EC:2.7.11.24 - FACTA Search

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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)

MAP kinase phosphatase 3 (MKP3, also known as DUSP6 and PYST1) is involved in extracellular signal receptor kinase (ERK) regulation and functions as a specific phosphatase to the activated (phosphorylated) forms of ERK1 and ERK2. MKP3 displays allosteric activation, which aids in tightly regulating its function to ERK substrates, but not other related MAPKs. Due to MKP3's specificity for the ERK signaling pathway, the development of specific activators or inhibitors to the enzyme have been suggested in order to expressly influence the ERK1 and ERK2 pathways. To produce the high yields of MKP3 protein necessary for physico-chemical characterization of MKP3 and for high throughput screening of its small-molecule activators and inhibitors, we have cloned, purified and, and identified refolding conditions suitable for producing full-length, human MKP3 from Escherichia coli inclusion bodies. Furthermore, we demonstrate the use of a 96-well plate format refolding assay in which the ERK-induced activity of MKP3 is simulated by 33% DMSO. The assay allowed for rapid detection of MKP3's function following a refolding screen in the absence of ERK and thus provides quick and inexpensive testing of MKP3 activity. Following screening, the refolded product was confirmed to be correctly folded by steady-state kinetic analysis and by the CD spectroscopy-determined secondary structure content. CD data were consistent with 36% helix and 14% sheet, which compared to an expected 32.9% helix and 12.4% sheet. These data indicated that MKP3 was properly folded, making it a suitable protein for use in functional studies.
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PMID:Over-expression and refolding of MAP kinase phosphatase 3. 1745 23

Our previous study has shown that anti-Thy-1 antibody promotes neurite outgrowth of cultured dorsal root ganglion (DRG) neurons in a protein kinase A (PKA)-dependent manner. The present study provided another intracellular signaling pathway for the neurotrophic effect of anti-Thy-1 antibody. In DMSO-treated control cells, Thy-1 was enriched in microdomain-like structures on cell membranes by immunofluorescence observation. Treatment of DRG neurons with anti-Thy-1 antibody not only stimulated neurite outgrowth, but also increased the branching complexity of the neurites in both small and large neurons. We have previously shown that anti-Thy-1 antibody causes a time-dependent activation of mitogen-activated protein kinase (MEK) and of cyclic AMP response-element binding protein (CREB). Here, anti-Thy-1 antibody elicited a transient activation of c-Src kinase, and the activation of c-Src kinase appeared occurring upstream of the activation of MEK and CREB, since pretreatment with the Src kinase inhibitor, PP2, effectively abolished the anti-Thy-1 antibody-induced neurite outgrowth and the phosphorylation of MEK and CREB. CREB phosphorylation might result in upregulation of certain neurite outgrowth-related proteins. We therefore conclude that anti-Thy-1 antibody activates the c-Src kinase-MEK-CREB cascade and overcomes the inhibitory effect of Thy-1 on neurite outgrowth in DRG neurons.
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PMID:Anti-Thy-1 antibody-induced neurite outgrowth in cultured dorsal root ganglionic neurons is mediated by the c-Src-MEK signaling pathway. 1748 86

Although 17beta-estradiol administration following trauma-hemorrhage prevents the suppression in splenic macrophage cytokine production, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta and which signaling pathways are involved in such 17beta-estradiol effects. Utilizing ER-alpha- or ER-beta-specific agonists, this study examined the role of ER-alpha and ER-beta in 17beta-estradiol-mediated restoration of macrophage cytokine production following trauma-hemorrhage. In addition, since MAPK and NF-kappaB are known to regulate macrophage cytokine production, we also examined the activation of those signaling molecules. Male rats underwent trauma-hemorrhage (mean arterial pressure of 40 mmHg for 90 min) and fluid resuscitation. The ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), the ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), 17beta-estradiol (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic macrophages were isolated, and their IL-6 and TNF-alpha production and activation of MAPK and NF-kappaB were measured. Macrophage IL-6 and TNF-alpha production and MAPK activation were decreased, whereas NF-kappaB activity was increased, following trauma-hemorrhage. PPT or 17beta-estradiol administration after trauma-hemorrhage normalized those parameters. DPN administration, on the other hand, did not normalize the above parameters. Since PPT but not DPN administration following trauma-hemorrhage was as effective as 17beta-estradiol in preventing the suppression in macrophage cytokine production, it appears that ER-alpha plays the predominant role in mediating the salutary effects of 17beta-estradiol on macrophage cytokine production following trauma-hemorrhage and that such effects are likely mediated via normalization of MAPK but not NF-kappaB signaling pathways.
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PMID:Estrogen receptor-alpha predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage. 1755 37

