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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms underlying primary glucocorticoid resistance or hypersensitivity are not well understood. Using transfected COS-1 cells as a model system, we studied gene regulation by naturally occurring mutants of the glucocorticoid receptor (GR) with single-point mutations in the regions encoding the ligand-binding domain or the N-terminal domain reflecting different phenotypic expression. We analyzed the capacity of these GR variants to regulate transcription from different promoters, either by binding directly to positive or negative glucocorticoid-response elements on the DNA or by interfering with protein-protein interactions. Decreased dexamethasone (DEX) binding to GR variants carrying mutations in the ligand-binding domain correlated well with decreased capacity to activate transcription from the mouse mammary tumor virus (MMTV) promoter. One variant, D641V, which suboptimally activated MMTV promoter-mediated transcription, repressed a PRL promoter element containing a negative glucocorticoid-response element with wild type activity. DEX-induced repression of transcription from elements of the intercellular adhesion molecule-1 promoter via nuclear factor-kappaB by the D641V variant was even more efficient compared with the wild type GR. We observed a general DEX-responsive AP-1-mediated transcriptional repression of the collagenase-1 promoter, even when receptor variants did not activate transcription from the MMTV promoter. Our findings indicate that different point mutations in the GR can affect separate pathways of gene regulation in a differential fashion, which can explain the various phenotypes observed.
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PMID:Differential hormone-dependent transcriptional activation and -repression by naturally occurring human glucocorticoid receptor variants. 921 62

The glucocorticoid receptor (GR) can both activate and repress transcription of target genes by interaction with specific genomic response elements, glucocorticoid response elements (GREs). Activation of transcription is usually the result of the direct interaction between GR and the GRE, whereas GR-mediated transcription repression is either the result of the indirect action of GR, mediated by a response element as a result of protein.protein interaction or by an occlusion mechanism in which GR displaces a general or regulatory transcription factor. A specific mutation of rat GR, K461A, has previously been described to transform the indirect protein.protein interaction-dependent transrepressive effect of GR into an activating function (Starr, D. B., Matsui, W., Thomas, J. R., and Yamamoto, K. R. (1996) Genes Dev. 10, 1271-1283). In HOS D4 and COS7 cells, this mutation was shown to transform the transrepressive effect of wild-type GR, acting on reporter constructs containing the composite GRE from the proliferin gene (plfG) or the negative tethering GRE from the collagenase A promoter (colA), into an activating function. In contrast, the K461A mutation had no effect on the transrepressive effect of GR on the human osteocalcin gene in which repression apparently occurs through the binding of GR to a negative GRE that overlaps the TATA box. The transrepressive function, typically 40% of the basal level in the absence of hormone, required only the isolated DNA-binding domain of wild type or mutant GR and was independent of the nature of transactivation domain. Thus, mutation of rat GR at position 461 differentiates between transrepressive functions of GR dependent on GR.DNA interaction (repression by occlusion) and GR.protein interaction (active repression).
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PMID:The rat glucocorticoid receptor mutant K461A differentiates between two different mechanisms of transrepression. 926 Nov 12

