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)

Tenascin (TN) is a large oligomeric glycoprotein that is present transiently in the extracellular matrix (ECM) of cells and is involved in morphogenetic movements, tissue patterning, and tissue repair. It has multiple domains, both adhesive and anti-adhesive, that interact with cells and with fibronectin (FN) and other ECM macromolecules. We have studied the consequences of the interaction of TN with a FN matrix on gene expression in rabbit synovial fibroblasts. Fibroblasts plated on a mixed substrate of FN and TN, but not on FN alone, upregulated synthesis of four genes: collagenase, stromelysin, the 92-kDa gelatinase, and c-fos. Although the fibroblasts spread well on both FN and FN/TN substrates, nuclear c-Fos increased within 1 h only in cells that were plated on FN/TN. TN did not induce the expression of collagenase in cells plated on substrates of type I collagen or vitronectin (VN). Moreover, soluble TN added to cells adhering to a FN substrate or to serum proteins had no effect, suggesting that TN has an effect only in the context of mixed substrates of FN and TN. Collagenase increased within 4 h of plating on a FN/TN substrate and exhibited kinetics similar to those for induction of collagenase gene expression by signaling through the integrin FN receptor. Arg-Gly-Asp peptide ligands that recognize either the FN receptor or the VN receptor and function-perturbing anti-integrin monoclonal antibodies diminished the interaction of fibroblasts with a mixed substrate of FN, TN, and VN, but had no effect on the adhesion of fibroblasts to a substrate of FN and VN, suggesting that both receptors recognize the complex. Anti-TN68, an antibody that recognizes an epitope in the carboxyl-terminal type III repeats involved in the interaction of TN with both FN and cells, blocked the inductive effect of the FN/TN substrate, whereas anti-TNM1, an antibody that recognizes an epitope in the amino-terminal anti-adhesive region of epidermal growth factor-like repeats, had no effect. These data suggest that transient alteration of the composition of ECM by addition of proteins like TN may regulate the expression of genes involved in cell migration, tissue remodeling, and tissue invasion, in regions of tissue undergoing phenotypic changes.
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PMID:The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts. 751 5

The AP-1 consensus sequences (TGAGTCA) are the major 12-O-tetradecanoylphorbol113-acetate (TPA) responsive elements shared by several TPA inducible genes, such as c-sis, c-fos, c-myc, collagenase, stromelysin, hMTIIA and SV40. However, the role of AP-1 binding sites, which are present in the introns 3, 5, and 11 of ODC gene, in the regulation of TPA-induced ornithine decarboxylase (ODC) gene transcription are unknown. We determined the TPA responsiveness of the AP-1 sequences in the introns of ODC gene in CV-1 cells which induce ODC activity and mRNA in response to TPA treatment. ODC introns containing AP-1 sequences were inserted into the chloramphenicol acetyltransferase (CAT) reporter gene. Transient transfection of CV-1 cells with the intron-CAT constructs followed by TPA treatment did not induce CAT activity. However, when flanking regions of the AP-1 site in intron 3 were narrowed down to 74 bp, TPA induced CAT activity by 5- to 7-fold. The TPA-inducibility could be eliminated by mutation of the AP-1 site (TGAGTCA-->TGATGCCA or TGATGA) in 74 bp of intron 3. These results indicate that the AP-1 sequences in the intact ODC introns may not be responsive to TPA. The flanking sequences of the AP-1 site may be crucial to determine whether the AP-1 site is accessible to the TPA-induced transcriptional factor(s).
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PMID:Lack of 12-O-tetradecanoylphorbol-13-acetate responsiveness of ornithine decarboxylase introns which have AP-1 consensus sequences. 765 80

