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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased bone fragility attributed to osteopenia is a serious side effect of glucocorticoid treatment. Glucocorticoid-induced bone loss is caused primarily by hypofunction and apoptosis of osteoblasts, and secondarily by accelerated bone resorption. To explore the mechanism whereby dexamethasone (Dex) stimulates osteoclastogenesis in the coculture system, we analyzed the effect of Dex on the expression of both mouse osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL). Dex reduced OPG transcripts and OPG protein secretion by the ST2 osteoblastic cells. Since mainly the c-Jun homodimer maintains the steady-state transcription of the OPG gene, we examined the effect of Dex on c-Jun signaling in ST2 cells. Western blotting disclosed that Dex decreased the amount of phospho-c-Jun protein (p-c-Jun) and, correspondingly, the amount of the phosphorylated p46 isoform of Jun N-terminal kinase (JNK). The amount of phospho-SEK1 also decreased after Dex treatment, while the amounts of phospho-ERK and p38 remained constant. Among mitogen-activated protein (MAP) kinase inhibitors, the JNK inhibitor mimicked the inhibitory effect of Dex on OPG promoter activity. On the other hand, Dex treatment per se showed a nominal increase of RANKL gene expression. A part of Dex-mediated OPG gene suppression was achieved by the suppression of beta-catenin signaling. We speculate therefore that the bone resorptive action of Dex is mediated mainly by the inhibition of OPG by transrepressing the OPG gene through the AP-1 site, with a reduction (mediated mainly by the decrease in the p46 isoform of JNK) in the proportion of p-c-Jun in a JNK-dependent manner.
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PMID:Dexamethasone promotes osteoclastogenesis by inhibiting osteoprotegerin through multiple levels. 1751 44

We have previously shown that intrastriatal injection of Delta RR, the growth-compromised herpes simplex virus type 2 (HSV-2) vector for the antiapoptotic protein ICP10PK, prevents apoptosis caused by the excitotoxin N-methyl-D-aspartate (NMDA) in a mouse model of glutamatergic neuronal cell death (Golembewski et al. [2007] Exp. Neurol. 203:381-393). Because apoptosis regulation is stimulus and cell type specific, our studies were designed to examine the mechanism of Delta RR-mediated neuroprotection in striatal neurons. Organotypic striatal cultures (OSC) that retain much of the synaptic circuitry of the intact striatum were infected with Delta RR or a growth-compromised HSV-2 vector that lacks ICP10PK (Delta PK) and examined for neuroprotection-associated signaling. The mutated ICP10 proteins (p175 and p95) were expressed in 70-80% of neurons from Delta RR- and Delta PK-infected cultures, respectively, as determined by double-immunofluorescent staining with antibodies to ICP10 and NeuN or GAD65. Delta RR- but not Delta PK-treated OSC were protected from NMDA-induced apoptosis, as verified by ethidium homodimer staining, TUNEL, caspase-3 activation, and poly(AD-ribose) polymerase (PARP) cleavage. Neuroprotection was through ICP10PK-mediated activation of the survival pathways MEK/ERK and PI3-K/Akt, up-regulation of the antiapoptotic proteins Bag-1 and Bcl-2, and phosphorylation (inactivation) of the proapoptotic protein Bad. It was blocked by the MEK inhibitor U0126 or the PI3-K inhibitor LY294002, suggesting that either pathway can prevent NMDA-induced apoptosis. The data indicate that Delta RR-delivered ICP10PK stimulates redundant survival pathways that override proapoptotic cascades. Delta RR is a promising gene therapy platform against glutamatergic cell death.
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PMID:Growth-compromised HSV-2 vector Delta RR protects from N-methyl-D-aspartate-induced neuronal degeneration through redundant activation of the MEK/ERK and PI3-K/Akt survival pathways, either one of which overrides apoptotic cascades. 1789 11