We have previously reported that ursolic acid, a pentacyclic triterpene acid, inhibited the invasion of HT1080 human fibrosarcoma cells by reducing the expression of matrix metalloproteinase-9. Since the chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid, we investigated whether ursolic acid acts through the glucocorticoid receptor. The expression of matrix metalloproteinase-9 is thought to be regulated similarly with matrix metalloproteinase-1 and matrix metalloproteinase-3 as containing common 2-O-tetradecanoylphorbol-acetate responsible region, where AP-1 proteins can bind. Dexamethasone has been studied to repress the 2-O-tetradecanoylphorbol-acetate-induced expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 through a glucocorticoid receptor-mediated manner. In Northern blot analysis, we found that ursolic acid reduced the expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 induced by 2-O-tetradecanoylphorbol-acetate. Similarly, ursolic acid down-regulated 2-O-tetradecanoylphorbol-acetate-induction of matrix metalloproteinase-9 gene in the same manner of dexamethasone. RU486, a potent glucocorticoid receptor antagonist, was used for identifying that ursolic acid-induced down-regulation of matrix metalloproteinase-9 expression is mediated by its binding to glucocorticoid receptor. The effect of ursolic acid on the matrix metalloproteinase-9 expression was blocked by RU486, suggesting that ursolic acid acts via a glucocorticoid receptor in the regulation of matrix metalloproteinase-9. Western blot analysis and immunocytochemistry showed that ursolic acid increased glucocorticoid receptor fraction in the nucleus, although it decreased the synthesis of glucocorticoid receptor mRNA. In addition, ursolic acid did not decrease the expression of c-jun and DNA-binding activity of AP-1 to its cognate sequences. Taken together, we suggest that ursolic acid may induce the repression of matrix metalloproteinase-9 by stimulating the nuclear translocation of glucocorticoid receptor, and the translocated glucocorticoid receptor probably down-modulating the trans-activating function of AP-1 to 2-O-tetradecanoylphorbol-acetate responsible element of matrix metalloproteinase-9 promoter region.
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PMID:Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells. 948 41

The glucocorticoid receptor (GR) mediates the biological effects of glucocorticoids (GCs) through activation or repression of gene expression, either by DNA binding or via interaction with other transcription factors, such as AP-1. Work in tissue culture cells on the regulation of AP-1-dependent genes, such as collagenase (MMP-13) and stromelysin (MMP-3) has suggested that the antitumor and antiinflammatory activity of GCs is mediated, at least in part, by GR-mediated downmodulation of AP-1. Here, we have identified phorbol ester-induced expression of MMP-3 and MMP-13 in mouse skin as the first example of an in vivo system to measure negative interference between AP-1 and GR in the animal. Cell type-specific induction of these genes by tumor promoters is abolished by GCs. Importantly, this is also the case in GR(dim) mice expressing a DNA binding-defective mutant version of GR. In contrast, the newly identified target genes in skin, plasma glutathione peroxidase and HSP-27, were induced by GC in wild-type, but not in GR(dim) mice. Thus, these data suggest that the DNA binding-independent function of the GR is dispensable for repression of AP-1 activity in vivo and responsible for the antitumor promoting activity of GCs.
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PMID:The DNA binding-independent function of the glucocorticoid receptor mediates repression of AP-1-dependent genes in skin. 1061 94

RECEPTORS: The effect of glucocorticoids is mediated by a receptor mainly found in the cytoplasm. The glucocorticoid receptor is a member of the nuclear receptor superfamily. RECEPTOR ACTIVATION: When unstimulated, the glucocorticoid receptor is inactivated by its integration within a multiple-protein complex associating heat shock proteins, immunophilins and cyclophilins. When the hormone binds to its receptor, the complex dissociates and the receptor migrates to the nucleus. In the nucleus, the activated receptor provokes an upregulation or downregulation of target gene expression. GENE REGULATION: Gene expression may be regulated via an interaction between specific nucleic acid sequences of the glucocorticoid receptor and nuclear DNA (direct mechanism) or by protein-protein interactions (indirect mechanism). The expression of target genes is either inhibited or stimulated. PHARMACOLOGICAL CONSEQUENCES: The main pharmacological applications of glucocorticoids can be explained by these different mechanisms. The antiinflammatory action of glucocorticoids results from an inhibition of the transcription of the collagenase gene via an interaction with the AP-1 transcription factor. The anticancer action of glucocorticoids results from the induction of apoptotic cell death via a mechanism which would require the transcriptional activity of the glucocorticoid receptor.
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PMID:[Mode of action of glucocorticoids]. 1070 3