We have shown previously that the expression of collagenase is upregulated in rabbit synovial fibroblasts cultured on a substrate of antibody to the alpha 5 chain of the alpha 5 beta 1 integrin fibronectin receptor or on the 120-kD cell-binding chymotryptic fragment of plasma fibronectin, but remains at basal levels in cells plated on intact plasma fibronectin. We now have identified some of the components of a signaling pathway that couples the fibronectin receptor to the induction of collagenase transcription. We studied the control of collagenase gene expression in cells adhering to the 120-kD fragment of fibronectin, to antifibronectin receptor antibody, or to plasma fibronectin by transiently introducing promoter-reporter constructs into rabbit synovial fibroblasts before plating cells on these matrices. The constructs contained segments of the human collagenase promoter regulating transcription of chloramphenicol acyl transferase. Expression of constructs containing the -1200/-42-bp segment or the -139/-42-bp segment of the collagenase promoter inserted upstream from the reporter gene was induced to similar extents in cells plated on the 120-kD fragment of fibronectin or on anti-fibronectin receptor antibody, relative to that in fibroblasts plated on fibronectin. The expression of the construct containing the -66/-42-bp segment of the promoter was not regulated and was similar to that of the parent pBLCAT2 plasmid, suggesting that the -139/-67 region of the collagenase promoter, which contains PEA3- and AP1-binding sites, regulates the transcription of collagenase caused by integrin-derived signals. Expression of a reporter construct containing only the PEA3 and AP1 sites in the collagenase promoter (-90/-67) also increased in cells plated on the 120-kD fragment of fibronectin or on anti-fibronectin receptor antibody, relative to that in cells plated on fibronectin. Mutations in either the AP1 or PEA3 site of this minimal promoter abrogated its activity in cells plated on these inductive ligands. Expression of c-fos mRNA increased within 1 h of plating cells on the 120-kD fibronectin fragment or on anti-fibronectin receptor antibody, relative to that in cells plated on fibronectin. c-Fos protein accumulated in the nuclei of fibroblasts within 10 min of plating on the 120-kD fibronectin fragment. The increase in c-Fos was required for the increase in collagenase in cells plated on the 120-kD fibronectin fragment: incubation of cells with antisense, but not sense, c-fos oligonucleotides diminished both basal and induced expression of the -139/-42 collagenase promoter-reporter construct and decreased expression of the endogenous collagenase gene.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Components of the nuclear signaling cascade that regulate collagenase gene expression in response to integrin-derived signals. 779 Mar 65

Transcriptional activation of c-fos in response to both serum stimulation and DNA damage requires the serum response element. The inability of in vitro aged or senescent fibroblasts to proliferate in response to serum has been shown to be associated with repressed c-fos expression and reduced AP-1 binding activity. In contrast, we have observed similar levels of c-fos mRNA and protein expression in young (early passage) and old (late passage) cells following their treatment with ultraviolet (UV) irradiation or methyl methanesulfonate (MMS). Thus, the early events in the signal transduction pathway leading to transcriptional activation of c-fos following DNA damage are distinct from those mediating the gene's expression in response to mitogenic stimulation. Despite normal levels of c-fos expression, we observed a reduced level of AP-1 binding activity in old cells relative to young cells treated with UV irradiation or MMS. Reduced AP-1 binding activity is associated with reduced expression of the AP-1-dependent gene, collagenase, in old cells treated with DNA damaging agents. Since other DNA damage-inducible genes also contain an AP-1 regulatory element presumed to play a role in their expression, reduced AP-1 binding activity is likely to have a major impact on the old cell's ability to respond appropriately to DNA damage.
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PMID:Alterations in the molecular response to DNA damage during cellular aging of cultured fibroblasts: reduced AP-1 activation and collagenase gene expression. 779 Mar 98

