Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collecting ducts are a major site of renal production and action of both prostaglandins and nitric oxide. Experiments were undertaken to examine whether nitric oxide regulates cyclooxygenase (COX)-2 expression and PGE(2) release in cultured collecting duct cells. In mIMCD-K2 cells, sodium nitroprusside (SNP) in the 50- to 800-microM range induced a marked dose- and time-dependent increase in COX-2 protein levels, determined by immunoblotting, and the induction was detectable at 4 h. This was preceded by induction of COX-2 mRNA as determined by real-time-RT-PCR. The COX-2 induction was accompanied by a significant rise in PGE(2) release as determined by enzyme immunoassay. S-nitroso-N-acetylpenicillamine (SNAP) had a similar stimulatory effect on COX-2 expression and PGE(2) release. 8-bromo-cGMP (200 microM) had no effect on COX-2 expression. The SNP-stimulated COX-2 expression was not affected by the guanylyl cyclase inhibitor methylene blue or the protein kinase G inhibitor KT-5823 (2.0 microM). In contrast, the SNP-stimulated COX-2 expression was significantly reduced by either the Erk1/2 inhibitor PD-98059 or the P38 inhibitor SB-203580 and was abolished by combination of the two kinase inhibitors. The stimulation was also significantly blocked by the SOD mimetic tempol. Thus we conclude that NO stimulates COX-2 expression in collecting duct cells through mechanisms involving MAP kinase and superoxide, but not cGMP.
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PMID:Nitric oxide stimulates COX-2 expression in cultured collecting duct cells through MAP kinases and superoxide but not cGMP. 1670 45

Previously, we reported that 2,2'-dichlorobiphenyl (2,2'-DCB)-induced decreases of amplitude and synchronization of uterine contractions are dependent on MAPK-induced phosphorylation of Connexin43 (Cx43) and inhibition of myometrial gap junctions. Recent studies show that oxidative stress inhibits uterine contractions and myometrial gap junctions also. The present study examines the hypothesis that 2,2'-DCB-induced modification of uterine contraction is dependent on oxidative stress-mediated inhibition of myometrial gap junctions via activation of mitogen-activated protein kinase (MAPK) and phosphorylation of Cx43. In uterine strips treated with alpha-tocopherol (100 microM), deferoxamine mesylate (Def, 50 microM), or superoxide dismutase (SOD, 1000 U) after a 1-h exposure to 100 microM 2,2'-DCB, modification of uterine contractions reversed 1 h after initiating antioxidant treatment. Treatment of uterine strips with 100 microM 2,2'-DCB for 1 h lowered total SOD activity and also induced a surge of superoxide generation after 5 min of exposure. However, myometrial cells exposed in culture to 100 microM 2,2'-DCB did not produce reactive oxygen species as determined by the lack of superoxide anion generation measured by the cytochrome c reduction assay, reactive species by the formazan assay, hydrogen peroxide by the 2',7'-dichlorofluorescein assay, and lipid peroxidation by the thiobarbituric acid-reactive substance assay. Furthermore, cotreatment with SOD or Def was unable to prevent 2,2'-DCB-induced phosphorylation of Cx43, activation of MAPK, and inhibition of myometrial gap junctions. Although antioxidants reversed 2,2'-DCB-induced inhibition of uterine contraction force and synchronization, the myometrial cell culture experiments failed to support oxidative stress as a mechanistic link between 2,2'-DCB-induced inhibition of myometrial gap junctions and modification of uterine contraction.
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PMID:Potential role for oxidative stress in 2,2'-dichlorobiphenyl-induced inhibition of uterine contractions but not myometrial gap junctions. 1675 Dec 30

