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)

The ERK, p38MAPK, JNK mitogen-activated protein kinases (MAPKs) are intracellular signaling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. These cascades are activated by a large variety of stimuli and display a high degree of homology. So far, seven MAPK isoforms have been invalidated in mice leading to the discovery of their important functions in development and differentiation. As we could expect because of their multiple and specific properties in vitro, knockout (KO) of MAPK pathways leads to distinct phenotypes in mice. Surprisingly, into a given cascade, KOs of the various isoforms assign specific non-redundant biological functions to each isoform, without compensation by the others. These results emphasize the notion that, although initiated by the same external stimuli, these intracellular cascades activate kinase isoforms each with its own specific role.
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PMID:Role of MAPKs in development and differentiation: lessons from knockout mice. 1685 12

Inhibitory avoidance (IA) learning relies on the formation of an association between stepping down from a platform present in a certain context (conditioned stimulus; CS) with an aversive unconditioned stimulus (US; i.e. a footshock). A single CS-US pairing establishes a robust long-term memory expressed as an increase in step-down latency at testing. However, repeated retrieval of the avoidance response in the absence of the US induces extinction of IA memory. That is, recurring presentation of the CS alone results in a new learning indicating that the CS no longer predicts the US. Although the signaling pathways involved in the consolidation of IA and other fear-motivated memories have been profusely studied, little is known about the molecular requirements of fear memory extinction. Here we report that, as happens with its consolidation, extinction of IA long-term memory requires activity of the p38 subfamily of mitogen-activated protein kinases (MAPK) in the CA1 region of the dorsal hippocampus. Moreover, we found that inhibition of hippocampal p38MAPK blocked memory reacquisition after extinction without affecting either the increase in IA memory retention induced by a second training session or animal's locomotor/exploratory activity and anxiety state.
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PMID:On the participation of hippocampal p38 mitogen-activated protein kinase in extinction and reacquisition of inhibitory avoidance memory. 1696 16

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine, whose primary targets include vascular endothelial cells. TNF-mediated adhesion molecule expression has been shown to play a central role in endothelial cells inflammatory responses and disorders such as atherosclerosis. However it is not fully understand how the TNF receptor subtypes, namely TNFR1 and TNFR2, regulate inflammatory responses in endothelial cells. The aim of this study was to elucidate the kinase signalling pathways that TNF receptors activate, and determine the pathways responsible for downstream expression of adhesion molecules, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human endothelial cells. Using human umbilical vein endothelial cells (HUVEC), we demonstrated that TNF activates a range of mitogen-activated protein kinases (MAPKs), including the extracellular-regulated kinase (ERK) pathway and the p38MAPK and c-Jun N-terminal kinase (JNK) stress kinase pathways. Human endothelial cells express both TNF receptor subtypes at low levels, however using TNFR-specific agonistic agents, we uncovered that TNF acts through its TNFR1 receptor subtype to activate NF-kappaB transcriptional pathways. Further investigation revealed that ICAM-1 and VCAM-1 mRNA and protein are induced by TNFR1 (but not TNFR2) in a wholly NF-kappaB-dependent manner. These findings reveal for the first time that TNF stimulation of adhesion molecules ICAM-1 and VCAM-1 in human endothelial cells occurs through the TNFR1 subtype and is mediated by the NF-kappaB pathway, but not the ERK, p38MAPK or JNK kinase pathways.
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PMID:TNFR1-induced NF-kappaB, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells. 1729 86

