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

The transcription factor ER81 has been shown to be involved in ontogenesis and breast tumor formation. ER81 is activated by many signals through phosphorylation directly mediated by mitogen-activated protein kinases (MAPKs), but also by an unknown protein kinase(s). Here, mitogen- and stress-activated protein kinase 1 (MSK1), which itself is directly activated by distinct classes of MAPKs, is identified to regulate ER81 function. MSK1 expression enhances ER81-dependent transcription upon stimulation of especially the p38-MAPK pathway. Two serine residues in ER81 are phosphorylated by MSK1, and mutating these serine residues to alanines dramatically diminishes the ability of MSK1 to stimulate ER81. However, mutation of the MSK1 phosphorylation sites in ER81 does not completely abrogate the ability of MSK1 to activate ER81 function, suggesting that MSK1 may also target cofactors of ER81. Consistently, MSK1 interacts with two homologous coactivators of ER81, CBP and p300, and stimulates the transactivation domains of CBP. Thus, MSK1 may regulate ER81-dependent transcription via direct phosphorylation of ER81 as well as via stimulation of CBP/p300, which might be important for ER81's normal function and during mammary tumor formation.
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PMID:Regulation of the ER81 transcription factor and its coactivators by mitogen- and stress-activated protein kinase 1 (MSK1). 1256 67

We investigated the activation of mitogen-activated protein kinases (MAPKs) pathways by purinergic stimulation in cardiac myocytes from adult rat hearts. ATPgammaS increased the phosphorylation (activation) of the extracellular signal regulated kinase 1 and 2 (ERK1/2) and p38 MAPK. ERK1/2 and p38 MAPK activation was differential, ERK1/2 being rapid and transient while that of p38 MAPK slow and sustained. Using selective inhibitors, activation of ERK1/2 was shown to involve protein kinase C and MEK1/2 while that of p38 MAPK was regulated by both protein kinase C and protein kinase A. Furthermore, we show that purinergic stimulation induces the phosphorylation of the MAPK downstream target, mitogen- and stress-activated protein kinase 1 (MSK1), in cardiac myocytes. The time course of MSK1 phosphorylation closely follows that of ERK activation. Inhibitors of the ERK and p38 MAPK pathways were tested on the phosphorylation of MSK1 at two different time points. The results suggest that ERKs initiate the response but both ERKs and p38 MAPK are required for the maintenance of the complete phosphorylation of MSK1. The temporal relationship of MSK1 phosphorylation and cPLA2 translocation induced by purinergic stimulation, taken together with previous findings, is an indication that cPLA2 may be a downstream target of MSK1.
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PMID:Regulation of MAPK pathways in response to purinergic stimulation of adult rat cardiac myocytes. 1261 79

Mucin hypersecretion is commonly observed in many inflammatory diseases of the respiratory tract. MUC5AC is generally recognized to be a major airway mucin because MUC5AC is highly expressed in the goblet cells of human airway epithelium. Moreover, it is regulated by various inflammatory cytokines. However, the mechanisms by which the interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induce MUC5AC gene expression in normal nasal epithelial cells, and the signal molecules involved, especially in the downstream signaling of mitogen-activated protein (MAP) kinases, remain unclear. Here we show that pharmacologic or genetic inhibition of either ERK or p38 MAP kinase pathway abolished IL-1beta- and TNF-alpha-induced MUC5AC gene expression in normal human nasal epithelial cells. Our results also indicate that the activation of mitogen- and stress-activated protein kinase 1 (MSK1) and cAMP-response element-binding protein and cAMP-response element signaling cascades via ERK and p38 MAP kinases are crucial aspects of the intracellular mechanisms that mediate MUC5AC gene expression. Taken together, these studies give additional insights into the molecular mechanism of IL-1beta- and TNF-alpha-induced MUC5AC gene expression and enhance our understanding on mucin hypersecretion during inflammation.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells. 1269 Jan 13

Activation of the Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signal transduction pathway or the SAPK2/p38 pathway results in the activation of mitogen- and stress-activated protein kinase 1 (MSK1). This activation of MSK1 leads to a rapid phosphorylation of histone H3 at Ser(10). Previously, we had demonstrated that Ser(10) phosphorylated H3 was elevated in Ciras-3 (c-Ha-ras-transformed 10T12) mouse fibroblasts and that H3 phosphatase activity was similar in Ciras-3 and 10T12 cells. Here, we demonstrate that the activities of ERK and MSK1, but not p38, are elevated in Ciras-3 cells relative to these activities in the parental 10T12 cells. Analyses of the subcellular distribution of MSK1 showed that the H3 kinase was similarly distributed in Ciras-3 and 10T12 cells, with most MSK1 being present in the nucleus. In contrast to many other chromatin modifying enzymes, MSK1 was loosely bound in the nucleus and was not a component of the nuclear matrix. Our results provide evidence that oncogene-mediated activation of the Ras-mitogen-activated protein kinase signal transduction pathway elevates the activity of MSK1, resulting in the increased steady-state levels of phosphorylated H3, which may contribute to the chromatin decondensation and aberrant gene expression observed in these cells.
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PMID:Mitogen- and stress-activated protein kinase 1 activity and histone h3 phosphorylation in oncogene-transformed mouse fibroblasts. 1560 75

