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)

We have tested the hypothesis that antidepressants affect the expression of the glucocorticoid receptor gene, by looking at glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and glucocorticoid-binding activity after treatment of different cell lines with desipramine. Treatment of LTK- cells or Neuro 2A cells with desipramine produced a 50-200% increase in chloramphenicol acetyltransferase activity transcribed from a 2.7-kilobase glucocorticoid receptor gene promoter region. In cell lines derived from both neuronal and non-neuronal sources, glucocorticoid receptor mRNA concentration doubled after desipramine treatment, and this was associated with a 2-fold higher functional glucocorticoid binding capacity and increased glucocorticoid sensitivity, as measured with the reporter plasmid pMMTVCAT. Antidepressant-induced increases in glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and functional glucocorticoid binding activity suggest a novel mechanism of action for these drugs on the hypothalamic-pituitary-adrenal axis.
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PMID:Increased glucocorticoid receptor gene promoter activity after antidepressant treatment. 161 6

Neutral endopeptidase (NEP, also known as enkephalinase, CALLA, or EC 3.4.24.11) is a membrane-bound peptidase present in many different cell types. Previous studies have shown that it modulates the actions of a variety of biologically active peptides on several airway responses. More recent studies have demonstrated that reductions in neutral endopeptidase activity in animal airways is associated with increased responses to exogenously applied and endogenously released peptides. To study the regulation of NEP expression, we used human airway epithelial cells transformed in vitro with an origin-defective SV40 plasmid. Enzymatic activity, measured using [3H-Tyr,D-Ala2]leucine enkephalin, increased with cell density (1.4 ng/10(6) cells at 530 cells/cm2 and 21 ng/10(6) cells at confluence, 400 X 10(3) cells/cm2). In both confluent and nonconfluent cultures, the glucocorticoid budesonide increased neutral endopeptidase activity in time- and concentration-dependent fashions. Maximal increases of 10 ng/10(6) cells greater than control were observed after 6 days of incubation at 10(-7) M budesonide. Dexamethasone also increased NEP, suggesting that the effect is due to glucocorticoid receptor effects. Transcription, as assessed by Northern blot analysis of total cellular RNA, showed that NEP-specific RNAs also increased with increasing concentration of glucocorticoid. We conclude that neutral endopeptidase can be increased by cell growth or density and by glucocorticoids and that the effects of glucocorticoids are mediated by increased NEP gene expression.
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PMID:Glucocorticoids induce neutral endopeptidase in transformed human tracheal epithelial cells. 184 94

The beta 2-adrenergic receptor (ADRB2R) mediates the response of various cel types to neurotransmitters, hormones, and drugs. The platelet-derived growth factor (PDGF) interacts with its receptor (PDGFR) to stimulate mesenchymal cell proliferation. In the human, ADRB2R and PDGFR have been mapped to the q31--q32 region of chromosome 5 (HSA5). Here we report the mapping of Pdgfr and Adrb2r to mouse chromosome 18 (MMU18) using somatic cell hybrid mapping techniques. Together with previous mapping of genes for the glucocorticoid receptor (human locus GRL; mouse locus Gr1-1), the class II HLA invariant chain (human locus PHLAG; mouse locus Ii) and the FMS protooncogene to HSA5 and MMU18, the assignment of both Pdgfr and Adrb2r to MMU18 expands the conserved autosomal syntenic group.
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PMID:Genes for beta 2-adrenergic receptor and platelet-derived growth factor receptor map to mouse chromosome 18. 256 67

Glucocorticoids stimulate, while insulin inhibits, the hepatic transcription of insulin-like growth factor-binding protein-1 (IGFBP-1). In the present studies, human HEP G2 hepatoma cells were transiently transfected with human (h)IGFBP-1 promoter constructs. Activity of a construct containing the first 1205 base pairs (bp) of the hIGFBP-1 promoter was stimulated 6-9.5-fold by dexamethasone, and this increase was inhibited approximately 76% by insulin. Deletion and site-directed mutations of the hIGFBP-1 promoter (a) identified two glucocorticoid response elements, located within the first 200 bp of the promoter, which are essential for dexamethasone-stimulated promoter activity and which specifically bind human glucocorticoid receptor; (b) showed that a recently characterized insulin-responsive element, located approximately 110 bp 5' to the transcription start site (Suwanichkul, A., Morris, S.L., and Powell, D. R. (1993) J. Biol. Chem. 268, 17063-17068), confers the entire inhibitory effect of insulin not only on basal but also on glucocorticoid-stimulated promoter activity; and (c) showed that this insulin-responsive element is essential for maximal glucocorticoid-stimulated activity. These studies suggest that the interaction of proteins that bind to a cluster of cis elements located in the first 200 bp of the hIGFBP-1 promoter are of major importance in modulating the opposing effects of glucocorticoids and insulin on hepatic hIGFBP-1 expression.
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PMID:Glucocorticoids and insulin regulate expression of the human gene for insulin-like growth factor-binding protein-1 through proximal promoter elements. 798 14

