Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Occlusive accelerated atherosclerosis of coronary grafts is the predominant factor that limits longevity of heart transplant recipients. This form of vascular disease affects both the large epicardial and the smaller intramyocardial vessels, leading to characteristic clinical presentation that necessitates the use of sophisticated techniques for their accurate detection. Accelerated atherosclerosis after transplantation is a multifactorial disease with many events contributing to its progression. The initial vascular injury associated with ischemia-reperfusion appears to aggravate preexisting conditions in the donor vasculature in addition to activation of new immunological and nonimmunological mechanisms. Throughout these events, the endothelium remains a primary target of cell- and humoral-mediated injury. Changes in the vascular intima leads to alterations in vascular smooth muscle cell (VSMC) physiology, resulting in VSMC phenotypic modulation with the orchestration of a broad spectrum of growth and inflammatory reactions, which might be a healing response to vascular injury. Endogenous nitric oxide (NO) pathways regulate a multiplicity of cellular mechanisms that play a major role in determining the structure and function of the vessel wall during normal conditions and during remodeling associated with accelerated atherosclerosis. Recently identified signaling pathways, including mitogen-activated protein kinase, cGMP-dependent protein kinase, phosphatidylinositol 3-kinase, and transcriptional events in which nuclear factor kappa B and activator protein 1 take part, can be associated with NO modulation of cell cycle perturbations and phenotypic alteration of VSMC during accelerated atherosclerosis. This article reviews recent progress covering the aforementioned matters. We start by summarizing the clincal aspects and pathogenesis of accelerated atherosclerosis associated with transplantation, including clinical presentation and detection. This summary is followed by a discussion of the multiple factors of the disease process, including immunological and nonimmunolgical contributions. The next section focuses on cellular responses of the VSMCs relevant to lesion formation, with special emphasis on classical and recent paradigms of phenotypic modulation of these cells. To examine the influence of NO on VSMC phenotypic modulation and consequent lesion development, we briefly overview characteristics of NO production in the normal coronary vascular bed and the changes in endogenous NO release and activity during atherosclerosis. This overview is followed by a section covering molecular mechanisms whereby NO regulates a range of signaling pathways, transcriptional events underlying cell cycle perturbation, and phenotypic alteration of VSMC in accelerated atherosclerosis.
Gen Pharmacol 2000 Feb
PMID:Transplant atherosclerosis: role of phenotypic modulation of vascular smooth muscle by nitric oxide. 1097 14

This study tests the hypothesis that insulin-like growth factor 1 (IGF-1)-induced vasodilation is due to the stimulation of tyrosine phosphatase. Rat aortic segments (endothelium intact) were placed in muscle baths for force measurement. Segments were contracted to serotonin [5-hydroxytyptamine (5-HT), 10(-7)-10(-5) M] before and after incubation with IGF-1 (10-100 nM; 90 min). IGF-1 caused a 20% inhibition of 5-HT-induced contractions. This inhibition was reversed by the tyrosine phosphatase inhibitors sodium orthovanadate and molybdate. Orthovanadate did not alter inhibitory properties of the calcium channel antagonist verapamil, suggesting that the phosphatase inhibitors were relatively specific. IGF-1-induced inhibition was not altered by blockade of nitric oxide synthase. Western blot analysis confirmed that the 5-HT-induced stimulation of tyrosine phosphorylation of the 42-kDa extracellular signal-regulated mitogen-activated protein kinase protein was reduced by IGF-1 (52% inhibition), an inhibition that was attenuated by orthovanadate. These data are consistent with the hypothesis that the vasodilator activity of IGF-1 is mediated by the activation of a tyrosine phosphatase.
Gen Pharmacol 2000 Feb
PMID:Insulin-like growth factor inhibits vascular contraction to 5-hydroxytryptamine: involvement of tyrosine phosphatase. 1097 21

Human cytomegalovirus infection of quiescent fibroblasts was found to induce a bi-phasic activation of mitogen-activated protein kinase (MAPK) kinase 1 and 2 (MKK1/2) and two of their downstream targets, extracellular signal regulated kinase 1 and 2 (ERK1/2), as determined by Western blot analysis using phospho-specific antibodies. Treatment of infected fibroblasts with U0126, a potent and specific inhibitor of MKK1/2 kinase activity, completely blocked ERK1/2 activation following HCMV infection without affecting cell viability. Anti-viral studies demonstrate that in the presence of U0126, viral titres are reduced and viral DNA replication is inhibited. In addition, protein levels of two viral early genes that are required for viral DNA replication, UL44 and UL84, are significantly decreased in the presence of U0126. These results suggest that HCMV-mediated activation of MKK1/2 kinase activity enhances virus infectivity by ensuring timely initiation of viral DNA replication, possibly by regulating early gene expression.
J Gen Virol 2001 Mar
PMID:The role of MKK1/2 kinase activity in human cytomegalovirus infection. 1117 89

