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)

Bcl10, a CARD-containing protein identified from the t(1;14)(p22;q32) breakpoint in MALT lymphomas, has been shown to induce apoptosis and activate NF-kappaB in vitro. We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality. Surprisingly, bcl10-/- cells retained susceptibility to various apoptotic stimuli in vivo and in vitro. However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation. Early tyrosine phosphorylation, MAPK and AP-1 activation, and Ca2+ signaling were normal in mutant lymphocytes, but antigen receptor-induced NF-kappaB activation was absent. Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation.
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PMID:Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. 1116 38

We recently reported that alpha(1)-adrenoceptor (alpha(1)-AR) stimulation induces hypertrophy via activation of the mitogen/extracellular signal-regulated kinase (MEK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 pathway and generates reactive oxygen species (ROS) in adult rat ventricular myocytes (ARVM). Here we investigate the intracellular source of ROS in ARVM and the mechanism by which ROS activate hypertrophic signaling after alpha(1)-AR stimulation. Pretreatment of ARVM with the ROS scavenger Mn(III)terakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) completely inhibited the alpha(1)-AR-stimulated activation of Ras-MEK1/2-ERK1/2. Direct addition of H(2)O(2) or the superoxide generator menadione activated ERK1/2, which is also prevented by MnTMPyP pretreatment. We found that ARVM express gp91(phox), p22(phox), p67(phox), and p47(phox), four major components of NAD(P)H oxidase, and that alpha(1)-AR-stimulated ERK1/2 activation was blocked by four structurally unrelated inhibitors of NAD(P)H oxidase [diphenyleneiodonium, phenylarsine oxide, 4-(2-aminoethyl)benzenesulfonyl fluoride, and cadmium]. Conversely, inhibitors for other potential ROS-producing systems, including mitochondrial electron transport chain, nitric oxide synthase, xanthine oxidase, and cyclooxygenase, had no effect on alpha(1)-AR-stimulated ERK1/2 activation. Taken together, our results show that ventricular myocytes express components of an NAD(P)H oxidase that appear to be involved in alpha(1)-AR-stimulated hypertrophic signaling via ROS-mediated activation of Ras-MEK1/2-ERK1/2.
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PMID:Role of reactive oxygen species and NAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. 1188 Feb 81

Hyperoxia increases reactive oxygen species (ROS) production in vascular endothelium; however, the mechanisms involved in ROS generation are not well characterized. We determined the role and regulation of NAD(P)H oxidase in hyperoxia-induced ROS formation in human pulmonary artery endothelial cells (HPAECs). Exposure of HPAECs to hyperoxia for 1, 3, and 12 h increased the generation of superoxide anion, which was blocked by diphenyleneiodonium but not by rotenone or oxypurinol. Furthermore, hyperoxia enhanced NADPH- and NADH-dependent and superoxide dismutase- or diphenyleneiodonium-inhibitable ROS production in HPAECs. Immunohistocytochemistry and Western blotting revealed the presence of gp91, p67 phox, p22 phox, and p47 phox subcomponents of NADPH oxidase in HPAECs. Transfection of HPAECs with p22 phox antisense plasmid inhibited hyperoxia-induced ROS production. Exposure of HPAECs to hyperoxia activated p38 MAPK and ERK, and inhibition of p38 MAPK and MEK1/2 attenuated the hyperoxia-induced ROS generation. These results suggest a role for MAPK in regulating hyperoxia-induced NAD(P)H oxidase activation in HPAECs.
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PMID:Hyperoxia-induced NAD(P)H oxidase activation and regulation by MAP kinases in human lung endothelial cells. 1247 Oct 12

The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22(phox) subunit and superoxide production, were less in AT1a receptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB, olmesartan (0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT1 receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.
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PMID:Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan. 1470 52