The activator protein-1 (AP1) transcription complex remains active for long periods after axotomy, but its activity diminishes during target contact. This raises the possibility that the function of this complex is regulated by the synaptic connections. Using Aplysia californica, we found that crushing peripheral nerves in vivo enhanced AP1 binding in the sensory neurons that lasted for weeks and then declined as regeneration was completed. The AP1 complex in Aplysia is a c-Jun homodimer. Its activation, after axotomy, is mediated by Aplysia c-Jun-N-terminal kinase (apJNK), which enters the nucleus of sensory neurons and phosphorylates c-Jun at Ser-73 (p73-c-Jun). Active AP1 in the sensory neurons did not mediate apoptosis and was not involved in the appearance of the long-term hyperexcitability that develops in these cells after axotomy, and blocking the activation of apJNK in vitro did not influence neurite outgrowth. In contrast, the levels of activated apJNK and p73-c-Jun declined markedly when sensory neurons formed synapses with motor neuron L7 in vitro. Furthermore, inhibiting the pathway accelerated synaptogenesis between sensory neurons and L7. These data suggest that positive and negative modulation of the JNK-c-Jun-AP1 pathway functions in alerting the nucleus to the loss and gain of synapses, respectively.
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PMID:Synaptogenesis regulates axotomy-induced activation of c-Jun-activator protein-1 transcription. 1677 31

Natural adaptation to femoral artery occlusion in animals by collateral artery growth restores only approximately 35% of adenosine-recruitable maximal conductance (C(max)) probably because initially elevated fluid shear stress (FSS) quickly normalizes. We tested the hypothesis whether this deficit can be mended by artificially increasing FSS or whether anatomical restraints prevent complete restitution. We chronically increased FSS by draining the collateral flow directly into the venous system by a side-to-side anastomosis between the distal stump of the occluded femoral artery and the accompanying vein. After reclosure of the shunt collateral flow was measured at maximal vasodilatation. C(max) reached 100% already at day 7 and had, after 4 weeks, surpassed (2-fold) the C(max) of the normal vasculature before occlusion. Expression profiling showed upregulation of members of the Rho-pathway (RhoA, cofilin, focal adhesion kinase, vimentin) and the Rho-antagonist Fasudil markedly inhibited arteriogenesis. The activities of Ras and ERK-1,-2 were markedly increased in collateral vessels of the shunt experiment, and infusions of L-NAME and L-NNA strongly inhibited MAPK activity as well as shunt-induced arteriogenesis. Infusions of the peroxinitrite donor Sin-1 inhibited arteriogenesis. The radical scavengers urate, ebselen, SOD, and catalase had no effect. We conclude that increased FSS can overcome the anatomical restrictions of collateral arteries and is potentially able to completely restore maximal collateral conductance. Increased FSS activates the Ras-ERK-, the Rho-, and the NO- (but not the Akt-) pathway enabling collateral artery growth.
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PMID:The range of adaptation by collateral vessels after femoral artery occlusion. 1697 12

Extracellular-superoxide dismutase (EC-SOD) is the major SOD isozyme in blood vessel walls, normal cartilage and synovial fluid and may be important for the antioxidant capability of these tissues. We have reported that EC-SOD gene transferred mice exhibited significant suppression of clinical symptoms of type II collagen induced arthritis [Iyama, et al., Arthritis Rheum., 44, 2160-2167 (2001)] and plasma EC-SOD levels in type 2 diabetic patients were significantly negatively related to indices of insulin resistance [Adachi, et al., J. Endocrinol., 181, 413-417 (2004)]. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathological conditions of the above diseases and is a major therapeutic target, based on clinical studies with anti-TNF-alpha monoclonal antibodies such as infliximab. In this report, we investigated the effect of TNF-alpha on the expression of EC-SOD in cultured cells and the cooperating effect of infliximab. In the in vitro assays examined, expression of EC-SOD, but not other SOD isozymes, in smooth muscle and fibroblast cells were suppressed by the addition of TNF-alpha. Simultaneous addition of infliximab dose-dependently and significantly prevented the suppressive effects of TNF-alpha. p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, prevented significantly the suppressive effect of TNF-alpha suggesting that p38 MAPK is an important signaling molecule downstream of TNF-alpha to inhibit the EC-SOD expression. From the results, it is speculated that the decline in TNF-alpha activity by the administration of infliximab results in the liberation of EC-SOD from the suppressed state of gene expression. This reveals a potential usefulness of infliximab on TNF-alpha related pathological conditions such as arthritis and insulin resistance.
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PMID:Infliximab neutralizes the suppressive effect of TNF-alpha on expression of extracellular-superoxide dismutase in vitro. 1701 57

