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)

Urokinase-type plasminogen (uPA) activator regulates a variety of processes, including morphogenesis, cell differentiation, migration, and invasion. In previous studies, we demonstrated that uPA levels are significantly higher in anaplastic astrocytoma and glioblastoma than in low-grade glioma and normal brain tissue. In the present study, our goal was to determine whether the increase in uPA production in higher-grade gliomas is caused by an increase in mRNA stability or increased transcription of the gene in three human glioma cell lines of various grades (H4, SW1783, UWR3). The half-life of uPA mRNA was about 14 h in UWR3 and 8 h in SW1783 cells. In transient transfection studies of the wild-type -2109-bp human uPA promoter in the different grades of cell lines, the uPA promoter activity was increased two-fold in SW1783, anaplastic astrocytoma cells and six-fold in UWR3 glioblastoma cells, as compared with the uPA promoter activity in low-grade H4 cells. Using human uPA promoter chloramphenicol acetyl transferase (CAT) constructs with mutations of the AP-1 element at -1967 or the PEA-3 cis element at -1973, the activity of the uPA promoter was decreased 4-fold to 10-fold in all three human glioma cell lines. In transient transfection assays, the uPA promoter was stimulated 2.2-fold in UWR3 and SW1783 cells and 3.7-fold in H4 cells in response to phorbol-12-myristat-13-acetate. We further studied the activation and inhibition of uPA promoter by co-expression of a transactivation domain lacking c-jun: a dominant negative ERK1 and ERK2 mutant and a dominant negative c-raf in glioblastoma cell line showed repressed uPA promoter activity compared with the effect of the empty expression vector. We conclude from our findings that increased transcription is the more likely mechanism underlying the increase in uPA production in high-grade gliomas.
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PMID:Regulation of the uPA gene in various grades of human glioma cells. 1111 41

We reported previously that the production of urokinase-type plasminogen activator receptor (uPAR) protein is greater in high-grade glioblastomas than in low-grade gliomas. Transcriptional activation of the uPAR gene or increased stability of the uPAR mRNA that encodes this protein could cause the increased production of this protein in cell lines of different grades of gliomas. We found similar half-life of uPAR mRNA of 10-12 h in glioblastoma multiforme (UWR3) and anaplastic astrocytoma (SW1783) cells. However, the human uPAR promoter was up-regulated 6-8-fold in SW1783 cells and 11-13-fold in UWR3 cells as compared with its activity in low-grade gliomas, a finding that correlates well with previous findings of increases in uPAR mRNA and protein levels in higher-grade gliomas. uPAR mRNA level was increased 11-fold over a 24-h period in low-grade glioma cell lines after treatment with phorbol myristate acetate. The region spanning -144 to -123 bp of the human uPAR promoter that contains the Sp-1 site and a PEA-3 element and an AP-1 site at -184 plays major roles in uPAR promoter activity in glioblastoma cells. Specific antibodies used in an electrophoretic mobility shift assay identified fra-1, fra-2, Jun D, and c-Jun proteins in the nuclear protein complex that bind a 51-mer containing the AP-1 consensus sequence at -184 and its flanking sequences in the uPAR promoter. We further studied the inhibition of uPAR promoter by coexpression of a transactivation domain lacking C-Jun; a dominant-negative ERK1 and ERK2 mutant and a dominant-negative C-raf in glioblastoma cell lines showed the repressed uPAR promoter activity compared with the effect of the empty expression vector. We conclude from our findings that increased transcription is the more likely mechanism underlying the increase in uPAR production in high-grade gliomas.
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PMID:Regulation of the urokinase-type plasminogen activator receptor gene in different grades of human glioma cell lines. 1123 78