We have examined the hypothesis that neuronal programmed cell death requires a genetic program; we used a model wherein rat sympathetic neurons maintained in vitro are deprived of NGF and subsequently undergo apoptosis. To evaluate gene expression potentially necessary for this process, we used a PCR-based technique and in situ hybridization; patterns of general gene repression and selective gene induction were identified in NGF-deprived neurons. A temporal cascade of induced genes included "immediate early genes," which were remarkable in that their induction occurred hours after the initial stimulus of NGF removal and the synthesis of some required ongoing protein synthesis. The cascade also included the cell cycle gene c-myb and the genes encoding the extracellular matrix proteases transin and collagenase. Concurrent in situ hybridization and nuclear staining revealed that while c-jun was induced in most neurons, c-fos induction was restricted to neurons undergoing chromatin condensation, a hallmark of apoptosis. To evaluate the functional role of the proteins encoded by these genes, neutralizing antibodies were injected into neurons. Antibodies specific for either c-Jun or the Fos family (c-Fos, Fos B, Fra-1, and Fra-2) protected NGF-deprived neurons from apoptosis, whereas antibodies specific for Jun B, Jun D, or three nonimmune antibody preparations had no protective effect. Because these induced genes encode proteins ranging from a transcription factor necessary for death to proteases likely involved in tissue remodeling concurrent with death, these data may outline a genetic program responsible for neuronal programmed cell death.
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PMID:Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. 779 22

Osteoporosis, especially the juxtaarticular osteoporosis of involved joints, is a characteristic manifestation of rheumatoid arthritis (RA). Histomorphometric studies suggest the existence of increased bone turnover in RA: impaired bone formation and hightened osteoclasic bone resorption. Recent studies show that important mediators in the pathogenesis of RA such as prostaglandin E, interleukin 1 (IL1) or tumor necrosis factor (TNF) alpha also play important roles in bone remodelling. Prostaglandin E2 promotes maturation of osteoclasts from hematopoietic precursor cells. IL1 inhibits collagen synthesis in osteoblasts. IL1 enhances collagenase and stromelysin gene expression and stimulates osteoclastic bone resorption. TNF alpha inhibits bone collagen synthesis and causes osteoclastic bone resorption. TNF alpha, and possibly IL1, enhances collagenase and stromelysin gene expression by stimulating the AP-1 promoter sites of the genes. Constitutive expression of c-fos induces joint destruction without lymphocyte infiltration in antigen-induced arthritis in mice, and supports cell growth of human rheumatoid synovial cells, possibly acting on the AP-1 sites. Furthermore, constitutive c-fos expression decreases collagen synthesis in osteoblasts and increases the mediator secretion from osteoblasts thereby stimulating osteoclastic bone resorption. These findings suggest that signal transduction through AP-1 transcriptional regulation sites may play an important role in the pathogenesis of joint destruction and osteoporosis in RA.
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PMID:Osteoporosis in rheumatoid arthritis: a molecular biological aspect of connective tissue gene activation. 780 9

The administration of 150 nM etoposide, an inhibitor of DNA topoisomerase II activity, decreased the proliferation and induced the differentiation of U937 human promonocytic cells, as determined by nitroblue tetrazolium reduction, surface accumulation of CD11b/CD18 and CD11c/CD18 integrins, and c-fms protooncogene expression. The expression of these differentiation markers started to be detected at 24 h of treatment. Etoposide caused little cell damage, as determined by trypan blue exclusion and by apoptotic-like DNA degradation, which was slightly initiated at 48 h. The treatment induced a transient increase in c-fos, c-jun, and jun B mRNA levels, with maximum values at 12 h, a transient increase in collagenase mRNA level, with maximum value at 48 h, and a progressive increase in vimentin and lamin A and C mRNAs. These changes were qualitatively similar to those produced by 12-O-tetradecanoylphorbol-13-acetate. Etoposide also caused a transient increase of total AP-1 binding activity, with maximum value at 12 h of treatment, as determined by gel retardation assays. The drug produced an early transient activation (3-6 h) of membrane-bound protein kinase C, followed by the later activation (48 h) of both the membrane and cytosolic enzyme. The protein kinase C inhibitors, sphinganine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), attenuated the induction of differentiation markers by etoposide. These results suggest that protein kinase C and AP-1-dependent gene expression could be involved in myeloid cell differentiation by DNA topoisomerase II inhibitors.
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PMID:Etoposide-induced differentiation of U937 promonocytic cells: AP-1-dependent gene expression and protein kinase C activation. 781 32

