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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein kinase p38 plays a critical role in inflammation, cell cycle progression, differentiation, and apoptosis. The activity of p38 is stimulated by a variety of extracellular stimuli, such as the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), and subjected to regulation by other intracellular signaling pathways, including the cyclic AMP (cAMP) pathway. Yet the underlying mechanism by which cAMP inhibits p38 activation is unknown. Here we show that the induction of dynein light chain (DLC) by cAMP response element-binding protein (CREB) is required for cAMP-mediated inhibition of p38 activation. cAMP inhibits p38 activation via the protein kinase A-CREB pathway. The inhibition is mediated by the CREB target gene Dlc, whose protein product, DLC, interferes with the formation of the MKK3/6-p38 complex, thereby suppressing p38 phosphorylation activation by MKK3/6. The inhibition of p38 activation by cAMP leads to suppression of NF-kappaB activity and promotion of apoptosis in response to TNF-alpha. Thus, our results identify DLC as a novel inhibitor of the p38 pathway and provide a molecular mechanism by which cAMP suppresses p38 activation and promotes apoptosis.
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PMID:Cyclic AMP inhibits p38 activation via CREB-induced dynein light chain. 1644 37

Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positive GABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observed in vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and cAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons.
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PMID:A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. 1645 84

The objective of the study was to identify the functional outcome of intracellular versus extracellular angiotensin II-AT(1) receptor interactions in vascular cells. Rat vascular smooth muscle cell line A10 was transfected, independently and concurrently, with plasmids encoding fluorescent fusion proteins of rat angiotensin II (pECFP/AII, encodes AII fused downstream of enhanced cyan fluorescent protein) and the rat AT(1a) receptor (pAT(1)R/EYFP, encodes the rat AT(1a) receptor fused upstream of enhanced yellow fluorescent protein). The AII fluorescent fusion protein possesses no secretory signal peptide and deconvolution microscopy established that is maintained within these cells predominantly in the nucleus. AT(1)R/EYFP was absent from the nucleus when expressed exclusively or in untreated cells but accumulated in the nucleus following exogenous AII treatment or when co-expressed with ECFP/AII. Furthermore, expression of ECFP/AII stimulated proliferation of A10 vascular smooth muscle cells (VSMCs) 1.6-fold (P < 0.05). Transfection of a control, pECFP/AII(C) (which encodes a scrambled AII peptide fused to ECFP) had no growth effect. In light of the intracellular growth effects of ECFP/AII, we sought to elucidate the underlying signaling pathways. We found that extracellular AII treatment of A10 cells activated cAMP response element-binding protein (CREB) as determined by one-hybrid assays and immunoblots. Expression of intracellular ECFP/AII similarly activated CREB. However, intracellular and extracellular AII activated CREB through different phosphorylation pathways. Exogenous AII treatment of A10 cells activated p38MAPK and ERK1/2 phosphorylation as determined by Western blot analyses and one-hybrid assays. The p38MAPK inhibitor, SB203580, and the ERK kinase inhibitor, PD98059 each partially inhibited exogenous AII-conferred CREB activation confirming that p38MAPK and ERK1/2 mediate CREB phosphorylation in this system. In contrast, expression of ECFP/AII (intracellular AII) in A10 VSMCs activated p38MAPK but not ERK1/2; inhibition of p38MAPK by SB203580 inhibited intracellular AII-induced CREB phosphorylation. In summary, extracellular AII stimulates at least one pathway common to intracellular AII. This common pathway, in the case of exogenous AII, likely reflects intracellular signaling following internalization of receptor-ligand complex. Extracellular AII also stimulates a unique pathway, apparently reflecting interaction with plasma membrane-associated AT(1)R.
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PMID:Nuclear accumulation of the AT1 receptor in a rat vascular smooth muscle cell line: effects upon signal transduction and cellular proliferation. 1651 13

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a naturally occurring polyphenolic compound found abundantly in grape skins and red wines, has been found to pharmacologically precondition the heart against ischemia reperfusion injury through the potentiation of a survival signal involving cAMP response element-binding protein-dependent phosphatidylinositol 3-kinase-Akt-BclII pathway. The present study was designed to determine whether, similar to ischemic preconditioning, resveratrol uses mitogen-activated protein kinases (MAPKs) as upstream signaling targets. The isolated rat hearts were preperfused for 15 min with Krebs-Henseleit bicarbonate buffer in the absence (control) or presence of extracellular signal-regulated kinase (ERK) 1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059), p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB-202190), mitogen- and stress-activated protein kinase 1 (MSK-1) inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), protein kinase A inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3fg: 3',2',1'-kl]-pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT5720), resveratrol only, resveratrol plus PD98059, resveratrol plus SB-202190, resveratrol plus H89, or resveratrol plus KT5720. Consistent with previous reports, resveratrol provided cardioprotection as evidenced by its ability to improve postischemic ventricular function, reduction of myocardial infarct size, and cardiomyocyte apoptosis. The cardioprotection afforded by resveratrol was partially abolished with PD98059 or SB-202190, suggesting that ERK1/2 and p38 MAPK play roles in resveratrol-mediated preconditioning. An MSK-1 inhibitor, H89, abolished resveratrol-mediated preconditioning, indicating MSK-1 to be the downstream target molecule for both ERK1/2 and p38 MAPK. KT5720 had no effect on resveratrol-mediated cardioprotection. Corroborating these results, Western blot analysis revealed phosphorylation of ERK1/2, p38 MAPK, MAPK-activated protein (MAPKAP) kinase 2, and MSK-1 with resveratrol and inhibition of phosphorylation with corresponding inhibitors. These results showed for the first time that resveratrol triggers an MAPK signaling pathway involving ERK1/2 and p38 MAPK, the former using MSK-1 as the downstream target and the latter, using both MAPKAP kinase 2 and MSK-1 as downstream targets.
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PMID:Potentiation of a survival signal in the ischemic heart by resveratrol through p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1/cAMP response element-binding protein signaling. 2233

