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 basis by which transforming growth factor (TGF)-beta 1 protects certain tumor cells from tumor necrosis factor (TNF) cytotoxicity was investigated. When pretreated, with TGF-beta 1, -beta 2, and -beta 3, murine L929S fibroblasts developed resistance to TNF cytotoxicity. Time course experiments revealed that TGF-beta 1 initially induced both cellular protein-tyrosine phosphorylation and simultaneous secretion of a novel extracellular matrix TNF-resistance triggering (TRT) protein(s), which closely preceded the acquisition of TNF-resistance. TGF-beta 2 and -beta 3 also increased tyrosine phosphorylation. However, both molecules failed to stimulate TRT secretion. The increased levels of phosphorylation, particularly to 9 specific protein tyrosine kinase inhibitor-sensitive cellular proteins, appeared to alter the TNF killing pathway. TGF-beta 1-induced TRT secretion required participation of unknown serum factors. TRT adhered strongly to polystyrene plates and resisted treatment with heat (60 degrees C, 30 min), collagenase, alpha 2-macroglobulin, heparin, antibodies against TGF-beta s, and limited trypsin digestion. Notably, TRT promoted TNF-resistance via activation of tyrosine and serine/threonine kinase functions in L929S. Thus, the molecular pathway involves TGF-beta 1-mediated initiation of a rapid tyrosine phosphorylation of cellular protein substrates (which alters TNF cytotoxic pathway), and a simultaneous secretion of TRT, which in turn signals the cells to maintain the levels of phosphorylation, thereby sustaining the TNF-resistance.
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PMID:Transforming growth factor-beta 1 induction of novel extracellular matrix proteins that trigger resistance to tumor necrosis factor cytotoxicity in murine L929 fibroblasts. 753 77

Tumor necrosis factor alpha (TNF-alpha) has been shown to induce the production of interstitial collagenase by fibroblasts and chondrocytes. We investigated the role of TNF-alpha in collagenase gene expression by U937 monocyte/macrophage cells. Transcription of the TNF-alpha gene was observed after 0.5 h of phorbol myristate acetate (PMA) stimulation. Collagenase mRNA expression was not observed until 5-7 h of activation with PMA. TNF-alpha was detected in the culture supernatants 2-3 h before transcription of the collagenase gene. Neutralization of TNF-alpha protein with anti-TNF-alpha antibodies significantly reduced collagenase mRNA expression. Protein kinase C (PKC) and protein tyrosine kinase (PTK) inhibition essentially abolished both PMA-induced TNF-alpha protein secretion and collagenase mRNA expression. Collagenase gene expression induced by exogenous TNF-alpha in U937 cells stimulated with a suboptimal concentration of PMA was suppressed by PTK, but not PKC, inhibition. The pyrrolidine derivative of dithiocarbamate, a potent inhibitor of nuclear factor-kappa B (NF-kappa B) activation, resulted in a marked reduction in collagenase gene transcription, however, no reduction of TNF-alpha secretion was noted. Anti-TNF-alpha antibodies inhibited PMA-induced NF-kappa B activation. These observations demonstrate an important role for TNF-alpha in the autocrine regulation of collagenase gene expression by U937 cells. Additionally, TNF-alpha-induced PTK and NF-kappa B activation were important in collagenase gene expression in this cell line.
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PMID:Autocrine regulation of collagenase gene expression by TNF-alpha in U937 cells. 855 60