In addition to ultraviolet radiation, human skin is also exposed to infrared radiation (IR) from natural sunlight. IR typically increases the skin temperature. This study examined whether or not heat shock-induced ROS stimulates MMPs in keratinocyte HaCaT cells. In HaCaT cells, heat shock was found to increase the intracellular ROS levels, including hydrogen peroxide and superoxide. The heat shock treatment induced MMP-1 and MMP-9, but not MMP-2, at the mRNA and protein levels. Moreover, heat shock caused the rapid activation of the three distinct MAPKs, ERK, JNK, and p38 kinase. The heat shock-induced expression of MMP-1 and MMP-9 was significantly suppressed by a pretreatment with the antioxidant NAC or catalase. On the other hand, SOD inhibited heat shock-induced activity of MMP-9 induction, but not MMP-1. A pretreatment with NAC or catalase, but not SOD, attenuated the phosphorylation of ERK, JNK, and p38 kinase by heat shock. The potential sites of ROS generation by heat shock along with its role in the heat shock-induced expression of MMP-1 and MMP-9 were next analyzed. These results indicate that heat shock-induced ROS is promoted via NADPH oxidase, xanthine oxidase, and mitochondria. Indeed, the NADPH oxidase and xanthine oxidase activities were increased by heat shock. Overall, the ROS produced by heat shock may play an important role in the heat shock-induced activation of MAPKs, which can induce MMP-1 and-9 expressions.
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PMID:Reactive oxygen species produced by NADPH oxidase, xanthine oxidase, and mitochondrial electron transport system mediate heat shock-induced MMP-1 and MMP-9 expression. 1803 52

Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H2O2 are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22phox, p47phox and the small G-protein Rac1. NADPH oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis.
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PMID:Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. 1840 51

Activating mutation in KIT or platelet-derived growth factor-alpha can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6-13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S- and G(2) phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination.
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PMID:Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression. 1848

The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist. Mutations disabling this conformational change cause impairment of ERK but not JAK2 and STAT5 activation by the GHR in FDC-P1 cells. This results from the use of two associated tyrosine kinases by the GHR, with JAK2 activating STAT5, and Lyn activating ERK1/2. We provide evidence that Lyn signals through phospholipase C gamma, leading to activation of Ras. Accordingly, mice with mutations in the JAK2 association motif respond to GH with activation of hepatic Src and ERK1/2, but not JAK2/STAT5. We suggest that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment. Our findings could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.
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PMID:An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. 1848 18

Gonadotropin-releasing hormone (GnRH) is a ten-amino acid peptide hormone that plays pivotal roles in reproduction in vertebrates and octopus. Recently, six GnRH forms (t-GnRH-3-8) and four GnRH receptor subtypes (Ci-GnRHR-1-4) were identified in the protochordate, Ciona intestinalis. In this study, we show the functional modulation of Ci-GnRHR-1 via heterodimerization with the orphan receptor subtype, Ci-GnRHR-4. The dimerization between Ci-GnRHR-1 and R-4 was detected by co-immunoprecipitation and immunoblot analysis. Binding assays confirmed the binding of t-GnRHs to Ci-GnRHR-1 but not to R-4, and verified no alternation in ligand-binding affinity between Ci-GnRHR-1 homodimer and Ci-GnRHRI&4 heterodimer. The heterodimer was found to stimulate the elevation of intracellular calcium, time-extension of ERK phosphorylation, and up-regulation of cell proliferation, all in a ligand specific manner, compared with the Ci-GnRHR-1 homodimer. In combination, these results indicated that Ci-GnRHR-4 is not an inactive receptor, but a modulatory factor for Ci-GnRHR-1 in C. intestinalis.
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PMID:Functions of a GnRH receptor heterodimer of the ascidian, Ciona intestinalis. 1865 98