Cyclooxygenase-2 (COX-2) is induced in response to lipopolysaccharide (LPS). However, the signaling mechanisms of LPS-induced COX-2 expression in cardiomyocytes are not well understood. The aim of this study was to investigate the role of gp91(phox)-containing NADH oxidase signaling pathway in LPS-induced COX-2 expression in cardiomyocytes. Cultured neonatal mouse cardiomyocytes showed basal COX-2 expression and PGE2 production. In response to LPS, COX-2 expression and PGE2 production increased by two- to four-fold, which were completely blocked by a selective COX-2 inhibitor NS398. LPS also increased NADH oxidase (gp91(phox) and p47(phox) subunits) expression and superoxide generation. Deficiency of gp91(phox) or suppression of p22(phox) expression decreased NADH oxidase activity and down-regulated COX-2 expression and PGE2 production stimulated by LPS. Pharmacological inhibitors of NADH oxidase prevented LPS-induced COX-2 expression and PGE2 production. The effect of NADH oxidase was mediated through MAPK activation, since inhibition of NADH-oxidase activity prevented phosphorylation of ERK1/2, p38, and JNK1/2, as well as selective inhibition of each subfamily of MAPK by siRNAs and a dominant negative mutant of JNK1 decreased COX-2 expression and completely abrogated PGE2 production in response to LPS. Furthermore, LPS-induced NF-kappaB activation was decreased by inhibition of NADH oxidase, ERK1/2 or JNK1/2 activation, suggesting that LPS increases NF-kappaB activity and COX-2 expression via NADH oxidase-dependent activation of ERK1/2 and JNK1/2. In conclusion, NADH oxidase signaling represents a novel pathway leading to COX-2 expression via MAPK/NF-kappaB-dependent mechanisms in cardiomyocytes during LPS stimulation. Our study suggests that gp91(phox)-containing NADH oxidase is a potential therapeutic target of sepsis.
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PMID:NADH oxidase signaling induces cyclooxygenase-2 expression during lipopolysaccharide stimulation in cardiomyocytes. 1554 60

Differential display PCR analysis (DD-PCR) was used to identify novel genes that respond to IGF-I treatment in human MCF-7 breast cancer cells. Fifty-three cDNAs showed alterations in their mRNA levels in IGF-I treated cells. One of these genes showed a significant increase in the mRNA level in IGF-I treated cells in comparison to non-treated cells. We named this gene HIRF1 (human IGF-I regulated factor 1). Nucleotide blast analysis revealed that this gene has a 100% sequence identity with the sequence for BTG1 (B-cell translocation gene) binding factor 1 (human CCR4-associated factor 1 gene, hCAF1). By alignment of cloned HIRF1 cDNA and genomic DNA 8p21.3-p22 sequence, we were able to determine the exon-intron structure of the cloned HIRF1 gene on chromosome 8. Northern blot and real-time PCR analysis showed that BTG1 and c-fos reached their maximal expression fairly early within 10 min to 1 h, and decreased to basal levels after 3 h of IGF-I treatment. HIRF1/hCAF1 expression reached maximal stimulation after 3 h of IGF-I treatment and then gradually decreased to basal level. HIRF1 and BTG1 mRNA was inhibited by inhibitors of the cell signaling pathways, PI3/Akt kinase and MAPK kinases (ERK1/2 and p38). In summary, cloned HIRF1/hCAF1 is coregulated with BTG1 in response to IGF-I. The regulation of these genes as early response genes may have an important role in differentiation, growth and proliferation of breast cancer cells.
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PMID:Insulin-like growth factor I differentially regulates the expression of HIRF1/hCAF1 and BTG1 genes in human MCF-7 breast cancer cells. 1678 64

To explore the role of angiotensin II Type 1 receptor-associated protein (ATRAP) in vascular remodeling, we developed transgenic mice for mouse ATRAP cDNA and examined remodeling after inflammatory vascular injury induced by polyethylene cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3- to 4-fold in the heart, aorta, and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate, and heart/body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22(phox), a reduced nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal-regulated kinase, signal transducer and activator of transcription 1, and signal transducer and activator of transcription 3 after cuff placement was significantly reduced in ATRAP-Tg mice. Pressor response and cardiac hypertrophy induced by angiotensin II infusion and pressure overload were also attenuated in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in vascular remodeling as a negative regulator.
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PMID:Attenuation of inflammatory vascular remodeling by angiotensin II type 1 receptor-associated protein. 1692 92