Hwansodan has been used as a prescription for senile and vascular dementia in Oriental medicine. We investigated the neuroprotective effects of Hwansodan water extract on the apoptotic death of PC12 cells by serum deprivation. Hwansodan significantly rescued PC12 cells from apoptotic death by serum deprivation in a dose-dependent manner. The nuclear staining of PC12 cells clearly showed that Hwansodan attenuated nuclear condensation and fragmentation, which represents typical neuronal apoptotic characteristics. Hwansodan also prevents DNA fragmentation and caspase-3-like protease activation in serum-deprived PC12 cells and induces the tyrosine phosphorylation of proteins around 44 kDa, which was identified as ERK1 with electrophoretic gel mobility shift by Western blot. In addition, MEK inhibitor PD98059 and Ras inactivator, alpha-hydroxyfarnesylphosphonic acid and mevastatin, attenuated the neuroprotective effects of Hwansodan in serum-deprived PC12 cells. These results indicate that Ras/MEK/ERK signaling pathway plays a role in neuroprotective effects of Hwansodan in serum-deprived PC12 cells.
Gen Pharmacol 2000 Apr
PMID:Hwansodan protects PC12 cells against serum-deprivation-induced apoptosis via a mechanism involving Ras and mitogen-activated protein (MAP) kinase pathway. 1128 16

The possible effects of zinc in the modulation of the activity of glycolytic enzymes phosphofructokinase and pyruvate kinase through tyrosine kinase-mediated signal transduction in isolated digestive gland cells from mussels (Mytilus galloprovincialis Lam.) were investigated. Addition of micromolar concentrations of zinc resulted in both time- and concentration-dependent stimulation of glycolytic enzyme activities similar to those previously observed with insulin; however, zinc pretreatment prevented the glycolytic effect of insulin in mussel cells. The insulin-like effect of zinc was mediated by increased tyrosine phosphorylation of multiple proteins, as demonstrated by Western blotting with antiphosphotyrosine antibodies. The pattern of zinc-induced phosphorylation resembled that induced by insulin. Moreover, both zinc and insulin induced activation of mitogen activated protein kinases (MAPKs); however, whereas zinc gave a clear effect on the stress-activated p-38 MAPK, insulin activated extracellular-activated MAPK (ERK2) and inhibited p-38. The results demonstrate that zinc can act as a physiological regulator of tyrosine kinase-mediated cell signaling in mussel digestive gland cells, in particular at the level of MAPK activation. Activation of p-38 by zinc may be a key step in prevention of the glycolytic effect of insulin in mussel cells. These data underline the importance of cross talk between different MAPKs in determination of the response to extracellular stimuli in marine invertebrate cells.
Gen Comp Endocrinol 2001 Apr
PMID:Insulin-like effect of zinc in mytilus digestive gland cells: modulation of tyrosine kinase-mediated cell signaling. 1135 54

Mistletoe lectins are of high biological activity and exert cytotoxic effects. We have previously shown that Korean mistletoe, Viscum album var. coloratum, lectin-II specifically induces apoptotic cell death in cancer cells, not normal lymphocytes. The destructive mechanism by mistletoe lectins on tumor cells was mediated by activation of c-JUN N-terminal kinase (JNK)/stress-activated protein kinase. Herein, we investigated the involvement of caspase cascade and its proteolytic cleavage effects on biosubstrates of human myeloleukemic U937 cells by D-galactoside and N-acetyl-galactosamine-specific Korean mistletoe lectin-II. Mistletoe lectin-II induced ladder pattern DNA fragmentation and activation of caspase-3, -8, and -9 of U937 cells, but not caspase-1 protease, in a time- and dose-dependent manner. Consistent with catalytic activation of protease, both poly(ADP-ribose) polymerase (PARP) and protein kinase C-delta (PKC-delta) are also cleaved in mistletoe lectin-II-treated U937 cells. An inhibitor of caspase-3-like protease, DEVD-CHO peptide, significantly inhibited mistletoe lectin-II-induced apoptosis, PARP cleavage, and fragmentation of DNA. These results provide the evidence that Korean mistletoe lectin-II induces apoptotic death of U937 cells via activation of caspase cascades.
Gen Pharmacol 2000 May
PMID:Activation of caspase cascades in Korean mistletoe (Viscum album var. coloratum) lectin-II-induced apoptosis of human myeloleukemic U937 cells. 1136 91

