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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) of Gram-negative bacteria interacts with a CD14-independent receptor of mouse bone marrow granulocytes (BMC), and triggers in these cells the expression of CD14, an inducible type of LPS receptor (iLpsR). This particular response of BMC to LPS required the activation of protein tyrosine kinase and p38 MAP kinase. The inhibition of the LPS effect by the MEK inhibitor PD-98059 suggested that the ERK pathway was also involved. Unexpectedly, protein kinase C, myosin light chain kinase, cAMP-, cGMP-, and Ca(2+)/calmodulin-dependent kinases, as well as ecto-protein kinases, were not required for iLpsR expression. However, other yet unidentified serine/threonine protein kinase(s) were implied since the BMC response to LPS was markedly reduced after exposure to three inhibitors of such kinases (K-252a, H-7, and KT-5823). The atypical kinase requirements observed in this study may be due either to a novel signaling LPS receptor complex present in BMC, or to the particular events involved in CD14 biosynthesis.
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PMID:Protein phosphorylation pathways involved during lipopolysaccharide-induced expression of CD14 in mouse bone marrow granulocytes. 1086 78

We report here that the cyclic GMP-inhibited cyclic AMP specific phosphodiesterase (PDE3B) is expressed as a membrane-bound protein in clonal insulin-secreting BRIN-BD11 cells. This was shown using SKF94836 (PDE3 inhibitor) which maximally inhibited membrane-bound cyclic AMP PDE activity by approximately 25-30% and by RT-PCR. We also demonstrated that insulin growth factor-1 (IGF-1) activates PDE3B in BRIN-BD11 cells. We therefore evaluated the role of phosphoinositide 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) pathways in regulating this enzyme. We report here that the PI3K inhibitor, wortmannin, prevented the IGF-1-dependent stimulation of PDE3B activity. In contrast, the inhibitor of MEK-1 activation, PD098059 (which reduced IGF-1-stimulated p42/p44 MAPK phosphorylation), had no effect on PDE3B activation. Furthermore, IGF-1-dependent stimulation of p42/p44 MAPK and PDE3B was abolished in serum-deprived cells and this was associated with apoptosis. We propose that the deregulation of the PI3K/PDE3B pathway might result in increased intracellular cyclic AMP accumulation, which promotes apoptosis. This was supported by the finding that the adenylyl cyclase activator, forskolin, also induced apoptosis. Finally, we found that orthovanadate (a phosphotyrosine phosphatase inhibitor) fully restored the activation of p42/p44 MAPK in serum-deprived cells, but had only a small effect on PDE activity. This confirmed that p42/p44 MAPK is on a separate pathway to PDE3B. Therefore, IGF-1-dependent regulation of PDE3B may be linked to cell survival through PI3K and not p42/p44 MAPK.
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PMID:The role of the cyclic GMP-inhibited cyclic AMP-specific phosphodiesterase (PDE3) in regulating clonal BRIN-BD11 insulin secreting cell survival. 1102 47

Interaction between p38MAPK and p42/44MAPK in rat pinealocytes was examined by determining the effects of p38MAPK inhibitors on the phosphorylation of p42/44MAPK using Western blot analysis. Treatment with SB202190, a specific inhibitor of p38MAPK, increased p42/44MAPK phosphorylation in a concentration-dependent manner. SB202190 also enhanced the magnitude and the duration of norepinephrine-activated p42/44MAPK phosphorylation. The effect of SB202190 on p42/44MAPK phosphorylation was abolished by PD98059 or UO126, inhibitors of MEK, suggesting that SB202190 is acting upstream of MEK in activating p42/44MAPK. The SB202190-induced phosphorylation of p42/44MAPK was not blocked by inhibitors of cGMP-dependent kinase (KT5823), protein kinase C (calphostin C) or Ca2+/calmodulin dependent kinase (KN93) suggesting that these pathways may not be involved in the effect of SB202190. SB202190 further increased p42/44MAPK phosphorylation that was stimulated by 8-bromo-cGMP, 4beta phorbol 12-myristate 13-acetate, or ionomycin. In contrast, inhibition of p42/44MAPK phosphorylation by dibutyryl-cAMP persisted when p42/44MAPK phosphorylation was increased by SB202190. Furthermore, inhibition of p42/44MAPK phosphorylation had no effect on p38MAPK activation. These results suggest that inhibition of p38MAPK causes activation of p42/44MAPK and acts synergistically with norepinephrine in the regulation of p42/44MAPK activation in rat pinealocytes.
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PMID:p38MAPK inhibition enhances basal and norepinephrine-stimulated p42/44MAPK phosphorylation in rat pinealocytes. 1108 54

