selected cellular transcripts revealed the following. (i) In HSV-1-infected cells, NF-kappaB is activated by activated protein kinase R. Furthermore, the blockade of NF-kappaB translocation by suppression of protein kinase R activation does not render the cell more susceptible to apoptosis induced by viral gene expression. (ii) A number of mRNA up-regulated in infected cells [e.g. IkappaBalpha (inhibitory kappaBalpha), the immediate-early response protein IEX-1 and c-fos] are partially degraded and not translated. The degradation is U(L)41-dependent and results in deadenylation, endonucleolytic cleavage and 3'-5' degradation. The 5'-portion resulting from the endonucleolytic cleavage tends to linger in the infected cells. To date, the RNAs processed in this manner contained ARE (AU-rich elements) in their 3'-untranslated domains. RNAs lacking ARE were expressed and not degraded in this manner. (iii) Tristetraprolin and T-cell internal antigen-1, cellular proteins involved in the degradation of ARE-containing RNAs, are induced and activated in infected cells and tristetraprolin interacts physically with the U(L)41 protein.
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PMID:Post-transcriptional processing of cellular RNAs in herpes simplex virus-infected cells. 1549 91

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Infection by herpes simplex virus type 1 (HSV-1) induces a persistent nuclear translocation of NFkappaB. To identify upstream effectors of NFkappaB and their effect on virus replication, we employed mouse embryo fibroblast (MEF)-derived cell lines with deletions of either IKK1 or IKK2, the catalytic subunits of the IkappaB kinase (IKK) complex. Infected MEFs were assayed for virus yield, loss of IkappaBalpha, nuclear translocation of p65, and NFkappaB DNA-binding activity. Absence of either IKK1 or IKK2 resulted in an 86 to 94% loss of virus yield compared to that of normal MEFs, little or no loss of IkappaBalpha, and greatly reduced NFkappaB nuclear translocation. Consistent with reduced virus yield, accumulation of the late proteins VP16 and gC was severely depressed. Infection of normal MEFs, Hep2, or A549 cells with an adenovirus vector expressing a dominant-negative (DN) IkappaBalpha, followed by superinfection with HSV, resulted in a 98% drop in virus yield. These results indicate that the IKK-IkappaB-p65 pathway activates NFkappaB after virus infection. Analysis of NFkappaB activation and virus replication in control and double-stranded RNA-activated protein kinase-null MEFs indicated that this kinase plays no role in the NFkappaB activation pathway. Finally, in cells where NFkappaB was blocked because of DNIkappaB expression, HSV failed to suppress two markers of apoptosis, cell surface Annexin V staining and PARP cleavage. These results support a model in which activation of NFkappaB promotes efficient replication by HSV, at least in part by suppressing a host innate response to virus infection.
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PMID:Efficient replication by herpes simplex virus type 1 involves activation of the IkappaB kinase-IkappaB-p65 pathway. 1556 69

In this study, we investigated the signaling pathway involved in cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in human pulmonary epithelial cells (A549). PMA-induced COX-2 expression was attenuated by PKC inhibitors (Go 6976 and Ro 31-8220), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), and an NF-kappaB inhibitor (PDTC), but not by a tyrosine kinase inhibitor (genistein) or a p38 MAPK inhibitor (SB 203580). PMA also caused the activation of Ras, Raf-1, and ERK1/2. PMA-induced activation of Ras and Raf-1 was inhibited by Ro 31-8220 and manumycin A. PMA-mediated activation of ERK1/2 was inhibited by Ro 31-8220, manumycin A, GW 5074, and PD 098059. Stimulation of cells with PMA caused IkappaBalpha phosphorylation, IkappaBalpha degradation, and the formation of a NF-kappaB-specific DNA-protein complex. The PMA-mediated increase in kappaB-luciferase activity was inhibited by Ro 31-8220, manumycin A, GW5074, PD 098059, and PDTC. Taken together, these results indicate that PMA might activate PKC to elicit activation of the Ras/Raf-1/ERK1/2 pathway, which in turn initiates NF-kappaB activation, and finally induces COX-2 expression and PGE2 release in A549 cells.
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PMID:Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways. 1556 61


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