Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Replication-defective adenoviruses (Ad) utilized as vectors for gene transfer are known to induce an inflammatory and immune response upon exposure to respiratory cells in vitro and in vivo. Among the different mediators of inflammation, we recently demonstrated that a replication-defective Ad serotype 5, deleted in the early genes E1 and E3 (Ad.CFTR), induces the proinflammatory intercellular adhesion molecule 1 (ICAM-1) in A549 respiratory cells in vitro and in lung portions of nonhuman primates in vivo, Gene Ther. 5, 131-136). More recently, we described the involvement of the nuclear factor kappaB (NF-kappaB) in the induction of ICAM-1 upon 24 h of exposure of the same Ad5-derived vector, Gene Ther. 8, 1436-1442). Here we investigated whether the early phase of virus-cell interaction is sufficient to stimulate ICAM-1 upregulation. A549 cells were exposed to wild-type Ad5 (Ad5), to Ad.CFTR, and to Ad5 inactivated by incubation at 56 degrees C (Ad5/56 degrees C). Ad5, Ad.CFTR, and Ad5/56 degrees C activated NF-kappaB and increased ICAM-1 mRNA levels within 4 h after exposure. The role of the mitogen-activated protein kinases (MAPKs) on the ICAM-1 mRNA induction was studied. ICAM-1 mRNA upregulation was inhibited upon incubation with several chemicals, namely, the ERK1/2 inhibitors PD98059 and AG1288 (by 98 and 67%, respectively), of the p38/MAPK pathway SB203580 (by 50%), of the JNK pathway dimethylaminopurine (by 83%), and of the NF-kappaB parthenolide (by 96%). Ad5 and Ad5/56 degrees C stimulated ERK1/2, p38/MAPK, and JNK1 starting 10 min and peaking 20-30 min after exposure. The present results indicate a link between the activation of the three major MAPK pathways, NF-kappaB, and the upregulation of ICAM-1 gene expression evoked by Ad5 in the very initial phase of infection.
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PMID:MAP kinases and NF-kappaB collaborate to induce ICAM-1 gene expression in the early phase of adenovirus infection. 1266 93

Host cell invasion is essential for the pathogenicity of the obligate intracellular protozoan parasite Toxoplasma gondii. In the present study, we evaluated the ability of T. gondii tachyzoites to trigger phosphorylation of the different mitogen-activated protein kinases (MAPK) in human monocytic cells THP1. Kinetic experiments show that the peak of extracellular-signal-regulated kinase (ERK1/2), P38 and cjun-NH2 terminal kinase (JNKs) phosphorylation occurs between 10 and 60 min. The use of specific inhibitors of ERK1/2, P38 and JNK1/2 phosphorylation indicates the specificity of MAPKs phosphorylation during invasion. Signaling through cellular and parasite mitogen-activated protein (MAP) kinase pathways appears to be critical for T. gondii invasion.
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PMID:Activation of the cellular mitogen-activated protein kinase pathways ERK, P38 and JNK during Toxoplasma gondii invasion. 1266 50

Many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) might be mediated by connective tissue growth factor (CTGF). The present study investigates the role of mitogen-activated protein (MAP) kinase in the expression of CTGF mRNA in the human lung fibroblast line, HFL-1. TGF-beta1 enhanced CTGF mRNA levels in a time- and concentration-dependent manner, and this enhancement was also dependent upon transcription. Inhibition of p38 MAP kinase or extracellular signal-regulated kinase (ERK) activation did not affect TGF-beta1-induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-beta1-induced CTGF expression in a concentration-dependent manner. TGF-beta1 activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-beta1-induced JNK, but not p38 MAP kinase activation. Finally, JNK1 and JNK2 antisense oligonucleotides attenuated cellular levels of JNK1 and JNK2 protein, respectively, and repressed TGF-beta1-induced CTGF expression. These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.
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PMID:C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth factor-beta1 in human lung fibroblasts. 1276 Sep 70