Previously, we observed that 70-kDa ribosomal protein S6 kinase (p70(s6k)) plays an essential role during the early phase of oocyte maturation in Rana dybowskii. To investigate further the early signal transduction components involved in this process, the possible role of phosphatidylinositol-3 kinase (PI3 kinase) during oocyte maturation was examined. Progesterone-induced oocyte maturation was significantly inhibited by wortmannin and LY294002, specific inhibitors of PI3 kinase. In contrast, protein kinase C activator 12-0-tetradecanoylphorbol-13-acetate-induced oocyte maturation was not inhibited by wortmannin. Protein synthesis was also significantly suppressed by wortmannin treatment during oocyte maturation. Moreover, PI3 kinase inhibitor suppressed progesterone-induced phosphorylation of S6 kinase in a dose-dependent manner. Likewise, PI3 kinase inhibitors significantly inhibited the phosphorylation of mitogen-activated protein (MAP) kinase which was increased during oocyte maturation. Finally, progesterone-induced H1 kinase activity was also inhibited by PI3 kinase inhibitors in a dose-dependent manner. Taken together, these results suggest that PI3 kinase is an initial component of the signal transduction pathway which precedes p70(s6k), MAP kinase, and MPF production during progesterone-induced maturation of amphibian oocyte.
Gen Comp Endocrinol 2002 Apr
PMID:Involvement of phosphatidylinositol 3 kinase in the progesterone-induced oocyte maturation in Rana dybowskii. 1203 Jul 77

Japanese encephalitis virus (JEV) infection generates a rapid inflammatory response including peripheral neutrophil leucocytosis and infiltration of neutrophils into extraneural tissue. The level of inflammation correlates well with the clinical outcome in Japanese encephalitis patients. Non-steroidal anti-inflammatory drugs (NSAIDs), used medicinally for their analgesic and anti-inflammatory properties, are being considered for prevention of cardiovascular disease and cancer, as well as for treatment of human immunodeficiency virus infection. Apart from their ability to inhibit prostaglandin synthesis, the mechanisms underlying the beneficial therapeutic effects are largely unknown. We used aspirin, indomethacin and sodium salicylate to study the role of NSAIDs in JEV propagation in vitro. We found that NSAIDs suppressed JEV propagation in neuronal and non-neuronal cells. Blockade of cyclooxygenase activity by NSAIDs caused decreased production of free radicals and prostaglandins. However, these pharmacological alterations did not seem to correlate well with the antiviral effects. When cells were treated with the mitogen-activated protein kinase (MAPK) inhibitors PD 98059 and SB 203580, salicylate lost its antiviral effect. The activation of MAPK by anisomycin mimicked the action of salicylate in suppressing JEV-induced cytotoxicity. The decreased phosphorylation of extracellular signal-regulated kinase (ERK) was induced by JEV infection and the decrease in ERK was reversed by salicylate. Our data suggest that the signalling pathways of MAPK play a role in the antiviral action of salicylate.
J Gen Virol 2002 Aug
PMID:Suppression of Japanese encephalitis virus infection by non-steroidal anti-inflammatory drugs. 1212 53

Olfactory receptor neurons (ORNs) were infected upon intranasal inoculation with the R404BP strain of neurovirulent influenza A virus. Virus-infected neurons and a small fraction of neighbouring uninfected neurons displayed apoptotic neurodegeneration substantiated by the immunohistochemistry for activated caspase-3 molecules and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling method. However, virus infection was restricted within the peripheral neuroepithelium and all mice survived the infection. Virus-infected ORNs revealed upregulated expression of the Fas ligand molecules, activating the c-Jun N-terminal kinase signal transduction pathway. In addition, Iba1-expressing activated microglia/macrophages appeared to partake in phagocytic activities, eventually clearing apoptotic bodies. These results raise the possibility that induction of apoptosis in olfactory receptor neurons at an early stage of infection may provide protective effects against invasion of the neurovirulent virus from the peripheral to the CNS.
J Gen Virol 2002 Sep
PMID:Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis. 1218 63

The Wis1-Sty1 mitogen-activated protein (MAP) kinase cascade is one of the major signaling systems involved in a wide range of stress responses in Schizosaccharomyces pombe. It is known that Deltawis1 and Deltasty1 mutants exhibit highly pleiotropic phenotypes, including a phenotype of temperature sensitivity for growth. In this study, we screened multicopy suppressor genes that allow both the Deltawis1 and Deltasty1 mutants to grow simultaneously at a non-permissive temperature, 37 degrees C. Two such multicopy suppressors were cloned and characterized as sds23(+) and hxk2(+) genes. The former is known to specify a protein that functions as a multicopy suppressor for mutations of the PP1 protein phosphatase and the 20S cyclosome/anaphase-promoting complex (APC), and the latter encodes hexokinase 2. It was revealed that the multicopy sds231 gene restored a defect in the mating efficiency caused by the Deltawis1 and Deltasty1 mutations, whereas the multicopy hxk2(+) gene suppressed a phenotype of heat-shock sensitivity for growth of these mutant cells. These findings are discussed with special reference to the Wis1-Sty1 MAP kinase signaling pathway in S. pombe.
J Gen Appl Microbiol 1997 Aug
PMID:Characterization of multicopy suppressor genes that complement a defect in the Wis1-Sty1 MAP kinase cascade involved in stress responses in Schizosaccharomyces pombe. 1250 21


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