D-Galactosamine (D-Galn: 300 mg/kg) was intraperitoneally administered to rats. After 6 h the activity of plasma GOT and GPT was significantly higher than that of the control group and plasma GOT and GPT activities increased thereafter. These results indicated that the necrotic process was initiated at about 6 h and developed thereafter. With coadministration of DMSO (1 h before administration of D-Galn: 2.5 mL/kg, oral), plasma GOT and GPT were significantly lower, showing that DMSO inhibited the necrotic action of D-Galn. After 6-24 h of D-Galn administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced 6 h after D-Galn intoxication and thereafter. DMSO significantly restored the liver vitamin C level 24 h after D-Galn injection, demonstrating that DMSO effectively ameliorated the oxidative stress caused by D-Galn, resulting in the prevention of necrosis of the liver. Phosphorylated JNK and phospho-ERK were significantly increased transiently 6-12 h after treatment with D-Galn. These results indicated that oxidative stress and the activation of JNK took place almost simultaneously. Phosphorylated p38 MAPK was not changed and DMSO treatment did not affect the change of these MAPKs by D-Galn.
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PMID:Inhibitory effect of dimethyl sulfoxide (DMSO) on necrosis and oxidative stress caused by D-galactosamine in the rat liver. 1761 4

Atherosclerosis is a key factor in vascular disease, and cigarette smoking is a well-known risk factor that may induce an inflammatory response and enhance plaque formation in arteries. Thromboxane (Tx) is one key inflammatory mediator involved in the pathogenesis of cardiovascular disease. The present study was designed to test if lipid soluble smoking particles (DSP) enhance TxA(2) receptor (TP) expression in rat mesenteric arteries, and if intracellular mitogen-activated protein kinase (MAPK) pathways play a role. Organ culture of rat mesenteric arteries in the presence of DSP (0.2 microl/ml for 24h) resulted in markedly elevated contractile responses to the Tx analog U46619, compared with the control DMSO. There was no increase in TP receptor mRNA expression, while the protein expression was significantly enhanced. This up-regulation was not affected by a general transcriptional inhibitor actinomycin D, but was almost completely abolished by cycloheximide, a general translational inhibitor. Dexamethasone, a glucocorticoid, manifested a potent inhibitory effect as well. These results suggest that the up-regulation of TP receptor occurs via post-transcriptional events, and mainly translation. This is supported by experiments with specific inhibitors for c-Jun-NH(2)-terminal kinase (SP600125), extracellular signal-regulated kinase 1 and 2 (PD98059 and U0126) and p38 (SB203580) that had no inhibitory effect on the up-regulation of TP receptors. Collectively, the results show that MAPK pathways are not involved in TP receptor up-regulation. Study on TP receptor mRNA stability showed that during organ culture, the TP receptor mRNA was stable in both DMSO and DSP group, but the latter elicited a tendency to stabilize the TP receptor mRNA at higher level. Thus, post-transcriptional mechanisms are responsible for the up-regulation of TP receptor by DSP, in which enhanced translation is the major cause of the elevated protein expression and the enhanced contraction.
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PMID:Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms. 1770 24