Galectin 3, a 30 kDa galactoside-binding protein distributed widely in epithelial and immune cells, contains no signal sequence and is externalized by a mechanism independent of the endoplasmic reticulum (ER)-Golgi complex. We show here that hamster galectin 3 overexpressed in transfected cos-7 cells is secreted at a very low rate. A chimaera of galectin 3 fused to the N-terminal acylation sequence of protein tyrosine kinase p56(lck), Nt-p56(lck)-galectin 3, which is myristoylated and palmitoylated and rapidly transported to plasma membrane domains, is efficiently released from transfected cells indicating that movement of cytoplasmic galectin 3 to plasma membrane domains is a rate limiting step in lectin secretion. N-terminal acylation is not sufficient for protein secretion since p56(lck) and the chimaera Nt-p56(lck)-CAT are not secreted from transfected cells. The amino-terminal half of galectin 3 is sufficient to direct export of a chimaeric CAT protein indicating that part of the signal for plasma membrane translocation lies in the N-terminal domains of the lectin. Immunofluorescence studies show that Nt-p56(lck)-galectin 3 aggregates underneath the plasma membrane and is released by membrane blebbing. Vesicles of low buoyant density isolated from conditioned medium are enriched in galectin 3. The lectin is initially protected from exogenous collagenase but is later released in soluble protease-sensitive form from the lectin-loaded vesicles. Using murine macrophages, which secrete their endogenous galectin 3 at a moderate rate especially in the presence of Ca2+-ionophores, we were also able to trap a galectin 3-loaded vesicular fraction which was released into the culture supernatant.
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PMID:Plasma membrane targetting, vesicular budding and release of galectin 3 from the cytoplasm of mammalian cells during secretion. 919 Oct 41

Neurotrophins induce neuronal differentiation by binding to a subclass of ligand-stimulated protein tyrosine kinase receptors and activating signal transduction pathways that mediate altered patterns of gene expression. Nerve growth factor (NGF) induced differentiation of PC12 pheochromocytoma cells is one of the major model systems used to study neuronal differentiation in response to neurotrophins. Although epidermal growth factor (EGF) does not induce PC12 cell differentiation, NGF and EGF activate many of the same signal transduction pathways and induce transcription of many of the same genes in PC12 cells. We have now employed cDNA representational difference analysis to identify four genes (activity-regulated cytoskeletal protein, collagenase 1, plasminogen activator inhibitor-1, and VH6/MKP-3) as genes preferentially induced withing 4 hours by NGF in PC12 cells.
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PMID:Identification of genes preferentially induced by nerve growth factor versus epidermal growth factor in PC12 pheochromocytoma cells by means of representational difference analysis. 937 91

Cytokines and growth factors regulate physiologic and pathologic turn-over of cartilage extracellular matrix (ECM) by altering the balance between tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs). Oncostatin M (OSM) is a cytokine of the IL-6 family whose levels are increased in the serum and synovial fluids of patients with rheumatoid arthritis. We examined responsiveness of the TIMP-3 gene to OSM in articular chondrocytes and studied the regulatory and signaling mechanisms of this response. OSM induced TIMP-3 mRNA and protein expression in a dose- and time-dependent fashion. Concomitantly, stromelysin-1 and collagenase-1 RNA and activities were also induced. A cartilage matrix growth factor, TGF-beta, induced TIMP-3, but combined OSM and TGF-beta did not further increase the extent of induction, suggesting a lack of synergy between the two. OSM induction of TIMP-3 gene expression was dependent upon de novo protein synthesis and transcription. RNA decay time-courses suggested that the OSM-mediated increase of TIMP-3 RNA was not due to enhanced message stability and, along with inhibition by actinomycin-D, suggested a transcriptional control. The antiinflammatory glucocorticoid, dexamethasone, down-regulated this augmentation. Investigation of the signaling mechanisms revealed that protein tyrosine kinase inhibitors genistein and herbimycin A, as well as the specific mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059, suppressed OSM-induced TIMP-3 message expression, suggesting the involvement of tyrosine kinases and mitogen-activated protein kinase cascades in the signaling of OSM leading to TIMP-3 RNA enhancement. Thus OSM can potentially alter the cartilage matrix metabolism by regulating genes like TIMP-3 and matrix metalloproteinases.
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PMID:Oncostatin M up-regulates tissue inhibitor of metalloproteinases-3 gene expression in articular chondrocytes via de novo transcription, protein synthesis, and tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms. 979 37