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response. The resultant outcomes are cytoprotective but also proapoptotic. ER chaperones and misfolded proteins exit to the secretory pathway and are retrieved to the ER, during which process the KDEL receptor plays a significant role. Using an expression of a mutant KDEL receptor that lacks the ability for ligand recognition, we show that the impairment of retrieval by the KDEL receptor led to a mis-sorting of the immunoglobulin-binding protein BiP, an ER chaperone that has a retrieval signal from the early secretory pathway, which induced intense ER stress response and an increase in susceptibility to ER stress in HeLa cells. Furthermore, we show that the ER stress response accompanied the activation of p38 mitogen-activated protein (MAP) kinases and c-Jun amino-terminal kinases (JNKs) and that the expression of the mutant KDEL receptor suppressed the activation of p38 and JNK1 but not JNK2. The effect of the expression of the mutant KDEL receptor was consistent with the effect of a specific inhibitor for p38 MAP kinases, because the inhibitor sensitized HeLa cells to ER stress. We also found that activation of the KDEL receptor by the ligand induced the phosphorylation of p38 MAP kinases. These results indicate that the KDEL receptor participates in the ER stress response not only by its retrieval ability but also by modulating MAP kinase signaling, which may affect the outcomes of the mammalian ER stress response.
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PMID:The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades. 1282 50

Recent studies indicate a potential role for Fra-1, a heterodimeric partner of activator protein (AP)-1, in toxicant-induced epithelial injury, repair, and cellular transformation. Here we have investigated the effects of diesel exhaust particles (DEP) on fra-1 expression in C10 cells, a murine lung epithelial cell line. DEP markedly upregulated fra-1, but not fra-2, expression. The increase in fra-1 mRNA expression correlated well with its protein- and DNA-binding activity. DNA-binding assays also revealed a predominant presence of Jun-B and Jun-D in the AP-1 complex. Interestingly, DEP did not alter Jun-B and Jun-D protein levels. Transcriptional analysis revealed that fra-1 induction is regulated in part at the transcriptional level. The -379 to +32 bp 5'-flanking region mediated this induction. Furthermore, inhibitors of ERK1/2, JNK1, and p38 mitogen-activated protein kinases (MAPKs) significantly suppressed DEP-stimulated fra-1 transcription, suggesting their involvement in the induction process. Consistent with this finding, DEP stimulated phosphorylation of ERK1/2, JNK1, and p38 MAPKs with a distinct activation pattern. Overexpression of Fra-1 downregulated c-Jun and Nrf2 enhanced AP-1- and ARE-mediated reporter gene expression, respectively. In contrast, Fra-1 had the opposite effect on matrix metalloproteinase (MMP)-9 promoter activity. In particular, it bound to the functional AP-1 site of the MMP-9 promoter after DEP stimulation. Consistent with this result, DEP also markedly upregulated MMP-9 promoter activity. Collectively, these findings suggest that fra-1 induction by DEP may play a role in selectively regulating gene expression involved in alveolar epithelial cell injury and repair.
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PMID:DEP-induced fra-1 expression correlates with a distinct activation of AP-1-dependent gene transcription in the lung. 1456 43

After balloon angioplasty, locally expressed tumor necrosis factor (TNF)-alpha disrupts endothelial cell (EC) proliferation and reendothelialization of the injured vessel. We have previously reported that TNF inhibits the EC cycle and downregulates the transcription factor E2F1. Ectopic expression of E2F1 at the site of injury improves reendothelialization of the injured vessel. In this study, we report that c-Jun N-terminal kinase (JNK) 1 and p38 mitogen-activated protein kinases (MAPKs) are differentially required for E2F1 expression and activity in ECs. Overexpression of constitutively active JNK1 mimicked TNF-mediated inhibitory events, whereas dominant-negative JNK1 prevented these effects. E2F cis elements in the promoter of E2F1 gene mediate suppressive actions of TNF, because removal of these sites rendered E2F1 promoter activity insensitive to TNF. JNK1 physically interacted with E2F1 and inactivated it via direct phosphorylation. Additionally, TNF inhibited Rb phosphorylation and dissociation from E2F1. Overexpression of constitutively active p38 MAPK facilitated Rb-E2F1 dissociation, whereas that of dominant-negative p38 MAPK did not. Taken together, these data suggest a differential requirement of JNK1 and p38 MAPK in TNF regulation of E2F1. Targeted inactivation of JNK1 at arterial injury sites may represent a potential therapeutic intervention for ameliorating TNF-mediated EC dysfunction.
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PMID:Tumor necrosis factor-mediated E2F1 suppression in endothelial cells: differential requirement of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signal transduction pathways. 1457 93