In the research field of nuclear receptors, the studies on the protein factors which interact with the steroid hormone receptors and regulate the transcriptional activity, and on the alpha and beta isoforms of glucocorticoid receptor have been in great progress. The include "intermediary Factors" such as RIP140, TIF-1, for the AF-2 which contribute to ligand-dependent transactivation function of the receptors. ARA70 which specifically interacts with androgen receptor was also cloned recently. Informations obtained from steroid hormone receptor knockout-mice experiments can also be available for the estrogen, glucocorticoid, and progesterone receptors. Furthermore, there have been more than sixty orphan receptors identified in these eight years, including HNF, Ad4BP, DAX-1, and nur77/NGFIB, some of which are mutation target genes of human congenital diseases.
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PMID:[Recent progress in the research field of nuclear receptors]. 928 39

The mitogen-activated protein kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 phosphorylate and activate transcription factors that promote proliferative and inflammatory responses, whereas glucocorticoid receptor (GR) activation inhibits cell growth and inflammation. We demonstrate that JNK and ERK but not p38 phosphorylate GR in vitro primarily at Ser-246. Selective activation of either ERK or JNK in vivo inhibits GR-mediated transcriptional activation, which depends on receptor phosphorylation at Ser-246 by JNK but not ERK. Thus, JNK inhibits GR transcriptional activation by direct receptor phosphorylation, whereas ERK does so indirectly. We propose that phosphorylation of GR by JNK or of a GR cofactor by ERK provides mechanisms to ensure the rapid inhibition of GR-dependent gene expression when it conflicts with mitogenic or proinflammatory signals.
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PMID:Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. 948 36

Detection and monitoring the expression and level of intracellular glucocorticoid receptor (GCR) is necessary in many clinical and experimental situations. Binding of radioactive steroids (3H dexamethasone) to the cytosolic fractions of cells has been recently used. However, it is an expensive, time-consuming technique difficult to use in routine diagnostics. In this article we describe a novel, simple method for GCR detection, using a FITC-conjugated anti-GCR monoclonal antibody (mAb) for flow cytometric measurements in permeabilized cells. The monoclonal antibody was raised against a conserved sequence (150-176 amino acids) of the regulatory part of the receptor. Synthetic peptide (called APTEK-26) fragment of the receptor conjugated to different carriers (TG, BSA) was used for immunization and screening of the hybridomas. The a-GCR 8E9, 3C8 and 5E4 clones (IgG1) were further characterized by immunoserological methods for their reactivity against overlapping synthetic peptide fragments of the receptor and by Western blot technique on cytosolic fraction of HEP G2 cells (containing the GCR). Furthermore the mAbs could be used for the FACS based detection of GCR, despite its low number of antigen structure within the cells. Solving the problem of nonspecific binding of the secondary antibodies we used our high affinity IgG1 a-GCR mAbs directly labeled with the fluorescent dye FITC. The fluorescent labeling of the GCRs in HEP G2 cell line and human peripheral blood mononuclear cells (PBMC) were demonstrated by flow cytometric analysis after fixation with 4% paraformaldehyde and permeabilization with saponin. Competition with molar excess of unlabelled antibodies and with the GCR peptide fragment confirmed the specific binding of the 8E9 and 5E4 mAbs to the GCRs. Monitoring the GCR level by flow cytometry would be useful in clinical diagnostics, e.g., in steroid-treated patients and in steroid-resistant states.
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PMID:Production and flow cytometric application of a monoclonal anti-glucocorticoid receptor antibody. 969 55