Mouse mammary whole organ culture (WOC) and explant culture of lactating tissue were used to investigate the mechanism by which glucocorticoids maintain secretory epithelium following lobuloalveolar development. The relative number of mammary epithelial cells expressing glucocorticoid receptors did not change with the loss of secretory epithelium during involution as demonstrated with competitive binding assays and immunohistochemistry for the glucocorticoid receptor. Furthermore, glucocorticoids did not inhibit AP-1 binding activity. However, Northern analysis demonstrated that genes associated with the breakdown of the extracellular matrix were not expressed in tissues cultured with glucocorticoids, in contrast to their upregulation during involution of mammary tissue cultured with insulin alone. Tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression was lowest in tissue cultured in the presence of glucocorticoids and increased 2.3-, 3.4-, and 9-fold when tissues were involuted in the presence of insulin (Ins) alone, Ins and hydrocortisone (Hyd) with 0. 005 mg/ml, or 0.01 mg/ml collagenase IV, respectively. These data indicate that glucocorticoids maintain mammary differentiation in part by inhibiting the turnover of basement membrane.
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PMID:Glucocorticoids maintain the extracellular matrix of differentiated mammary tissue during explant and whole organ culture. 1080 14

The amnion, a single layer of epithelial cells (EC) overlying layers of mesenchymal cells (MC) has been identified as a source of intrauterine prostaglandins (PG). The objectives of the present study were: (1) to establish a technique for the isolation and culture of pure amnion EC and MC preparations, (2) to characterize the cellular expression of PGHS-II and PGHS activity within these separated amnion cells and (3) to characterize the pattern of glucocorticoid stimulation of these separated amnion cells. Term gestation human amnion was collected after elective caesarean section or vaginal delivery. A trypsin digestion was used to isolate EC and a mechanical digestion and collagenase dispersion was used to isolate MC. Following 48 or 96 h in culture, cells were incubated for 24 h in the presence or absence of 1 microm arachidonic acid and treated with cortisol (F: 10-1000 nm) or 1 microm dexamethasone (DEX). Cell types were identified by immunohistochemistry (IHC). Immunoreactive PGHS-II (ir-PGHS-II) and glucocorticoid receptor (ir-GR) were localized by IHC. PGHS activity was measured as PGE(2)output determined by radioimmunoassay. Mean PGE(2)production by MC at 72 h was 22-fold greater (P<0.05) and at 120 h was 32-fold greater (P<0.03) than PGE(2)output by EC. Administration of arachidonic acid stimulated a 5.0-fold increase in PGE(2)output (P<0.0002) by EC after 72 h and a 3.6-fold increase (P<0.05) after 120 h but did not alter MC PGE(2)output. Despite exogenous substrate, EC PGE(2)output remained significantly less than PGE(2)output by MC. There was no difference in PG production by EC and MC with the onset of labour. Ir-GR expression was found in both EC and MC. F and/or DEX with and without arachidonic acid (AA) stimulated PGE(2)output by EC. Only DEX and not F increased PGE(2)output by MC. These data suggest that relatively pure EC and MC preparations can be established from amnion. PG output and its regulation appears to differ within these two amnion cell types, dependent upon (1) substrate availability and (2) the regulation of PGHS activity.
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PMID:The characterization of human amnion epithelial and mesenchymal cells: the cellular expression, activity and glucocorticoid regulation of prostaglandin output. 1083 75