Parathyroid hormone-related protein (PTHrP) increases the content and mRNA level of insulin in a mouse beta-cell line, MIN6, and primary-cultured mouse islets. We examined the mechanism of PTHrP-induced insulin expression. The PTHrP effect was markedly augmented by SB203580, a mitogen-activated protein (MAP) kinase inhibitor, and SB203580 itself increased insulin expression extensively, even without PTHrP. Because SB203580 inhibits both p38 and c-jun NH(2)-terminal kinases (JNKs), we investigated the JNK-specific inhibitor SP600125. SP600125 also increased insulin content and its mRNA level. PTHrP induced dephosphorylation of JNK1/2, and PTHrP-induced insulin expression was blocked by a dominant-negative type JNK-APF. We suspected that dual specificity MAP kinase phosphatases (MKPs) may be involved in the PTHrP-induced insulin expression by inactivating JNK1/2. MIN6 cells contained at least five MKPs, among which only MKP-1 was inducible by PTHrP. PTHrP-induced insulin expression was blocked by the MKP-1 expression inhibitor Ro-31-8220, indicating that the PTHrP effect is mediated by MKP-1. Indeed, adenoviral MKP-1 expression increased insulin expression by decreasing a phosphorylation form of JNKs and a resulting phosphorylated form of c-jun in MIN6 cells. The phosphorylated form of c-jun is known to repress cAMP-dependent insulin gene promoter activity. Thus, MKP-1 controls the insulin expression by downregulating a JNK/c-jun pathway.
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PMID:Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells. 1457 90

The trichothecene mycotoxin deoxynivalenol (DON) induces IgA hyperelevation and mesangial IgA deposition in mice that mimics the early stages of human IgA nephropathy (IgAN). Among potential mediators of this disease, interleukin-6 (IL-6) is likely to play a particularly critical role in IgA elevation and disease exacerbation. Based on previous findings that dietary fish oil (FO) suppresses DON-induced IgAN, we hypothesized that FO inhibits the induction of IL-6 expression by this mycotoxin in vivo and in vitro. Mice were fed modified AIN 93G diet amended with 7% corn oil (CO) or with 1% corn oil plus 6% menhaden fish oil (FO) for up to 8 weeks and then exposed acutely to DON by oral gavage. DON-induced plasma IL-6 and splenic mRNA elevation in FO-fed mice were significantly suppressed after 8 weeks when compared to the CO-fed group. The effects of FO on phosphorylation of mitogen-activated protein kinases (MAPKs), critical upstream transducers of IL-6 up-regulation, were also assessed. DON-induced phosphorylation of extracellular signal regulated protein kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) was significantly suppressed in spleens of mice fed with FO, whereas p38 was not. Splenic COX-2 mRNA expression, which has been previously shown to enhance DON-induced IL-6, was also significantly decreased by FO, whereas plasma levels of the COX-2 metabolite, prostaglandin E2, were not affected. To confirm in vivo findings, the effects of pretreatment with the two primary n-3 PUFAs in FO, eicosapentaenoic acid (20:5[n-3]; EPA) and docosahexaenoic acid, (22:6[n-3]; DHA), on DON-induced IL-6 expression were assessed in LPS-treated RAW 264.7 macrophage cells. Consistent with the in vivo findings, both EPA and DHA significantly suppressed IL-6 superinduction by DON, as well as impaired DON-induced ERK1/2 and JNK1/2 phosphorylation. In contrast, the n-6 PUFA arachidonic acid (20:4[n-3]) had markedly less effects on these MAPKs. Taken together, the capacity of FO and its component n-3 PUFAs to suppress IL-6 expression as well as ERK 1/2 and JNK 1/2 activation might explain, in part, the reported suppressive effects of these lipids on DON-induced IgA nephropathy.
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PMID:Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. 1469 Jul 64