Macrocyclic nonaketide compounds, radicicol and its two analogues, 87-250904-F1 and LL-Z1640-2, have various biological activities. Here we show that these compounds inhibit signal-dependent transcriptional activation with different specificity with distinct mechanism. Although all three compounds inhibited PMA-induced AP-1 transcriptional activity in cell-based reporter assay, these compounds exhibited differential effects in separate transcriptional reporter assays for NF-kappaB and glucocorticoid receptor. Next we found that one of these compounds, LL-Z1640-2, was a signal-specific inhibitor of the JNK/p38 pathways. In contrast to LL-Z1640-2, radicicol and 87-250904-F1 did not inhibit JNK/p38 activation. Recently, radicicol was reported as an inhibitor of activated-Ras-induced ERK activation. These results indicated that radicicol and LL-Z1640-2 showed distinct specificity to various MAP kinase pathways despite their structural similarity. Furthermore, LL-Z-1640-2 inhibited anisomycin-induced but not TNF-induced JNK/p38 activation, indicating that the inhibition mechanism is signal-specific.
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PMID:A radicicol-related macrocyclic nonaketide compound, antibiotic LL-Z1640-2, inhibits the JNK/p38 pathways in signal-specific manner. 1009 3

Activation of the glucocorticoid receptor (GR) triggers apoptosis in T cells. However, activation of the T cell antigen receptor (TCR) blocks glucocorticoid-induced apoptosis, implying functional crosstalk between these two distinct signaling systems. By reconstructing or selectively blocking TCR-stimulated signaling pathways, we show here that TCR activation of the mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK) cascade via Ras is necessary and sufficient to inhibit GR-mediated death in immortalized T and thymocyte cell lines and in primary T cells. Moreover, we found that activation of various pathway components (TCR, Ras, MEK1) altered the transcriptional regulatory activity of GR. In contrast, phosphatidylinositol 3-kinase and Akt, which down-regulate other lymphocyte apoptosis pathways, did not inhibit glucocorticoid-induced apoptosis. Our findings, which link signaling from the TCR cell surface receptor to that from the GR intracellular receptor, demonstrate the importance of the integration of signal transduction pathways in defining regulatory circuits. Because the TCR/Ras/MEK pathway has been shown previously to be essential for positive selection of thymocytes, the TCR/Ras/MEK signaling to GR crosstalk described herein may affect T cell development and homeostasis.
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PMID:Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling. 1086 Sep 97

Previously, we have demonstrated that oxidative stress or Ras/ERK activation leads to the transcriptional repression of alpha-subunit of epithelial Na(+) channel (ENaC) in lung and salivary epithelial cells. Here, we further investigated the coordinated molecular mechanisms by which alpha-ENaC expression is regulated. Using both stable and transient transfection assays, we demonstrate that the overexpression of high mobility group protein I-C (HMGI-C), a Ras/ERK-inducible HMG-I family member, represses glucocorticoid receptor (GR)/dexamethasone (Dex)-stimulated alpha-ENaC/reporter activity in salivary epithelial cells. Northern analyses further confirm that the expression of endogenous alpha-ENaC gene in salivary Pa-4 cells is suppressed by an ectopic HMGI-C overexpression. Through yeast two-hybrid screening and co-immunoprecipitation assays from eukaryotic cells, we also discovered the interaction between HMGI-C and PIAS3 (protein inhibitor of activated STAT3 (signal transducer and activator of transcription 3)). A low level of ectopically expressed PIAS3 cooperatively inhibits GR/Dex-dependent alpha-ENaC transcription in the presence of HMGI-C. Reciprocally, HMGI-C expression also coordinately enhances PIAS3-mediated repression of STAT3-dependent transactivation. Moreover, overexpression of antisense HMGI-C construct is capable of reversing the repression mediated by Ras V12 on GR- and STAT3-dependent transcriptional activation. Together, our results demonstrate that Ras/ERK-mediated induction of HMGI-C is required to effectively repress GR/Dex-stimulated transcription of alpha-ENaC gene and STAT3-mediated transactivation. These findings delineate a network of inhibitory signaling pathways that converge on HMGI-C.PIAS3 complex, causally associating Ras/ERK activation with the repression of both GR and STAT3 signaling pathways in salivary epithelial cells.
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PMID:Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells. 1139 Mar 95


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