Synovial fluid basic calcium phosphate (BCP) crystals are common in osteoarthritis and are associated with severe degenerative arthropathy. Besides stimulating synovial fibroblast-like cells to proliferate, BCP crystals are a potent inducer of human matrix metalloproteinases (hMMPs), which can speed up the articular joint tissue degeneration of osteoarthritis patients. Here, we report that transfections with hMMP1 luciferase reporter plasmids in fibroblast-like synoviocytes revealed that the induction of hMMP1 promoter by BCP crystals was mainly mediated through the -72AP-1 element. Elimination of the -72AP-1 element either by mutation or deletion abolished the induction of hMMP1 promoter activity by BCP crystals almost completely. Interestingly, a mutation at the -88PEA-3 site also abolished the induction of hMMP1 promoter. Further mutation at the -181AP-1 site resumed the induction, indicating that the -181AP-1 element had an effect opposite to the -72AP-1 element. The effect of -181AP-1 could be inactivated either by a mutation at this -181AP-1 site or by the -88PEA-3 element. In addition, dominant negative Ras, Raf, and MEK1/2 could block the induction of hMMP1, and a MEK1/2-specific inhibitor (UO126) could block the induction of hMMP1 and c-Fos by BCP crystals. Taken together, these data indicate that multiple elements, including at least AP-1 and PEA-3, are involved in the induction of hMMP1 gene expression by BCP crystals and that the induction follows the Ras/MAPK/c-Fos/AP-1/MMP1 signaling pathway.
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PMID:Basic calcium phosphate crystals induce matrix metalloproteinase-1 through the Ras/mitogen-activated protein kinase/c-Fos/AP-1/metalloproteinase 1 pathway. Involvement of transcription factor binding sites AP-1 and PEA-3. 1168 65

Although inhibition of Na+/H+ exchanger isoform 1 (NHE-1) reduces cardiomyocyte hypertrophy, the mechanisms underlying this effect are not known. Recent evidence suggests that this may be associated with improved mitochondrial function. To understand the mechanistic bases for mitochondrial involvement in the antihypertrophic effect of NHE-1 inhibition, we examined the effect of the NHE-1-specific inhibitor N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD87580; 5 microM) on the hypertrophic phenotype, mitogen-activated protein kinase (MAPK) activity, mitochondrial membrane potential (Deltapsim), permeability transition (MPT) pore opening, and superoxide generation in phenylephrine (PE)-treated neonatal rat cardiomyocytes. EMD significantly suppressed markers of cell hypertrophy, including cell surface area and gene expression of atrial natriuretic peptide and alpha-skeletal actin. EMD inhibited the PE-induced MPT pore opening, prevented the loss in Deltapsim, and attenuated superoxide generation induced by PE. Moreover, the activation of p38 MAPK (p38) and extracellular signal-regulated kinase (ERK) 1/2 MAPKs induced by PE was significantly attenuated in the presence of EMD as well as the antioxidant catalase. To examine the role of MPT and mitochondrial Ca2+ uniport in parallel with EMD, the effects of cyclosporin A (0.2 microM) and ruthenium red (10 microM) were evaluated. Both agents significantly attenuated PE-induced hypertrophy and inhibited both mitochondrial dysfunction and p38 and ERK1/2 MAPK activation. Our results suggest a novel mechanism for attenuation of the hypertrophic phenotype by NHE-1 inhibition that is mediated by a reduction in PE-induced MAPK activation and superoxide production secondary to improved mitochondrial integrity.
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PMID:Antihypertrophic effect of Na+/H+ exchanger isoform 1 inhibition is mediated by reduced mitogen-activated protein kinase activation secondary to improved mitochondrial integrity and decreased generation of mitochondrial-derived reactive oxygen species. 1651 48