The mitogen-activated protein kinase cascades elicit modification of chromatin proteins such as histone H3 by phosphorylation concomitant with gene activation. Here, we demonstrate for the first time that the mixed lineage kinase-like mitogen-activated protein triple kinase (MLTK)-alpha phosphorylates histone H3 at Ser28. MLTK-alpha but neither a kinase-negative mutant of MLTK-alpha nor MLTK-beta interacted with and phosphorylated histone H3 in vivo and in vitro. When overexpressed in 293T or JB6 Cl41 cells, MLTK-alpha phosphorylated histone H3 at Ser28 but not at Ser10. The interaction between MLTK-alpha and histone H3 was enhanced by stimulation with ultraviolet B light (UVB) or epidermal growth factor (EGF), which resulted in the accumulation of MLTK-alpha in the nucleus. UVB- or EGF-induced phosphorylation of histone H3 at Ser28 was not affected by PD 98059, a MEK inhibitor, or SB 202190, a p38 kinase inhibitor, in MLTK-alpha-overexpressing JB6 Cl41 cells. Significantly, UVB- or EGF-induced phosphorylation of histone H3 at Ser28 was blocked by small interfering RNA of MLTK-alpha. The inhibition of histone H3 phosphorylation at Ser28 in the MLTK-alpha knock-down JB6 Cl41 cells was not due to a defect in mitogen- and stress-activated protein kinase 1 or 90-kDa ribosomal S6 kinase (p90RSK) activity. In summary, these results illustrate that MLTK-alpha plays a key role in the UVB- and EGF-induced phosphorylation of histone H3 at Ser28, suggesting that MLTK-alpha might be a new histone H3 kinase at the level of mitogen-activated protein kinase kinase kinases.
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PMID:Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha. 1568 25

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

The interaction of Borrelia burgdorferi, the causative agent of Lyme borreliosis, with phagocytic cells induces the activation of NF-kappaB and the expression of proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha). B. burgdorferi-induced TNF-alpha production is also dependent on the activation of p38 mitogen-activated protein (MAP) kinase. The specific contribution of these signaling pathways to the response of phagocytic cells to the spirochete and the molecular mechanisms underlying this response remain unresolved. We now show that p38 MAP kinase activity regulates the transcriptional activation of NF-kappaB in response to spirochetal lysate stimulation of phagocytic cells. The regulation occurs at the nuclear level and is independent of the translocation of the transcription factor to the nucleus or its capacity to bind to specific DNA target sequences. In RAW264.7 cells, p38alpha MAP kinase regulates the phosphorylation of NF-kappaB RelA. p38 MAP kinase phosphorylates the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 in turn phosphorylates the transcriptionally active subunit of NF-kappaB, RelA. The repression of MSK1 expression with small interfering RNA results in reduced RelA phosphorylation and a significant decrease in the production of TNF-alpha in response to B. burgdorferi lysates. Overall, these results clarify the contribution of the signaling pathways that are activated in response to the interaction of spirochetes with phagocytic cells to TNF-alpha production. Our results situate p38 MAP kinase activity as a central regulator of the phagocytic proinflammatory response through MSK1-mediated transcriptional activation of the transcription factor NF-kappaB.
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PMID:p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to Borrelia burgdorferi antigens. 1707 60

The activity of the p38 mitogen-activated protein kinases (MAPKs) is increased in lesional psoriatic skin, supporting a possible role of these kinases in the pathogenesis of psoriasis. Recently, increased focal activation of the downstream target mitogen- and stress-activated protein kinase 1 (MSK1) was demonstrated in psoriatic epidermis. The purpose of this study is to investigate MSK2 and the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) in psoriatic skin and in cultured normal human keratinocytes. In lesional psoriatic skin, significantly increased MSK2 (Ser196) and CREB (Ser133) activation was demonstrated by phospho blotting. Immunofluorescence staining of phosphorylated MSK2 (Ser196) revealed colocalization with phosphorylated MSK1 (Thr 581) in the epidermis. Keratinocyte cultures stimulated with anisomycin and IL-1beta showed increased MSK2 (Ser196) and CREB (Ser133) phosphorylation. Such activation was abolished during preincubation with a p38 inhibitor. Keratinocytes transfected with small interfering RNA showed a stronger decrease in CREB phosphorylation in MSK1/2 double-transfected cells than in MSK1 and MSK2 single-transfected cells. This study demonstrate for the first time the expression of MSK2 in keratinocytes and increased MSK2 and CREB activation in lesional psoriatic skin. Our results indicate that the p38-MAPK/MSK1/MSK2 and CREB signalling pathway may play a role in the pathogenesis of psoriasis.
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PMID:Mitogen- and stress-activated protein kinase 2 and cyclic AMP response element binding protein are activated in lesional psoriatic epidermis. 1742 37