In a previous study, we reported that a brief exposure to swim stress transforms an electrically induced, protein synthesis-independent early long-term potentiation (early LTP) into a protein synthesis-dependent late LTP ["reinforcement of LTP" in the hippocampal dentate gyrus (DG)] (Korz and Frey, 2003). This transformation depends on activation of mineralocorticoid receptors (MRs) by corticosterone, and on intact basolateral amygdala (BLA) function. Here, we demonstrate that a brief swim experience results in lasting changes in levels of hippocampal cellular signaling molecules that are known to be involved in the induction of late LTP. Within the DG, MRs were rapidly upregulated, whereas glucocorticoid receptor (GR) levels were elevated with a 3 h delay. Levels of phosphorylated mitogen-activated protein kinase 2 (pMAPK2) and p38 MAPK, as well as phosphorylated calcium/calmodulin-dependent protein kinase II (pCaMKII) were enhanced shortly after swim stress and remained elevated until 24 h, whereas levels of phosphorylated cAMP response element-binding protein (pCREB) remained unchanged. MR and GR were upregulated with a longer delay within the CA1 region, whereas levels of pMAPK2 and p38MAPK were rapidly increased, but the former returned to basal levels after 3 h. Levels of pCREB and pCaMKII were maintained in an enhanced state after swim stress. DG-LTP reinforcement requires a serotonergic but not dopaminergic heterosynaptic receptor activation that probably mediates the BLA-dependent modulation of LTP under stress. Thus, molecular alterations induced by specific stress resemble late LTP-related molecular changes. These changes, in interaction with stress-specific heterosynaptic processes, may support the transformation of early LTP into late LTP. The results contribute to the understanding of the rapid consolidation of cellular and possibly systemic memories triggered by stress.
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PMID:Long-term effects of brief acute stress on cellular signaling and hippocampal LTP. 1661 11

Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 microg of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-alpha; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.
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PMID:Stress increases vulnerability to inflammation in the rat prefrontal cortex. 1672 27

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng-/- mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/- mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng-/- mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/-, but not Ng-/- mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/- mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of alphaCaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/- mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.
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PMID:Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. 1676 30

Yeast Sin1 binds to the Sty1 kinase, a member of the stress-activated kinases (SAPKs), and is required for stress-induced phosphorylation and activation of the transcription factor Atf1, a homolog of the vertebrate-activating transcription factor-2 (ATF-2). Here we report that mammalian Sin1 plays an important role in the SAPK signaling pathway by binding to both ATF-2 and p38. In response to stress, ATF-2, a member of the ATF/cAMP response element-binding protein family, is phosphorylated by p38/Jun NH2-terminal protein kinase and activates the transcription of apoptosis-related genes. In contrast, in response to serum stimulation, ATF-2 is phosphorylated via the Ras effector pathway and leads to the induction of growth-related genes. We found that Sin1 binds directly to both ATF-2 and p38. Sin1 over-expression enhanced osmotic stress-induced phosphorylation of ATF-2 and ATF-2-mediated transcription, whereas knockdown of Sin1 expression by siRNA suppressed these responses. Moreover, a reduction in Sin1 expression suppressed osmotic stress-induced apoptosis and the expression of Gadd45beta, one of the ATF-2 target genes that is correlated with apoptosis. Decreased Sin1 expression, however, did not affect the serum stimulation-induced phosphorylation of ATF-2. Sin1 may contribute to ATF-2 signaling specificity by acting as a nuclear scaffold.
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PMID:Sin1 binds to both ATF-2 and p38 and enhances ATF-2-dependent transcription in an SAPK signaling pathway. 1705 22

Interruption in the brain's blood supply leads to an ischemic condition, which is characterised by a depletion of energy phosphates and related failure of ionic pumps, increased extracellular potassium, neuronal depolarisation and release of excitatory amino acids, e.g. glutamate. The subsequent activation of N-methyl-d-aspartate glutamate receptors triggers a wide range of intracellular signals, including the mitogen-activated protein kinase (MAPK) pathway. Activation and inhibition of the MAPK/extracellular regulated kinases (ERK) pathway are both reported to be neuroprotective in conditions associated with excitotoxic injury. The present study was designed to explore the involvement of this signalling pathway in cultured rat cortical neurons subjected to chemically-induced ischemia obtained by coupling the mitochondrial toxin 3-nitropropionic acid with glucose deprivation. Loss of neuronal viability, reduced neuronal energy state (ATP level and mitochondrial membrane potential) and increased cytoplasmic mitochondrial calcium were all observed. The NMDA antagonist MK-801 counteracted these effects, suggesting a glutamate-dependent ischemic cell death. Addition of U0126, a selective inhibitor of MAPK kinase, exacerbated this neuronal cell death. However, non-significant changes in activated cAMP response element-binding protein were seen. The rise in cytoplasmic calcium under ischemic conditions was associated with neuronal cell swelling. Both swelling and increase in cytoplasmic calcium were exacerbated and prevented by U0126 and MK-801, respectively. These data suggest that in this ischemic model the MAPK/ERK pathway might exert a regulatory effect on calcium entry independent from gene expression.
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PMID:MEK inhibition exacerbates ischemic calcium imbalance and neuronal cell death in rat cortical cultures. 1709 33

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.
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PMID:Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. 1713 41


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