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by slowly progressive skeletal muscle weakness in a humero-peroneal distribution, early contractures and prominent cardiomyopathy with conduction block. Mutations in EMD, encoding emerin, and LMNA, encoding A-type lamins, respectively, cause X-linked and autosomal dominant EDMD. Emerin and A-type lamins are proteins of the inner membrane of the nuclear envelope. Whereas the genetic cause of EDMD has been described and the proteins well characterized, little is known on how abnormalities in nuclear envelope proteins cause striated muscle disease. In this study, we analyzed genome-wide expression profiles in hearts from Emd knockout mice, a model of X-linked EDMD, using Affymetrix GeneChips. This analysis showed a molecular signature similar to that we previously described in hearts from Lmna H222P knock-in mice, a model of autosomal dominant EDMD. There was a common activation of the ERK1/2 branch of the mitogen-activated protein kinase (MAPK) pathway in both murine models, as well as activation of downstream targets implicated in the pathogenesis of cardiomyopathy. Activation of MAPK signaling appears to be a cornerstone in the development of heart disease in both X-linked and autosomal dominant EDMD.
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PMID:Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy. 1756 79

The possibility of a direct mitochondrial action of Na(+)/H(+) exchanger-1 (NHE-1) inhibitors decreasing reactive oxygen species (ROS) production was assessed in cat myocardium. Angiotensin II and endothelin-1 induced an NADPH oxidase (NOX)-dependent increase in anion superoxide (O(2)(-)) production detected by chemiluminescence. Three different NHE-1 inhibitors [cariporide, BIIB-723, and EMD-87580] with no ROS scavenger activity prevented this increase. The mitochondria appeared to be the source of the NOX-dependent ROS released by the "ROS-induced ROS release mechanism" that was blunted by the mitochondrial ATP-sensitive potassium channel blockers 5-hydroxydecanoate and glibenclamide, inhibition of complex I of the electron transport chain with rotenone, and inhibition of the permeability transition pore (MPTP) by cyclosporin A. Cariporide also prevented O(2)(-) production induced by the opening of mK(ATP) with diazoxide. Ca(2+)-induced swelling was evaluated in isolated mitochondria as an indicator of MPTP formation. Cariporide decreased mitochondrial swelling to the same extent as cyclosporin A and bongkrekic acid, confirming its direct mitochondrial action. Increased O(2)(-) production, as expected, stimulated ERK1/2 and p90 ribosomal S6 kinase phosphorylation. This was also prevented by cariporide, giving additional support to the existence of a direct mitochondrial action of NHE-1 inhibitors in preventing ROS release. In conclusion, we report a mitochondrial action of NHE-1 inhibitors that should lead us to revisit or reinterpret previous landmark observations about their beneficial effect in several cardiac diseases, such as ischemia-reperfusion injury and cardiac hypertrophy and failure. Further studies are needed to clarify the precise mechanism and site of action of these drugs in blunting MPTP formation and ROS release.
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PMID:Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. 1880 63

Preclinical studies have shown the potential antitumour efficacy of monoclonal antibodies (MAbs) directed to the epidermal growth factor receptor (EGFR). In this report, we investigated the cytotoxic effects of the MAb matuzumab (EMD 72000) towards A431 cells and compared it to cetuximab. While cetuximab induced cell cycle arrest and inhibited A431 cell proliferation, matuzumab did not. Both MAbs inhibited growth factor induced EGFR, HER2 and AKT phosphorylation; however, only cetuximab inhibited ERK 1/2 phosphorylation. Taken together, the data indicate that each antibody may elicit different responses on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival. When combined, MAbs synergistically inhibited cell proliferation and induced EGFR down-regulation with a strong inhibition of ERK1/2 and AKT phosphorylation. In addition, both MAbs efficiently inhibited VEGF expression and induced ADCC, highlighting their therapeutic potential in vivo when used either as a single agent or in combination.
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PMID:Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathway. 1916 13