Post-traumatic inflammatory reaction may contribute to progressive tissue damage after spinal cord injury (SCI). Two key transcription factors, nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1), are activated in inflammation. An increase in NF-kappaB binding activity has been shown in the injured spinal cord. We report activation of AP-1 after SCI. Electrophoretic mobility shift assay showed that AP-1 binding activity increased after SCI, starting at 1 hr, peaking at 8 hr, and declining to basal levels by 7 d. Methylprednisolone (MP) is the only therapeutic agent approved by the Food and Drug Administration for treating patients with acute traumatic SCI. MP reduced post-traumatic AP-1 activation. RU486, a glucocorticoid receptor (GR) antagonist, reversed MP inhibition of AP-1 activation. Immunostaining showed an increase in the expression of the Fos-B and c-Jun components of AP-1 in the injured cord. A c-fos antisense oligodeoxynucleotide (ODN) inhibited AP-1, but not NF-kappaB, activation after SCI. AP-1 and NF-kappaB can transactivate genes encoding matrix metalloproteinase-1 (MMP-1) and MMP-9. Western blotting and immunostaining show increased expression of MMP-1 and MMP-9 in the injured cord. MP inhibited MMP-1 and MMP-9 expression after SCI. RU486 reversed this MP effect. The c-fos antisense ODN, however, failed to suppress MMP-1 or MMP-9 expression. These findings demonstrate that MP may suppress post-traumatic inflammatory reaction by inhibiting both the AP-1 and NF-kappaB transcription cascades via a GR mechanism. Expression of inflammatory genes such as MMP-1 and MMP-9 that are transactivated jointly by AP-1 and NF-kappaB may not be suppressed by inhibiting only AP-1 activity.
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PMID:Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury. 1115 Mar 24

To investigate determinants of specific transcriptional regulation, we measured factor occupancy and function at a response element, col3A, associated with the collagenase-3 gene in human U2OS osteosarcoma cells; col3A confers activation by phorbol esters, and repression by glucocorticoid and thyroid hormones. The subunit composition and activity of AP-1, which binds col3A, paralleled the intracellular level of cFos, which is modulated by phorbol esters and glucocorticoids. In contrast, a similar AP-1 site at the collagenase-1 gene, not inducible in U2OS cells, was not bound by AP-1. The glucocorticoid receptor (GR) associated with col3A through protein-protein interactions with AP-1, regardless of AP-1 subunit composition, and repressed transcription. TIF2/GRIP1, reportedly a coactivator for GR and the thyroid hormone receptor (TR), was recruited to col3A and potentiated GR-mediated repression in the presence of a GR agonist but not antagonist. GRIP1 mutants deficient in GR binding and coactivator functions were also defective for corepression, and a GRIP1 fragment containing the GR-interacting region functioned as a dominant-negative for repression. In contrast, repression by TR was unaffected by GRIP1. Thus, the composition of regulatory complexes, and the biological activities of the bound factors, are dynamic and dependent on cell and response element contexts. Cofactors such as GRIP1 probably contain distinct surfaces for activation and repression that function in a context-dependent manner.
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PMID:Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. 1168 47

The expression of genes involved in the inflammatory response is controlled both transcriptionally and post-transcriptionally. Primary inflammatory stimuli, such as microbial products and the cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha), act through receptors of either the Toll and IL-1 receptor (TIR) family or the TNF receptor family. These cause changes in gene expression by activating four major intracellular signalling pathways that are cascades of protein kinases: namely the three mitogen-activated protein kinase (MAPK) pathways, and the pathway leading to activation of the transcription factor nuclear factor kappa B (NF kappa B). The pathways directly activate and induce the expression of a limited set of transcription factors which promote the transcription of inflammatory response genes. Many of the mRNAs are unstable, and are stabilized by the p38 MAPK pathway. Instability is mediated by clusters of the AUUUA motif in the 3' untranslated regions of the mRNAs. Control of mRNA stability provides a means of increasing the amplitude of a response and allows rapid adjustment of mRNA levels. Not all mRNAs stabilized by p38 contain AUUUA clusters; for example, matrix metalloproteinase-1 and -3 mRNAs lack these clusters, but are stabilized. Inflammatory gene expression is inhibited by glucocorticoids. These suppress MAPK signalling by inducing a MAPK phosphatase. This may be a significant mechanism additional to that by which the glucocorticoid receptor interferes with transcription factors.
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PMID:Control of the expression of inflammatory response genes. 1458 85


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