AMP-activated protein kinase influences cellular metabolism, glucose-regulated gene expression, and insulin secretion of pancreatic beta cells. Its sustained activation by culture at low glucose concentrations or in the presence of 5-aminoimidazole-4-carboxamide riboside (AICAR) was shown to trigger apoptosis in beta cells. This study shows that both low glucose- and AICAR-induced apoptosis are associated with increased formation of mitochondrial superoxide-derived radicals and decreased mitochondrial activity. Mitochondrial dysfunction was reflected by an increased oxidized state of the mitochondrial flavins (FMN/FAD) but not of NAD(P)H. It was accompanied by suppression of glucose oxidation and glucose-induced insulin secretion, while palmitate oxidation appeared unaffected. When the cellular accumulation of superoxide-derived radicals was quenched by the ROS scavengers vitamin E, N-acetylcysteine, or the SOD-mimetic compound MnTBAP, apoptosis was significantly inhibited. Both low glucose and AICAR also elevated the expression of BH3-domain-only Bcl-2 antagonists, and induced caspase-3 activation, causing caspase-dependent truncation of Bcl-2. Overexpression of recombinant human Bcl-2 prevented caspase-3 activation, endogenous Bcl-2 processing, and apoptosis, but did not attenuate oxygen radical formation, AMPK activation, or JNK phosphorylation. We conclude that apoptosis by prolonged AMPK activation in beta cells results from enhanced production of mitochondria-derived oxygen radicals and onset of the intrinsic mitochondrial apoptosis pathway, followed by caspase activation and Bcl-2 cleavage which may amplify the death signal.
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PMID:Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation. 1715 94

20-Hydroxyeicosatetraenoic acid (20-HETE) is formed by the omega-hydroxylation of arachidonic acid by cytochrome P450 4A and 4F enzymes, and it induces angiogenic responses in vivo. To test the hypothesis that 20-HETE increases endothelial cell (EC) proliferation via vascular endothelial growth factor (VEGF), we studied the effects of WIT003 [20-hydroxyeicosa-5(Z),14(Z)-dienoic acid], a 20-HETE analog on human macrovascular or microvascular EC. WIT003, as well as pure 20-HETE, stimulated EC proliferation by approximately 40%. These proliferative effects were accompanied by increased VEGF expression and release that were observed as early as 4 h after 20-HETE agonist addition. This was accompanied by increased phosphorylation of the VEGF receptor 2. The proliferative effects of 20-HETE were markedly inhibited by a VEGF-neutralizing antibody. Polyethylene glycol-superoxide dismutase (PEG-SOD) markedly inhibited both the increases in VEGF expression and the proliferative effects of 20-HETE. In contrast, administration of the NAD(P)H oxidase inhibitor apocynin had no effect to the proliferative response to 20-HETE. The 20-HETE agonist markedly increased superoxide formation as reflected by an increase in dihydroethidium staining of EC, and this increase was inhibited by PEG-SOD but not by apocynin. 20-HETE also increased the phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) in EC, whereas an inhibitor of MAPK [U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] suppressed the proliferative and the VEGF changes but not the pro-oxidant effects of 20-HETE. These data suggest that 20-HETE stimulates superoxide formation by pathways other than apocynin-sensitive NAD(P)H oxidase, thereby activating MAPK and then enhancing VEGF synthesis that drives EC proliferation. Thus, 20-HETE may be involved in the regulation of EC functions, such as angiogenesis.
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PMID:Activation of vascular endothelial growth factor through reactive oxygen species mediates 20-hydroxyeicosatetraenoic acid-induced endothelial cell proliferation. 1721 Jul 99