The c-Jun NH(2)-terminal kinase (JNK) subgroup of mitogen-activated protein kinases has been implicated largely in stress responses, but an increasing body of evidence has suggested that JNK also plays a role in cell proliferation and survival. We examined the effect of JNK inhibition, using either SP600125 or specific antisense oligonucleotides, on cell proliferation and cell cycle progression. SP600125 was selective for JNK in vitro and in vivo versus other kinases tested including ERK, p38, cyclin-dependent protein kinase 1 (CDK1), and CDK2. SP600125 inhibited JNK activity and KB-3 cell proliferation with the same dose dependence, suggesting that inhibition of proliferation was a direct consequence of JNK inhibition. Inhibition of proliferation by SP600125 was associated with an increase in the G(2)-M and apoptotic fractions of cells but was not associated with p53 or p21 induction. Antisense oligonucleotides to JNK2 but not JNK1 caused highly significant inhibition of cell proliferation. Wild-type mouse fibroblasts responded similarly with proliferation inhibition and apoptosis induction, whereas c-jun(-/-) fibroblasts were refractory to the effects of SP600125, suggesting that JNK signaling to c-Jun is required for cell proliferation. Studies in synchronized KB-3 cells indicated that SP600125 delayed transit time through S and G(2)-M phases. Correspondingly, JNK activity increased in late S phase and peaked in late G(2) phase. During synchronous mitotic progression, cyclin B levels increased concomitant with phosphorylation of c-Jun, H1 histone, and Bcl-2. In the presence of SP600125, mitotic progression was prolonged, and c-Jun phosphorylation was inhibited, but neither H1 nor Bcl-2 phosphorylation was inhibited. However, the CDK inhibitor roscovitine inhibited mitotic Bcl-2 phosphorylation. These results indicate that JNK, and more specifically the JNK2 isoform, plays a key role in cell proliferation and cell cycle progression. In addition, conclusive evidence is presented that a kinase other than JNK, most likely CDK1 or a CDK1-regulated kinase, is responsible for mitotic Bcl-2 phosphorylation.
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PMID:Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity: evidence that mitotic Bcl-2 phosphorylation is JNK-independent. 1470 47

Neurotrophins such as nerve growth factor (NGF) are considered putative neuroprotective compounds in the central nervous system. To investigate the cellular and molecular neuroprotective mechanisms of NGF under ischemia, we used a unique oxygen and glucose deprivation (OGD) device. In this system we used pheochromocytoma PC12 cells to elucidate NGF neuroprotective effect. PC12 cells were exposed to OGD, followed by addition of glucose and oxygen (OGD reperfusion). Neuronal cell death induced in this model was measured by the release of lactate dehydrogenase (LDH), activation of caspase-3 and mitogen-activated protein kinases (MAPKs), measured with specific anti-phospho-antibodies. Pretreatment of the cultures with 50 ng/mL NGF, 18 h prior to OGD insult, conferred 30% neuroprotection. However, treatment of the cultures with NGF concomitantly with the OGD insult did not result in neuroprotection. Time-course experiments showed marked activation of extracellular signal-regulated protein kinase, c-Jun N-terminal kinase (JNK), and p38 MAPK isoforms during the OGD phase but not during OGD reperfusion. Pretreatment of the cultures with 50 ng/mL NGF, 18 h prior to OGD insult, resulted in 50% attenuation of OGD-induced activation of JNK1, and 20% and 50% attenuation of OGD-induced activation of p38alpha and beta, respectively. These findings support the notion that NGF confers neuroprotection from OGD insult, a phenomenon coincidentally related to differential inhibition of MAPK stress kinase isoforms, and provide the PC12 model as an in vitro OGD system to investigate molecular mechanisms of neurotoxicity and neuroprotection.
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PMID:Nerve growth factor pretreatment attenuates oxygen and glucose deprivation-induced c-Jun amino-terminal kinase 1 and stress-activated kinases p38alpha and p38beta activation and confers neuroprotection in the pheochromocytoma PC12 Model. 1499 18


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