An imbalance between the activity of matrix metalloproteinases (MMPs) (proteolytic enzymes that degrade protein components of the extracellular matrix) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), may be one of the mechanisms responsible for tumor cell invasion. We have investigated the regulation of MMP-1 and TIMP-1 gene expression in benign and malignant (follicular, anaplastic, and papillary) human thyroid cells. As expected of cells with invasive potential, detectable MMP-1 messenger RNA (mRNA) levels were observed in malignant cells under basal conditions, in contrast to undetectable levels in benign cells. Exposure of these cells, for 1 h, to the active phorbol ester, phorbol 12-myristate 13-acetate (TPA, 100 nmol/L), acting via protein kinase C (PKC), elicited an increase in MMP-1 mRNA, with a peak stimulation after a 3- to 4-h culture period. Epidermal growth factor (EGF, 25 ng/mL), however, acting via protein tyrosine kinase (PTK), stimulated such gene expression in malignant cells but failed to do so in benign cells. TIMP-1 mRNA was not significantly altered by the TPA-PKC, EGF-PTK, or TSH-protein kinase A (PKA) pathways in malignant cells. In benign cells, however, TPA induced a small, though significant, increase in TIMP-1. The MMP-1 stimulation by EGF and lack of TPA-induced rise in TIMP-1 in malignant cells, in sharp contrast to the effects obtained in benign thyrocytes, seems to indicate that the MMP: TIMP balance favors a more extensive extracellular matrix protein breakdown by malignant thyrocytes, as expected of cells exhibiting invasive capacity. TSH (10-500 microU/mL) failed to significantly influence basal MMP-1 or TIMP-1 mRNA levels, but it caused a dose-dependent inhibition in TPA- and EGF-induced MMP-1 mRNA in malignant cells, and TPA-stimulated MMP-1 and TIMP-1 in benign cells. The repressive action of TSH on MMP-1 mRNA was mimicked by forskolin and 8-bromo-cAMP and was abrogated by the PKA inhibitor, H-89, suggesting that the TSH inhibitory action is PKA-mediated. In conclusion, the present study provides novel data on MMP-1 and TIMP-1 gene expression and their modulation by the major signal transduction pathways operating in human thyroid cells. Similar and divergent patterns have emerged in the regulation of such gene expression in benign and malignant human thyrocytes, in many instances in accord with the concept of MMP playing the role of stimulating, and TIMP inhibiting, cell invasion. Although MMP-1 may be just one of the many factors responsible for tumor cell invasion, the present findings demonstrating the possibility, at least in vitro, of repressing MMP gene expression may have important clinical ramifications.
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PMID:Similar and divergent patterns in the regulation of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP-1 gene expression in benign and malignant human thyroid cells. 1048 6

Oncostatin M (OSM), a member of the IL-6 superfamily of cytokines, is elevated in patients with rheumatoid arthritis and, in synergy with IL-1, promotes cartilage degeneration by matrix metalloproteinases (MMPs). We have previously shown that OSM induces MMP and tissue inhibitor of metalloproteinase-3 (TIMP-3) gene expression in chondrocytes by protein tyrosine kinase-dependent mechanisms. In the present study, we investigated signaling pathways regulating the induction of MMP and TIMP-3 genes by OSM. We demonstrate that OSM rapidly stimulated phosphorylation of Janus kinase (JAK) 1, JAK2, JAK3, and STAT1 as well as extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase 1/2 mitogen-activated protein kinases in primary bovine and human chondrocytes. A JAK3-specific inhibitor blocked OSM-stimulated STAT1 tyrosine phosphorylation, DNA-binding activity of STAT1 as well as collagenase-1 (MMP-1), stromelysin-1 (MMP-3), collagenase-3 (MMP-13), and TIMP-3 RNA expression. In contrast, a JAK2-specific inhibitor, AG490, had no impact on these events. OSM-induced ERK1/2 activation was also not affected by these inhibitors. Similarly, curcumin (diferuloylmethane), an anti-inflammatory agent, suppressed OSM-stimulated STAT1 phosphorylation, DNA-binding activity of STAT1, and c-Jun N-terminal kinase activation without affecting JAK1, JAK2, JAK3, ERK1/2, and p38 phosphorylation. Curcumin also inhibited OSM-induced MMP-1, MMP-3, MMP-13, and TIMP-3 gene expression. Thus, OSM induces MMP and TIMP-3 genes in chondrocytes by activating JAK/STAT and mitogen-activated protein kinase signaling cascades, and interference with these pathways may be a useful approach to block the catabolic actions of OSM.
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PMID:Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. 1120 8