We reported previously that vascular endothelial growth factor (VEGF) stimulates prostacyclin (PGI(2)) production via activation of the extracellular signal-regulated kinase (ERK) cascade. In this paper, we examined the role of protein kinase C (PKC) in this pathway. VEGF-induced PGI(2) generation and arachidonic acid release in human umbilical vein endothelial cells were inhibited by the PKC inhibitors GF109203X and calphostin C. VEGF increased PKC activity and immunoreactivity of the PKCdelta, alpha and epsilon isoforms in particulate fractions of cells. PKC inhibitors blocked VEGF-induced activation of ERK, MEK (mitogen-activated protein kinase kinase) and the cytosolic phospholipase A(2), but had little effect on ERK activation induced by basic fibroblast growth factor. GF109203X, calphostin C and the PKCdelta-selective inhibitor, rottlerin, did not inhibit activation of the KDR receptor for VEGF. Inhibition of Ca(2+) fluxes using BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] blocked VEGF-induced PGI(2) production but did not inhibit ERK activation. Neither activation nor inhibition of the NO/cGMP pathway had any effect on VEGF induction of ERK activity and PGI(2) synthesis. Wortmannin partially inhibited VEGF stimulation of PGI(2) production, but did not inhibit VEGF-induced ERK activity. VEGF-induced ERK activation and PGI(2) production were blocked by rottlerin, and VEGF increased association of PKCdelta with Raf-1, the upstream activator of MEK. The PKC-selective inhibitor Go6976 did not inhibit ERK activation and had only a partial effect on PGI(2) production. These findings indicate that activation of PKC plays a crucial role in VEGF signalling via the ERK cascade leading to PGI(2) synthesis and suggest that the PKCdelta isoform may be a key mediator of VEGF-induced activation of the ERK pathway via increased association with Raf-1.
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PMID:Vascular endothelial growth factor-induced prostacyclin production is mediated by a protein kinase C (PKC)-dependent activation of extracellular signal-regulated protein kinases 1 and 2 involving PKC-delta and by mobilization of intracellular Ca2+. 1117 Oct 46

We have studied the ability of cGMP and cAMP to modulate platelet-derived growth factor (PDGF)-stimulated 2-deoxy-D-glucose (deGlc) transport in primary cultures of vascular smooth muscle cells (VMSC) from rat aorta. PDGF stimulated deGlc transport in a time- and concentration-dependent manner. 8-Bromo-cGMP and atrial natriuretic peptide(1-28) [ANP(1-28)] were found to reduce PDGF-stimulated deGlc transport without affecting basal (unstimulated) transport activity. In contrast, 8-bromo-cAMP and dibutyryl-cAMP stimulated basal deGlc transport 2-fold and were without effect on PDGF-stimulated deGlc transport. 8-Bromo-cGMP also inhibited 8-bromo-cAMP-stimulated deGlc transport. The stimulation of deGlc transport by PDGF was sensitive to the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase (MEK) inhibitor PD98059, and we show that ERK1/2 was activated by PDGF. Neither 8-bromo-cGMP nor ANP(1-28) inhibited PDGF-stimulated ERK activation, suggesting that the effects of cGMP and ANP(1-28) were not mediated by inhibition of this kinase. Our data also argue against a role for cGMP-dependent protein kinase in mediating the effects of cGMP or ANP(1-28). Collectively, our data suggest that in VSMC: (i) cGMP and cAMP have opposing effects on deGlc transport; (ii) PDGF and cAMP have common elements in the pathways by which they activate deGlc transport; and (iii) a common element may be the target of the cGMP-mediated inhibition of deGlc transport.
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PMID:Regulation of glucose transport in aortic smooth muscle cells by cAMP and cGMP. 1117 Oct 47