A novel lectin (PCL) with specificity towards sialic acid was purified from Phaseolus coccineus L. (P. multiflorus willd) seeds using ion exchange chromatography on CM and DEAE-Sepharose, and gel filtration on Sephacryl S-200 column. PCL was a homodimer consisting of 29,831.265 Da subunits as determined by gel filtration and MS. Also, PCL was a non-metalloprotein and its N-terminal 23-amino acid sequence, ATETSFSFQRLNLANLVLNKESS, was determined. Subsequently, MTT method, cell morphological analysis and LDH activity-based cytotoxicity assays demonstrated that PCL was highly cytotoxic to L929 cells and induced apoptosis in a dose-dependent manner. Using caspase inhibitors, a typical caspase-dependent pathway was confirmed. PCL also showed remarkable antifungal activity towards some plant pathogenic fungi. Furthermore, when sialic acid-specific activity was fully inhibited, cytotoxicity and antifungal activity were abruptly decreased, respectively, suggesting a significant correlation between sialic acid-specific site and its bi-functional bioactivities.
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PMID:A novel sialic acid-specific lectin from Phaseolus coccineus seeds with potent antineoplastic and antifungal activities. 1875 89

All four members of the human epidermal growth factor (EGF) receptor (HER) family are implicated in human cancers. Although efficacious in a subset of patients, resistance to single-targeted anti-HER therapy [i.e., cetuximab (Erbitux) and trastuzumab (Herceptin)] is often associated with coexpression of other HER family members. This may be overcome by a HER ligand binding molecule that sequesters multiple EGF-like ligands, preventing ligand-dependent receptor activation. Toward this end, we have combined the HER-1/EGFR and HER-3 ligand binding domains, dimerized with fusion of an Fc fragment of human IgG1. This resulted in a mixture of HER-1/Fc homodimer (HFD100), HER-3/Fc homodimer (HFD300), and HER-1/Fc:HER-3/Fc heterodimer (RB200), also termed Hermodulins. The purified first-generation RB200 bound EGF and neuregulin 1 (NRG1)-beta1 ligands, determined by cross-linking and direct binding studies. The binding affinity for both was approximately 10 nmol/L by dissociation-enhanced lanthanide fluorescence immunoassay using europium (Eu)-labeled ligands. Competition studies with RB200 using Eu-EGF or Eu-NRG1-beta1 revealed that RB200 bound HER-1 ligands, including transforming growth factor-alpha and heparin-binding EGF, and HER-3 ligands NRG1-alpha and NRG1-beta3. RB200 inhibited EGF- and NRG1-beta1-stimulated tyrosine phosphorylation of HER family proteins, proliferation of a diverse range of tumor cells in monolayer cell growth assays, tumor cell proliferation as a single agent and in synergy with tyrosine kinase inhibitors, lysophosphatidic acid-stimulated cell proliferation, and tumor growth in two human tumor xenograft nude mouse models. Taken together, the data reveal that RB200 has the potential to sequester multiple HER ligands and interfere with signaling by HER-1, HER-2, and HER-3.
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PMID:Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts. 1885 26

Increased nitric oxide (NO) has been correlated with diabetic retinopathy. In this study we investigated the cell injury, production of NO in retinal pigment epithelial (RPE) cells exposed to increased glucose concentration, and its molecular mechanism involved. Cultured human RPE cells (ARPE-19) were exposed for 4 days with normal blood glucose concentration (5.5mM D-glucose), followed by exposure to either normal (5.5mM) or high (33 mM) concentrations of D-glucose for 48 h. To determine the cytotoxicity of high glucose, cell viability, ROS production and SOD activity were measured, respectively. The end product of NO (nitrite and nitrate) was determined by a colorimetric assay and nitrotyrosine levels were quantified by a competitive ELISA. The expression of iNOS and the activation of p38MAPK, ERK and JNK were analyzed by Western blot. Treatment of RPE cells with high glucose-induced a significant increased of iNOS, accompanied by an increase in cell damage, NO and nitrotyrosine levels. High glucose caused activation of p38MAPK and ERK, inhibition for p38MAPK and ERK abrogated the high glucose-induced increase in iNOS, cell injury and levels of NO and nitrotyrosine. High glucose causes increased cell damage and NO generation in RPE cells by a process of iNOS expression that requires the activation of p38MAPK and ERK.
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PMID:p38MAPK and ERK promote nitric oxide production in cultured human retinal pigmented epithelial cells induced by high concentration glucose. 1885 22


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