Ets-1 is a transcription factor regulating the expression of matrix-degrading proteinases and is believed to play a critical role in cell migration and tumor invasion. The aim of this study is to investigate the direct induction of ets-1 with consequential upregulation of collagenase-1 (MMP-1) by cell adhesion to extracellular matrix and to identify intracellular signal transduction pathways involved in ets-1 induction in cultured endothelial cells. The expressions of ets-1 mRNA and protein as well as MMP-1 protein were induced by cell adhesion to type I collagen and antisense ets-1 oligonucleotides impaired that MMP-1 expression. In addition, protein tyrosine kinase (PTK) and protein kinase C (PKC) inhibitors abrogated their induction, showing the suppression of focal adhesion kinase phosphorylation. These results suggest that ets-1 induced by cell adhesion to extracellular matrix directly upregulates MMP-1 expression via PTK and PKC activation in cultured endothelial cells.
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PMID:Ets-1 upregulates matrix metalloproteinase-1 expression through extracellular matrix adhesion in vascular endothelial cells. 1182 72

The blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC) regulates the passage of molecules and leukocytes in and out of the brain. Oxidative stress is a major underlying cause of neurodegenerative and neuroinflammatory disorders and BBB injury associated with them. Using human BMVEC grown on porous membranes covered with basement membrane (BM) matrix (BBB models), we demonstrated that reactive oxygen species (ROS) augmented permeability and monocyte migration across BBB. ROS activated matrix metalloproteinases (MMP-1, -2, and -9) and decreased tissue inhibitors of MMPs (TIMP-1 and -2) in a protein tyrosine kinase (PTK)-dependent manner. Increase in MMPs and PTK activities paralleled degradation of BM protein and enhanced tyrosine phosphorylation of tight junction (TJ) protein. These effects and enhanced permeability/monocyte migration were prevented by inhibitors of MMPs, PTKs, or antioxidant suggesting that oxidative stress caused BBB injury via degradation of BM protein by activated MMPs and by PTK-mediated TJ protein phosphorylation. These findings point to new therapeutic interventions ameliorating BBB dysfunction in neurological disorders such as stroke or neuroinflammation.
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PMID:Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. 1725 Jun 80

Blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC) regulates the passage of molecules and leukocytes in and out of the brain. Activation of matrix metalloproteinases (MMPs) and alteration of basement membrane (BM) associated with BBB injury was documented in stroke patients. While chronic alcoholism is a risk factor for developing stroke, underlying mechanisms are not well understood. We hypothesized that ethanol (EtOH)-induced protein tyrosine kinase (PTK) signaling resulted a loss of BBB integrity via MMPs activation and degradation of BM component, collagen IV. Treatment of BMVEC with EtOH or acetaldehyde (AA) for 2-48 h increased MMP-1, -2 and -9 activities or decreased the levels of tissue inhibitors of MMPs (TIMP-1, -2) in a PTK-dependent manner without affecting protein tyrosine phosphatase activity. Enhanced PTK activity after EtOH exposure correlated with increased phosphorylated proteins of selective receptor and nonreceptor PTKs. Up-regulation of MMPs activities and protein contents paralleled a decrease in collagen IV content, and inhibitors of EtOH metabolism, MMP-2 and -9, or PTK reversed all these effects. Using human BMVEC assembled into BBB models, we found that EtOH/AA diminished barrier tightness, augmented permeability, and monocyte migration across the BBB via activation of PTKs and MMPs. These findings suggest that alcohol associated BBB injury could be mediated by MMPs via BM protein degradation and could serve as a comorbidity factor for neurological disorders like stroke or neuroinflammation. Furthermore, our preliminary experiments indicated that human astrocytes secreted high levels of MMP-1 and -9 following exposure to EtOH, suggesting the role of BM protein degradation and BBB compromise as a result of glial activation by ethanol. These results provide better understanding of multifaceted effects of alcohol on the brain and could help develop new therapeutic interventions.
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PMID:Activation of protein tyrosine kinases and matrix metalloproteinases causes blood-brain barrier injury: Novel mechanism for neurodegeneration associated with alcohol abuse. 1794 53


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