Nitric oxide (NO) induces apoptosis in cardiac myocytes through an oxidant-sensitive mechanism. However, additional factors appear to modulate the exact timing and rate of NO-dependent apoptosis. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] 1/2, and p38MAPK) in NO-mediated apoptotic signaling. The NO donor S:-nitrosoglutathione (GSNO) induced caspase-dependent apoptosis in neonatal rat cardiac myocytes, preceded by a rapid (<10-minute) and significant (approximately 50-fold) activation of JNK1/2. Activation of JNK was cGMP dependent and was inversely related to NO concentration; it was maximal at the lowest dose of GSNO (10 micromol/L) and negligible at 1 mmol/L. NO slightly increased ERK1/2 beginning at 2 hours but did not affect p38MAPK activity. Inhibitors of ERK and p38MAPK activation did not affect cell death rates. In contrast, expression of dominant-negative JNK1 or MKK4 mutants significantly increased NO-induced apoptosis at 5 hours (56.77% and 57.37%, respectively, versus control, 40.5%), whereas MEKK1, an upstream activator of JNK, sharply reduced apoptosis in a JNK-dependent manner. Adenovirus-mediated expression of dominant-negative JNK1 both eliminated the rapid activation of JNK by NO and accelerated NO-mediated apoptosis by approximately 2 hours. These data indicate that NO activates JNK as part of a cytoprotective response, concurrent with initiation of apoptotic signaling. Early, transient activation of JNK serves both to delay and to reduce the total extent of apoptosis in cardiac myocytes.
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PMID:Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis. 1117 98

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac is associated with a decreased mortality from colorectal cancer. Sulindac causes regression of precancerous adenomatous polyps and inhibits the growth of cultured colon cell lines. Whereas induction of apoptotic cell death is thought to account for the growth inhibitory effect of sulindac, less is known about its biochemical mechanism(s) of action. Sulindac is metabolized in vivo to sulfide and sulfone derivatives. Both the sulfide and sulfone metabolites of sulindac as well as more potent cyclic GMP-dependent phosphodiesterase inhibitors were shown to cause inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation at doses (40-600 microM) and times (1-5 days) consistent with the induction of apoptosis by the drugs. Treatment of HCT116 human colon cancer cells with the specific mitogen-activated protein kinase kinase, U0126 (5-50 microM) resulted in a time- and dose-dependent inhibition of ERK1/2 phosphorylation, and induction of apoptosis. U0126 treatment (20 microM) increased basal apoptosis, and potentiated the apoptotic effect of sulindac sulfide and sulindac sulfone. These results suggest that the inhibition of ERK1/2 phosphorylation is responsible for at least part of the induction of programmed cell death by sulindac metabolites. Inhibition of ERK1/2 activity may, therefore, be a useful biochemical target for the development of chemopreventive and chemotherapeutic drugs for human colon cancer.
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PMID:Inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and induction of apoptosis by sulindac metabolites. 1124 63

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF-mediated EC activation. EC apoptosis is likely important in the process termed "plaque erosion" that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide-dependent protective pathways that involve enzymes PI3-kinase and Akt. Conversely, our laboratory has identified nitric oxide-independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen-activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF-mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre-exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen-activated protein kinase kinase inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Flow-mediated inhibition of JNK was unaffected by 0.1 mM L-nitroarginine, 100 pM 8-bromo-cyclic GMP, or 100 microM 8-bromo-cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow-mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.
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PMID:Endothelial atheroprotective and anti-inflammatory mechanisms. 1179 13

We previously showed that CGP 42112 (an angiotensin type 2 [AT(2)] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT(2), a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT(1)) and AT(2), in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT(1) antagonist that selectively simulates AT(2) stimulation) and the effect of Ang II plus PD 123319 (an AT(2) antagonist that selectively simulates AT(1) stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT(2), in a similar manner to that found with CGP 42112. Stimulation of AT(1) significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT(2) stimulation significantly inhibited TH enzyme activity, whereas AT(1) stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT(1) was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT(2) on TH enzyme activity, indicating that the stimulatory effect of AT(2) may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT(2) stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT(1) stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT(2) reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT(1) stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT(1) and AT(2) have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.
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PMID:Angiotensin II type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. 1179 93

The functional role of p53 in nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53-/- and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53-/- VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53-/- cells. NO-induced apoptosis in p53-/- VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53-/- VSMC with S-nitroso-N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH(2)-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.
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PMID:Potentiation of nitric oxide-induced apoptosis in p53-/- vascular smooth muscle cells. 1183 48


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