NADPH oxidases produce reactive oxygen species (ROS) that serve as co-stimulatory signals for cell proliferation. In mouse lung epithelial cells that express Nox1, Nox2, Nox4, p22(phox), p47(phox), p67(phox), and Noxo1, overexpression of Nox1 delayed cell cycle withdrawal by maintaining AP-1-dependent expression of cyclin D1 in low serum conditions. In cycling cells, the effects of Nox1 were dose dependent: levels of Nox1 that induced 3- to 10-fold increases in ROS promoted phosphorylation of ERK1/2 and expression of cyclin D1, whereas expression of Nox1 with Noxo1 and Noxa1 (or expression of Nox4 alone) that induced substantial increases in intracellular ROS inhibited cyclin D1 and proliferation. Catalase reversed the effects of Nox1 on cyclin D1 and cell proliferation. Diphenylene iodonium, an inhibitor of NADPH oxidase activity, did not affect dosedependent responses of ERK1/2 or Akt to serum, but markedly inhibited the sequential expression of c-Fos and Fra-1 required for induction of cyclin D1 during cell cycle re-entry. These results indicate that Nox1 stimulates cell proliferation in actively cycling cells by reducing the requirement for growth factors to maintain expression of cyclin D1, whereas during cell cycle re-entry, NADPH oxidase activity is required for transcriptional activation of Fos family genes during the immediate early gene response.
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PMID:Redox-dependent expression of cyclin D1 and cell proliferation by Nox1 in mouse lung epithelial cells. 1698 2

Patients with myelodysplasia (MDS) show an impaired reactive oxygen species (ROS) production in response to fMLP stimulation of GM-CSF-primed neutrophils. In this study, we investigated the involvement of lipid rafts in this process and showed that treatment of neutrophils with the lipid raft-disrupting agent methyl-beta-cyclodextrin abrogates fMLP-induced ROS production and activation of ERK1/2 and protein kinase B/Akt, two signal transduction pathways involved in ROS production in unprimed and GM-CSF-primed neutrophils. We subsequently showed that there was a decreased presence of Lyn, gp91(phox), and p22(phox) in lipid raft fractions from neutrophils of MDS. Furthermore, the plasma membrane expression of the lipid raft marker GM1, which increases upon stimulation of GM-CSF-primed cells with fMLP, was reduced significantly in MDS patients. By electron microscopy, we showed that the fMLP-induced increase in GM1 expression in GM-CSF-primed cells was a result of de novo synthesis, which was less efficient in MDS neutrophils. Taken together, these data indicate an involvement of lipid rafts in activation of signal transduction pathways leading to ROS production and show that in MDS neutrophils, an impaired lipid raft formation in GM-CSF-primed cells results in an impaired ROS production.
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PMID:The reduced GM-CSF priming of ROS production in granulocytes from patients with myelodysplasia is associated with an impaired lipid raft formation. 1707 51

Recent studies have demonstrated that lymphocyte-derived microparticles (LMPs) impair endothelial cell function. However, no data currently exist regarding the contribution of LMPs in the regulation of angiogenesis. In the present study, we investigated the effects of LMPs on angiogenesis in vivo and in vitro and demonstrated that LMPs strongly suppressed aortic ring microvessel sprouting and in vivo corneal neovascularization. In vitro, LMPs considerably diminished human umbilical vein endothelial cell survival and proliferation in a concentration-dependent manner. Mechanistically, the antioxidants U-74389G and U-83836E were partially protective against the antiproliferative effects of LMPs, whereas the NADPH oxidase (NOX) inhibitors apocynin and diphenyleneiodonium significantly abrogated these effects. Moreover, LMPs increased not only the expression of the NOX subunits gp91(phox), p22(phox), and p47(phox), but also the production of ROS and NOX-derived superoxide (O(2)(-)). Importantly, LMPs caused a pronounced augmentation in the protein expression of the CD36 antiangiogenic receptor while significantly downregulating the protein levels of VEGF receptor type 2 and its downstream signaling mediator, phosphorylated ERK1/2. In summary, LMPs potently suppress neovascularization in vivo and in vitro by augmenting ROS generation via NOX and interfering with the VEGF signaling pathway.
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PMID:Lymphocytic microparticles inhibit angiogenesis by stimulating oxidative stress and negatively regulating VEGF-induced pathways. 1804 16


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