Infection of a cell by lentiviruses, such as human immunodeficiency virus type 1 or feline immunodeficiency virus, results in the formation of a reverse transcription complex, the pre-integration complex (PIC), where viral DNA is synthesized. In non-dividing cells, efficient nuclear translocation of the PIC requires the presence of the inner nuclear lamina protein emerin (EMD). Here, we demonstrate that EMD phosphorylation is induced early after infection in primary non-dividing cells. Furthermore, we demonstrate that EMD phosphorylation is dependent on virion-associated mitogen-activated protein kinase (MAPK). Specific inhibition of MAPK activity with kinase inhibitors markedly reduced EMD phosphorylation and resulted in decreased integration of the proviral DNA into chromatin. Similarly, when a MEK1 kinase-inactive mutant was expressed in virus-producer cells, virus-induced phosphorylation of EMD was impaired and viral integration reduced during the subsequent infection. Expression of constitutively active MEK1 kinase in producer cells did not result in modulation of EMD phosphorylation or viral integration during subsequent infection. These studies demonstrate that, in addition to phosphorylating components of the PICs at an early step of infection, virion-associated MAPK plays a role in facilitating cDNA integration after nuclear translocation through phosphorylation of target-cell EMD.
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PMID:Lentivirus-associated MAPK/ERK2 phosphorylates EMD and regulates infectivity. 2046 47

The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated in triple-negative breast cancer (TNBC). Extracellular signal-related kinase (ERK), a member of the MAPK pathway, promotes cell proliferation, angiogenesis, cell differentiation, and cell survival. To assess the prognostic impact of ERK in TNBC patients, relative quantities of ERK (ERK-2 and pMAPK) and direct targets of the ERK pathway (MAPK/ERK kinase 1, phospho-enriched protein in astrocytes [PEA]-15, phosphorylated (p)PEA-15, tuberous sclerosis protein 2, p70S6 kinase, and p27) were measured using reverse-phase protein arrays in tumor tissue from patients with TNBC (n = 97) and non-TNBC (n = 223). Protein levels in patients with TNBC were correlated with clinical and tumor characteristics and outcome. The median age of patients with TNBC was 55 years (range, 27-86 years). Disease stage was I in 21%, II in 60%, and III in 20% of the patients. In a multivariate analysis, among patients with TNBC, those with ERK-2-overexpressing tumors had a lower overall survival rate than those with low ERK-2-expressing tumors (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.19-6.41). However, high pMAPK levels were associated with a significantly higher relapse-free survival rate (HR, 0.66; 95% CI, 0.46-0.95). In conclusion, ERK-2 and pMAPK are valuable prognostic markers in TNBC. Further studies are justified to elucidate ERK's role in TNBC tumorigenicity and metastasis.
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PMID:High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients. 2258 35

Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early-onset joint contractures, progressive muscular weakness and wasting and late-onset cardiac disease. The more common X-linked recessive form of EDMD is caused by mutations in either EMD (encoding emerin) or FHL1 (encoding four and a half LIM domains 1), while mutations in LMNA (encoding lamin A/C), SYNE1 (encoding nesprin-1) and SYNE2 (encoding nesprin-2) lead to autosomal dominant forms of the condition. Here, we identify a three-generation family with an extended EDMD phenotype due to a novel indel mutation in FHL1 that differentially affects the relative expression of the three known transcript isoforms produced from this locus. The additional phenotypic manifestations in this family-proportionate short stature, facial dysmorphism, pulmonary valvular stenosis, thoracic scoliosis, brachydactyly, pectus deformities and genital abnormalities-are reminiscent of phenotypes seen with dysregulated Ras-mitogen-activated protein kinase (RAS-MAPK) signalling [Noonan syndrome (NS) and related disorders]. The misexpression of FHL1 transcripts precipitated by this mutation, together with the role of FHL1 in the regulation of RAS-MAPK signalling, suggests that this mutation confers a complex phenotype through both gain- and loss-of-function mechanisms. This indel mutation in FHL1 broadens the spectrum of FHL1-related disorders and implicates it in the pathogenesis of NS spectrum disorders.
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PMID:Dysregulation of FHL1 spliceforms due to an indel mutation produces an Emery-Dreifuss muscular dystrophy plus phenotype. 2345 29


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