The existing literature indicates a crucial role of p38 MAP (mitogen-activated protein) kinase (p38MAPK) and its downstream target MAPKAP kinase 2 (MK2) in ischemic preconditioning (IPC). Accordingly, deletion of MK2 gene should abolish the cardioprotective ability of IPC. Interestingly, we were able to partially precondition the hearts from MK2(-/-) knockout mice suggesting the existence of an as yet unknown alternative downstream target of p38MAPK. A recent study from our laboratory also determined a crucial role of CREB (cyclic AMP response element binding protein) in IPC. Since CREB is a downstream target of MSK-1 (mitogen- and stress-activated protein kinase-1) situated at the crossroad of ERK (extracellular receptor kinase) and p38MAPK signaling pathways, we reasoned that MSK-1 could be a downstream molecular target for p38MAPK and ERK signaling in the IPC hearts. To test this hypothesis, the rat hearts were subjected to IPC by four cyclic episodes of 5 min ischemia and 10 min reperfusion. As expected, IPC induced the activation of ERK1/2, p38MAPK, MK2 and HSP (heat shock protein) 27 as evidenced by their increased phosphorylation; and the inhibition of p38MAPK with SB203580 almost completely, and the inhibition of ERK1/2 with PD098059 partially, abolished cardioprotective effects of IPC. Inhibition of MSK-1 with short hairpin RNA (shRNA) also abolished the IPC-induced cardioprotection. SB203580 partially blocked the effects of MSK-1 suggesting that MSK-1 sits downstream of p38MAPK. shRNA-MSK-1 blocked the contribution of both p38MAPK and ERK1/2 as it is uniquely situated at the downstream crossroad of both of these MAP kinases. Although MSK-1 sits downstream of both ERK1/2 and p38MAPK, ERK1/2 activation appears to play less significant role compared to p38MAPK, since its inhibition blocked MSK activation only partially. Consistent with these results, shRNA-MSK-1 blocked the partial PC in MK2(-/-) hearts, and in combination with SB203580, completely abolished the PC effects in the wild-type hearts. The IPC-induced survival signaling was almost completely inhibited with SB203580, and only partially with PD 098059 as evidenced from the inhibition patterns of IPC induced activation of CREB, Akt and Bcl-2. Again SB203580 alone or in combination with shRNA-MSK-1 inhibited IPC induced survival signal comparatively, suggesting that MSK-1 exists downstream of p38MAPK. Taken together, these results indicate for the first time MSK-1 as an alternative (other than MK2) downstream target for p38MAPK, which also transmits survival signal through the activation of CREB.
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PMID:Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target. 2323 Jun 4

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.
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PMID:p38 MAP-kinases pathway regulation, function and role in human diseases. 1748 47

G proteins provide signal-coupling mechanisms to heptahelical cell surface receptors and are critically involved in the regulation of different mitogen-activated protein kinase (MAPK) networks. The four classes of G proteins, defined by the G(s), G(i), G(q) and G(12) families, regulate ERK1/2, JNK, p38MAPK, ERK5 and ERK6 modules by different mechanisms. The alpha- as well as betagamma-subunits are involved in the regulation of these MAPK modules in a context-specific manner. While the alpha- and betagamma-subunits primarily regulate the MAPK pathways via their respective effector-mediated signaling pathways, recent studies have unraveled several novel signaling intermediates including receptor tyrosine kinases and small GTPases through which these G-protein subunits positively as well as negatively regulate specific MAPK modules. Multiple mechanisms together with specific scaffold proteins that can link G-protein-coupled receptors or G proteins to distinct MAPK modules contribute to the context-specific and spatio-temporal regulation of mitogen-activated protein signaling networks by G proteins.
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PMID:G protein regulation of MAPK networks. 1749 11

Oxidized low density lipoproteins (oxLDL), macrophages and T-lymphocytes are present in atherosclerotic lesions. We and others have shown that oxLDL is cytotoxic for macrophages, endothelial, smooth muscle and activated T-lymphocytes and induce apoptosis. Here we demonstrate that (i) oxidized LDL (oxLDL), oxidized VLDL (oxVLDL) and hydrogen peroxide (H2O2) induce apoptosis in human T-lymphocytes and (ii) mitogen-activated protein kinases are involved in this process. Apoptosis was monitored by immunofluorescence microscopy and flow cytometry for annexin V binding, Apo 2.7 expression, the TUNEL reaction and caspase 3 activity. In the presence of oxLDL (100 microg/ml), oxVLDL (50 microg/ml) and H2O2 (5 mM), the fraction of apoptotic cells increased within 6 hours to more than 70%. Preincubation of lymphocytes with the MAPKK inhibitor PD-98059 and the p38MAPK inhibitor SB-203580 almost completely abolished these effects. Furthermore, oxLDL and H2O2 but not native LDL strongly enhanced phosphorylation of JNK, p38MAPK and p42/44MAPK. The results suggest that in the resting lymphocyte apoptosis triggered by oxidized lipoproteins and oxidative stress depends on the activation of p44/42MAPK and p38MAPK cascades.
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PMID:Oxidized low density lipoproteins induce apoptosis in human lymphocytes: involvement of mitogen-activated protein kinases. 1769 85