Full-grown Xenopus oocytes are arrested at the prophase of the first meiotic division in a G(2)-like state. Progesterone triggers meiotic resumption also called the G(2)/M transition. This event is characterized by germinal vesicle breakdown (GVBD) and by a burst in phosphorylation level that reflects activation of M-phase-promoting factor (MPF) and MAPK pathways. Besides phosphorylation and ubiquitin pathways, increasing evidence has suggested that the cytosolic and nucleus-specific O-GlcNAc glycosylation also contributes to cell cycle regulation. To investigate the relationship between O-GlcNAc and cell cycle, Xenopus oocyte, in which most of the M-phase regulators have been discovered, was used. Alloxan, an O-GlcNAc transferase inhibitor, blocked G(2)/M transition in a concentration-dependent manner. Alloxan prevented GVBD and both MPF and MAPK activations, either triggered by progesterone or by egg cytoplasm injection. The addition of detoxifying enzymes (SOD and catalase) did not rescue GVBD, indicating that the alloxan effect did not occur through reactive oxygen species production. These results were strengthened by the use of a benzoxazolinone derivative (XI), a new O-GlcNAc transferase inhibitor. Conversely, injection of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate, an O-GlcNAcase inhibitor, accelerated the maturation process. Glutamine:fructose-6-phosphate amidotransferase inhibitors, azaserine and 6-diazo-5-oxonorleucine, failed to prevent GVBD. Such a strategy appeared to be inefficient; indeed, UDP-GlcNAc assays in mature and immature oocytes revealed a constant pool of the nucleotide sugar. Finally, we observed that cyclin B2, the MPF regulatory subunit, was associated with an unknown O-GlcNAc partner. The present work underlines a crucial role for O-GlcNAc in G(2)/M transition and strongly suggests that its function is required for cell cycle regulation.
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PMID:O-linked N-acetylglucosaminyltransferase inhibition prevents G2/M transition in Xenopus laevis oocytes. 1732 55

Activation of the vascular endothelium with cytokines such as TNF is widely used to study the role of the vasculature in proinflammatory disease. To gain insight into mechanisms of prolonged vascular endothelial activation we compared changes in gene expression induced by continuous activation in stable tmTNF-expressing cells with changes due to acute TNF challenge in vitro. Affymetrix Genechip analysis was performed on RNA from control, acute and continuous TNF-activated endothelial cells. Only 36% of the significant changes in gene expression were convergent between the acute and continuously activated endothelial cells compared with the control. From the divergently regulated genes, for example the cytokine ENA-78 was specifically induced in chronically activated cells, while E-selectin, a cell adhesion molecule, was upregulated only in acutely activated endothelial cells. Antioxidant SOD gene induction was noted in acute activation, while a regulatory NADPH oxidase subunit was selectively upregulated in continuously activated endothelium in accordance with significant reactive oxygen species induction occurred only in these cells. Accordingly, p38 and ERK1/2, two MAP kinases downstream of reactive oxygen species, were activated in stable transmembrane-spanning precursor (tm) TNF-expressing cells and were refractory to activation with soluble TNF or VEGF. In consequence, the increased p38 MAP kinase activity contributed to increased endothelial cell migration in tmTNF-expressing cells. These data suggest that continuous activation of endothelial cells leads to specific expression and functional changes, consistent with alterations observed in dysfunctional endothelium exposed to or involved in chronic inflammation.
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PMID:Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation. 1756 77

The mechanisms of sodium selenite-induced cell death in cervical carcinoma cells were studied during 24 h of exposure in the HeLa Hep-2 cell line. Selenite at the employed concentrations of 5 and 50 micromol/L produced time- and dose-dependent suppression of DNA synthesis and induced DNA damage which resulted in phosphorylation of histone H2A.X. These effects were influenced by pretreatment of cells with the SOD/catalase mimetic MnTMPyP or glutathione-depleting buthionine sulfoximine, suggesting the significant role of selenite-generated oxidative stress. Following the DNA damage, selenite activated p53-dependent pathway as evidenced by the appearance of phosphorylated p53 and accumulation of p21 in the treated cells. Concomitantly, selenite activated p38 pathway but its effect on JNK was very weak. p53- and p38-dependent signaling led to the accumulation of Bax protein, which was preventable by specific inhibitors of p38 (SB 203580) and p53 (Pifithrin-alpha). Mitochondria in selenite-treated cells changed their dynamics (shape and localization) and released AIF and Smac/Diablo, which initiated caspase-independent apoptosis as confirmed by the caspase-3 activity assay and the low effect of caspase inhibitors z-DEVD-fmk and z-VAD-fmk on cell death. We conclude that selenite induces caspase-independent apoptosis in cervical carcinoma cells mostly by oxidative stress-mediated activation of p53 and p38 pathways, but other selenite-mediated effects, in particular mitochondria-specific ones, are also involved.
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PMID:Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells. 1761 29


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