Protease-activated receptor-2 (PAR-2) may have proinflammatory effects in some tissues and protective effects in other tissues. The role of PAR-2 in in vivo myocardial ischemia-reperfusion has not yet been determined. This study tested the hypothesis that PAR-2 activation with the PAR-2 agonist peptide SLIGRL (PAR-2 AP) reduces myocardial infarct size when given at reperfusion in vivo, and this cardioprotection involves the ERK1/2 pathway. Anesthetized rats were randomly assigned to the following groups with 30 min of regional ischemia and 3 h reperfusion: 1) control with saline; 2) vehicle (DMSO); 3) PAR-2 AP, 1 mg/kg given intravenously 5 min before reperfusion; 4) scrambled peptide (SP), 1 mg/kg; 5) the ERK1/2 inhibitor PD-98059 (PD), 0.3 mg/kg given 10 min before reperfusion; 6) the phosphatidylinositol 3-kinase inhibitor LY-294002 (LY), 0.3 mg/kg given 10 min before reperfusion; 7) PD + PAR-2 AP, 0.3 mg/kg PD given 5 min before PAR-2 AP; 8) LY + PAR-2 AP, 0.3 mg/kg LY given 5 min before PAR-2 AP; 9) chelerythrine (Chel) alone, 5 mg/kg given 10 min before reperfusion; and 10) Chel + PAR-2 AP, Chel was given 5 min before PAR-2 AP (10 min before reperfusion). Activation of ERK1/2, ERK5, Akt, and the downstream targets of ERK1/2 [P90 RSK and bcl-xl/bcl-2-associated death promoter (BAD)] was determined by Western blot analysis in separate experiments. PAR-2 AP significantly reduced infarct size compared with control (36 +/- 2% vs. 53 +/- 1%, P < 0.05), and SP had no effect on infarct size (53 +/- 3%). PAR-2 AP significantly increased phosphorylation of ERK1/2, p90RSK, and BAD but not Akt or ERK5. Accordingly, the infarct-size sparing effect of PAR-2 AP was abolished by PD (PAR-2 AP, 36 +/- 2% vs. PD + PAR-2 AP, 50 +/- 1%; P < 0.05) and by Chel (Chel + PAR-2 AP, 58 +/- 2%) but not by LY (PAR-2 AP, 36 +/- 2% vs. LY + PAR-2 AP, 38 +/- 3%; P > 0.05). Therefore, PAR-2 activation is cardioprotective in the in vivo rat heart ischemia-reperfusion model, and this protection involves the ERK1/2 pathway and PKC.
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PMID:PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts. 1772 Jul 72

1. Activation of p38-mitogen-activated protein kinase (MAPK) has been implicated in the signalling cascade leading to protection by ischaemic preconditioning. This, however, is controversial and there is a plethora of conflicting data in the literature. Although many experimental differences may contribute to this, two in particular may be confounding: (i) the failure to account for p38-MAPK activation during aerobic perfusion; and (ii) the use of the anti-oxidant dimethylsulphoxide (DMSO) as the vehicle for the commonly used p38-MAPK inhibitor SB203580. We have investigated the effects of aerobic perfusion, ischaemia and preconditioning on p38-MAPK activation. In addition, we have used water-soluble SB203580 hydrochloride (SB203580.HCl) and DMSO to probe the role of p38-MAPK in preconditioning and ischaemic injury. 2. Activation of p38-MAPK in rat isolated hearts was assessed using a dual phosphospecific antibody during cannulation, aerobic perfusion and index, autolytic and preconditioned ischaemia. The effect of SB203580.HCl (10 mmol/L) in ischaemic preconditioning and ischaemia/reperfusion was tested using recovery of function and tetrazolium (TTC) staining as end-points. 3. Aerobic perfusion induced rapid activation (34% of maximal ischaemia-induced increase; P < 0.05) of p38-MAPK after 2 min that returned to baseline after 30 min. Index, autolytic and preconditioned ischaemia activated p38-MAPK, with index ischaemia peaking after 15 min (520% of basal; P < 0.05) before declining. SB203580.HCl blocked p38-MAPK activity, but did not block ischaemic preconditioning when bracketing the trigger phase and was not protective when given during ischaemia. 4. In the rat isolated heart, activation of p38-MAPK is neither a unique feature of preconditioning nor a prerequisite. Previous studies using SB203580 may have been complicated by failure to account for the activation of p38-MAPK by the protocol itself and the anti-oxidant properties of the most commonly used vehicle DMSO.
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PMID:Role of p38-mitogen-activated protein kinase in ischaemic preconditioning in rat heart. 1789 5