We investigated the bucillamine (Buc) mechanism inhibiting interleukin (IL)-1beta-induced vascular endothelial growth factor (VEGF) production from human fibroblast-like synoviocytes (HFLS) which derived from the inflamed synovium of an RA patient using SA981, its active metabolite. HFLS did not produce IL-1beta, spontaneously. While SA981 partially inhibited IL-1beta-induced VEGF production at concentrations of 10 to 100 microM (10.1% and 14.2% inhibition of total VEGF production under IL-1beta coexistence condition, respectively), it failed to inhibit IL-1beta-induced IL-6 production at the same concentrations. IL-1beta induced phosphorylation of the mitogen-activated protein (MAP) kinases, IkappaBalpha, c-Jun and Akt. SA981 at a concentration of 100 microM partially inhibited IL-1beta-induced phosphorylation of p38MAPK and Akt (12.0% and 36.1% inhibition of each total amount of phosphoprotein under IL-1beta coexistence condition, respectively). The VEGF promoter includes four transcription factors: AP1, hypoxia-inducible factor (HIF), Sp1 and AP2 binding elements. HIF-1beta, Sp1 and AP1 increased under IL-1beta coexistence conditions. At a concentration of 100 microM, SA981 attenuated increases in HIF-1beta and Sp1 (10.1% and 19.8% inhibition of each total amount of transcription factor under IL-1beta coexistence condition, respectively), but not AP1. These results suggest that SA981 partially inhibits VEGF production via modifications on IL-1beta signaling. Attenuation of the expression of HIF-1beta and Sp1 (but not AP1) may be a key with respect to SA981's selective inhibition of VEGF production.
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PMID:Bucillamine mechanism inhibiting IL-1beta-induced VEGF production from fibroblast-like synoviocytes. 1792 May 34

Angiotensin II (Ang II) highly stimulates superoxide anion production by neutrophils. The G-protein Rac2 modulates the activity of NADPH oxidase in response to various stimuli. Here, we describe that Ang II induced both Rac2 translocation from the cytosol to the plasma membrane and Rac2 GTP-binding activity. Furthermore, Clostridium difficile toxin A, an inhibitor of the Rho-GTPases family Rho, Rac and Cdc42, prevented Ang II-elicited O2-/ROS production, phosphorylation of the mitogen-activated protein kinases (MAPKs) p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2, and Rac2 activation. Rac2 GTPase inhibition by C. difficile toxin A was accompanied by a robust reduction of the cytosolic Ca(2)(+) elevation induced by Ang II in human neutrophils. Furthermore, SB203580 and PD098059 act as inhibitors of p38MAPK and ERK1/2 respectively, wortmannin, an inhibitor of phosphatidylinositol-3-kinase, and cyclosporin A, a calcineurin inhibitor, hindered both translocation of Rac2 from the cytosol to the plasma membrane and enhancement of Rac2 GTP-binding elicited by Ang II. These results provide evidence that the activation of Rac2 by Ang II is exerted through multiple signalling pathways, involving Ca(2)(+)/calcineurin and protein kinases, the elucidation of which should be insightful in the design of new therapies aimed at reversing the inflammation of vessel walls found in a number of cardiovascular diseases.
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PMID:Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils. 1797 62

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers. It is believed that tumor production of various immune suppressive mediators contributes to massively impaired immune functions, but the underlying signal transduction pathways are mostly unknown. Phosphorylation levels of MAP (mitogen-activated protein) kinase p38 were analyzed in permanent cell lines as well as in solid tumor tissue of HNSCC using flow cytometry and SDS-PAGE. Cytokine secretion was determined using the Cytometric Bead Array Flex Set system. MAP kinase p38 was shown to be activated in HNSCC by phorbol 12-myristate 13-acetate. Activation of p38 led to decreased cell proliferation and increased secretion of cytokines IL-6 and IL-8 in HNSCC. Our data provide novel insights into the origin of the HNSCC microenvironment. A better understanding of these molecular mechanisms in HNSCC is essential for novel drug development and improvement of the clinical perspective of this tumor type.
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PMID:Increased cytokine secretion in head and neck cancer upon p38 mitogen-activated protein kinase activation. 1798 98


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