Okadaic acid (OA) is a novel, non-phorbol ester-type tumor promoter, which is a specific inhibitor of protein phosphatases 1 and 2A. Treatment of human fibrosarcoma HT-1080 cells with OA resulted in induction of collagenase and stromelysin-1 mRNA levels, while mRNA levels for tissue inhibitor of metalloproteinases-1 were enhanced to a lesser extent. Induction of collagenase and stromelysin-1 mRNA levels was dependent on protein synthesis. Exposure of HT-1080 cells to OA resulted in marked and persistent induction of junB, junD, and c-fos mRNA levels up to 24 h, while c-jun mRNA levels were only slightly elevated. In transiently transfected HT-1080 cells, OA-elicited activation of a 3.8-kilobase collagenase promoter/reporter gene construct was entirely dependent on junB expression, as determined by cotransfection with a junB antisense expression construct. Overexpression of JunB in HT-1080 cells enhanced collagenase promoter activity by 10-fold, and OA augmented trans-activation of collagenase promoter by c-Jun and JunB. The results indicate that induction of collagenase gene expression by OA is mediated by enhanced JunB expression, as well as enhanced trans-activating capacity of AP-1 complexes containing c-Jun and JunB. These results also suggest that selective overexpression of junB may enhance invasive and metastatic potential of neoplastic cells.
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PMID:Okadaic acid-elicited transcriptional activation of collagenase gene expression in HT-1080 fibrosarcoma cells is mediated by JunB. 784 22

Terminally differentiated (TD) 3T3-T cells have a reduced capacity to repair ultraviolet (UV)-induced DNA damage, as compared with the repair capabilities of growth-arrested and cycling (stem) 3T3-T cells. In this study UV-induced expression of the immediate early response genes c-fos and c-jun and the secondary response gene type IV collagenase in TD, growth-arrested and stem 3T3-T cells was investigated by northern blot analysis. At each UV dose (0-10 J/m2) there was an increase in c-fos and, to a lesser extent, c-jun expression 0.5 h after irradiation in each 3T3-T phenotype as compared with unirradiated controls. Maximum induction of c-fos was reached at 0.5-1 J/m2 in TD and growth-arrested cells, which was 10-fold greater than in stem cells. The induction of c-jun in TD and growth-arrested cells reached maximums at 0.5 J/m2; at this dose each was greater than in stem cells. The increases in c-fos and c-jun expression were transient in each phenotype reaching maximums from 0.5 to 1 h after irradiation. The expression of type IV collagenase was increased in the non-cycling phenotypes at 2-8 h after irradiation. However, collagenase expression was not detected in unirradiated or irradiated stem cells. These results suggest that growth arrest, not differentiation or DNA repair capacity, is the primary influence on gene induction after UV irradiation.
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PMID:Influence of DNA repair capacity and cell differentiation on UV-induced gene expression. 790 8

We have previously shown that during wound healing migrating keratinocytes, which are in contact with the dermal matrix, express interstitial collagenase, whereas basal epidermal cells, which reside on an intact basement membrane, do not. Duplicating this in vivo pattern, collagenase production was induced in primary human keratinocytes grown on native type I collagen, but only background levels of enzyme were detected in cells cultured on denatured type I collagen or on Matrigel. Using genistein, herbimycin A, and sodium orthovanadate, we show that tyrosine kinase activity was required for collagen-mediated induction of keratinocyte collagenase. Similarly, collagenase steady-state mRNA levels and the activity of a transfected human collagenase-promoter CAT construct were inhibited by genistein and enhanced by orthovanadate. Staurosporine and H-7 also blocked collagenase production, indicating that protein kinase C activity was also required for collagen-mediated induction of keratinocyte collagenase. All inhibitory effects were dose-dependent, and no compound significantly affected total protein synthesis. Furthermore, both tyrosine kinase and protein kinase C inhibitors blocked phorbol ester-mediated induction of collagenase, but only protein kinase C antagonists abrogated phorbol ester-mediated induction of c-fos mRNA. These data suggest that similar signal transduction pathways are used by various agonists to mediate the stimulation of interstitial collagenase production.
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PMID:Collagen-stimulated induction of keratinocyte collagenase is mediated via tyrosine kinase and protein kinase C activities. 796 3


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