The differentiation of promyelocytic leukemic cells into mature cells is the major strategy for drug-based treatment of leukemia. Higher efficient methods to differentiate promyelocytic leukemic cells have been developed using various differentiation inducers including interferon-alpha, interleukin-4, tumor necrosis factor-alpha (TNF-alpha), and dimethyl sulfoxide (DMSO) as a single agent or in combination with each other. Here, we show that a combination of TNF-alpha with DMSO shows a synergic effect on HL-60 cell differentiation through the activation of ERK pathway. TNF-alpha enhanced CD11b expression and percent of cell population in the G1 phase induced by DMSO, which are hallmarks for HL-60 cell differentiation. Inhibition of ERK pathway abolished the synergic effect of TNF-alpha in combination with DMSO on HL-60 differentiation, but the inhibition NF-kappaB pathway did not. These results suggest that TNF-alpha synergistically increases DMSO-induced differentiation of HL-60 cells through the activation of ERK/MAPK-signaling pathway.
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PMID:Tumor necrosis factor-alpha enhances DMSO-induced differentiation of HL-60 cells through the activation of ERK/MAPK pathway. 1825 85

Exemestane-resistant breast cancer cell lines (i.e., ExeR), derived from MCF-7 cells expressing a high level of aromatase (MCF-7aro), were generated in our laboratory. The epidermal growth factor (EGF)-like protein amphiregulin (AREG) was highly expressed in ExeR cells based on cDNA microarray analysis. The high levels of AREG mRNA in ExeR cell lines were confirmed by real-time reverse transcription-PCR. The high levels of AREG protein in ExeR cell lysates and culture media were confirmed by Western blot analysis and ELISA, respectively. Furthermore, our Western blot analysis showed that whereas no AREG was detected in the DMSO control, overnight treatment of parental MCF-7aro cells with 1 micromol/L exemestane strongly induced the expression of AREG. This induction was totally blocked by 100 nmol/L of pure antiestrogen ICI 182,780, implying estrogen receptor (ER) dependence of exemestane-induced AREG expression. MCF-7aro cells were not able to proliferate in hormone-free medium, but were able to proliferate in conditioned medium from ExeR cells, similar to the treatment of recombinant human AREG. Small interference RNA targeting AREG inhibited ExeR proliferation, confirming that AREG is truly functioning as a growth factor of ExeR cells. The specific inhibitors to ER (ICI 182,780), EGF receptor (EGFR; AG1478), and mitogen-activated protein kinase (MAPK; U0126) all showed dose-dependent suppression of the proliferation of ExeR cells, indicating the involvement of the ER, EGFR, and MAPK pathways. Based on these findings, we propose a possible mechanism that underlies exemestane resistance: exemestane induces AREG in an ER-dependent manner. AREG then activates the EGFR pathway and leads to the activation of the MAPK pathway that drives cell proliferation.
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PMID:The role of amphiregulin in exemestane-resistant breast cancer cells: evidence of an autocrine loop. 1838 32

Magnolol, an active component extracted from Magnolia officinalis, has been reported to have protective effect on ischemia and reperfusion (I/R)-induced injury in experimental animals. The aim of the present investigation was to further evaluate the mechanism(s) by which magnolol reduces I/R-induced myocardial injury in rats in vivo. Under anesthesia, left anterior descending (LAD) coronary artery was occluded for 30 min followed by reperfusion for 24 h (for infarct size and cardiac function analysis). In some experiments, reperfusion was limited to 1 h or 6 h for analysis of biochemical and molecular events. Magnolol and DMSO solution (vehicle) were injected intra-peritoneally 1 h prior to I/R insult. The infarct size was measured by TTC technique and heart function was monitored by Millar Catheter. Apoptosis related events such as p-ERK, p-Bad, Bcl-xl and cytochrome c expression were evaluated by Western blot analysis and myocardial caspase-3 activity was also measured. Magnolol (10 mg/kg) reduced infarct size by 50% (P < 0.01 versus vehicle), and also improved I/R-induced myocardial dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in magnolol-treated rats. Magnolol increased the expression of phosphor ERK and Bad which resulted in inhibition of myocardial apoptosis as evidenced by TUNEL analysis and DNA laddering experiments. Application of PD 98059, a selective MEK1/2 inhibitor, strongly antagonized the effect of magnolol. Taken together, we concluded that magnolol inhibits apoptosis through enhancing the activation of ERK1/2 and modulation of the Bcl-xl proteins which brings about reduction of infarct size and improvement of cardiac function in I/R-induced injury.
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PMID:Anti-apoptotic effect of magnolol in myocardial ischemia and reperfusion injury requires extracellular signal-regulated kinase1/2 pathways in rat in vivo. 1864 Oct 58

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