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)

A cell culture inside a three-dimensional gel of fibrillar collagen is an experimental model used to study the response of cells to the extracellular matrix. Many cell types induce the contraction of gel and simultaneously decrease their production of type I collagen, whereas the expression of interstitial collagenase (matrix metalloproteinase-1; MMP-1) is enhanced. We have previously shown that in osteogenic cells the collagen receptor alpha2beta1 integrin is a positive regulator of MMP-1 and that the number of alpha2beta1 integrins on the cell surface also regulates the magnitude of contraction. However, the downregulation of collagen mRNA levels is not initiated by alpha2beta1 integrin. Here, we have studied in human KHOS-240 and MG-63 osteosarcoma cells and in human skin fibroblasts the effects of tyrosine kinase inhibitors on collagen gel contraction and on the regulation of MMP-1 and collagen alpha1(I) genes by extracellular collagen. The induction of MMP-1 could be inhibited by all tyrosine kinase inhibitors tested with the exception of genistein. None of them could prevent the downregulation of collagen expression. Thus, the collagen-induced alterations in the expression of MMP-1 and collagen alpha1(I) seem to be dependent on distinct signal transduction pathways. Many of the inhibitors, including genistein, could prevent the contraction of collagen gels. The effect was not related to their ability to inhibit cell growth, because an inhibitor specific for DNA synthesis and cell division did not have the same effect. Thus, we suggest that the process of collagen gel contraction requires protein-tyrosine phosphorylation and that the ability of cells to contract collagen gels is not related to the induction of MMP-1 or to the level of collagen alpha1(I) expression. Finally, we propose that the tyrosine kinase inhibitors might be considered as candidate molecules in the treatment of pathological scar contraction.
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PMID:Integrin alpha2beta1-dependent contraction of floating collagen gels and induction of collagenase are inhibited by tyrosine kinase inhibitors. 889 67

Collagenase-1 (matrix metalloproteinase-1 (MMP-1)) degrades the extracellular matrix and enhances the invasive phenotype of tumor cells. v-src activated MMP-1 transcription through a series of elements in the proximal promoter, including the E2BP (nt -172), polyoma virus enhancer A3 (PEA3) (nt -94), activator protein-1 (AP-1) (nt -72), and signal transducer and activator of transcription (STAT) (nt -57) consensus sites. Of these sites, PEA3 and STAT contributed specifically to induction by v-src, whereas the remaining elements were also involved in induction by the phorbol ester phorbol myristate acetate (PMA). However, in contrast to MMP-1 induction by PMA, an AP-1 site located at nt -186 did not contribute to v-src induction. These results suggest divergence of the tyrosine kinase- and protein kinase C-dependent pathways with respect to MMP-1 transcription. v-src induced MMP-1 through mitogen-activated protein kinases, with extracellular signal-regulated kinases playing a larger role than c-jun N-terminal kinase. Retinoic acid, which inhibits the progression of certain cancers, repressed v-src-induced MMP-1 transcription. Constitutive expression of retinoic acid receptors (RARs) alpha or beta, but not gamma, or of retinoid X receptor alpha, repressed v-src-induced collagenase-1 transcription. We concluded that oncogenic induction of MMP-1 by v-src depends on signaling pathways and cis-acting sequences that are distinct from those involved in phorbol ester activation. Furthermore, v-src induction of MMP-1 may, by acting in concert with other genes, enhance matrix degradation and tumor progression, and retinoic acid and RARs may antagonize this induction in an RAR type-specific manner.
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PMID:v-src activation of the collagenase-1 (matrix metalloproteinase-1) promoter through PEA3 and STAT: requirement of extracellular signal-regulated kinases and inhibition by retinoic acid receptors. 953 51

Collagenase-3 (MMP-13) is a matrix metalloproteinase (MMP) originally identified in breast carcinomas which is also produced at significant levels during fetal ossification and in arthritic processes. In this work, we have found that transforming growth factor beta1 (TGF-beta1), a growth factor widely assumed to be inhibitory for MMPs, strongly induces collagenase-3 expression in human KMST fibroblasts. In contrast, this growth factor down-regulated the expression in these cells of collagenase-1 (MMP-1), an enzyme highly related to collagenase-3 in terms of structure and enzymatic properties. The positive effect of TGF-beta1 on collagenase-3 expression was dose- and time-dependent, but independent of the effects of this growth factor on cell proliferation rate. Analysis of the signal transduction mechanisms underlying the up-regulating effect of TGF-beta1 on collagenase-3 expression demonstrated that this growth factor acts through a signaling pathway involving protein kinase C and tyrosine kinase activities. Functional analysis of the collagenase-3 gene promoter region revealed that the inductive effect of TGF-beta1 is partially mediated by an AP-1 site. Comparative analysis with the promoter region of the collagenase-1 gene which contains an AP-1 site at equivalent position, confirmed that TGF-beta1 did not have any effect on CAT activity levels of this promoter. Finally, by using electrophoretic mobility shift assays and antibody supershift analysis, we propose that c-Fos, c-Jun, and JunD may play major roles in the collagenase-3 activation by TGF-beta1 in human fibroblasts.
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PMID:Differential effects of transforming growth factor-beta on the expression of collagenase-1 and collagenase-3 in human fibroblasts. 954 14

Activation of human monocytes with lipopolysaccharide (LPS) results in the production of matrix metalloproteinases (MMPs) through a prostaglandin E2 (PGE2)-cAMP-dependent pathway. In this study, the early signaling events involved in this signal transduction pathway were evaluated. Pretreatment of human peripheral blood monocytes with herbimycin A, a tyrosine kinase inhibitor, or arachidonyl trifluoromethyl ketone (AACOCF3), a specific inhibitor of cytosolic phospholipase A2 (cPLA2) inhibited the induction of PGE2 by LPS. This resulted in the inhibition of protein expression of gelatinase B (MMP-9) and interstitial collagenase (MMP-1), two major MMPs secreted by activated monocytes. Addition of arachidonic acid (AA) reversed the inhibitory effect of herbimycin A or AACOCF3 on monocyte MMP production, indicating the importance of tyrosine phosphorylation and the involvement of cPLA2 at an early stage in the signal transduction pathway of MMPs. This finding was further supported by LPS-induced shift in cPLA2 migration and tyrosine phosphorylation based on immunoblotting and immunoprecipitation studies. These results provide evidence that tyrosine phosphorylation of cPLA2 is one of the initial steps needed for the LPS induced MMP production in human monocytes.
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PMID:Lipopolysaccharide induction of monocyte matrix metalloproteinases is regulated by the tyrosine phosphorylation of cytosolic phospholipase A2. 971 62

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
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PMID:Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. 987 71

Acidic fibroblast growth factor (FGF-1), a prototype member of the heparin-binding growth factor family, influences proliferation, differentiation, and protein synthesis in different cell types. However, its possible role on lung extracellular matrix (ECM) metabolism has not been evaluated. In this study we examined the effects of FGF-1 and FGF-1 plus heparin on type I collagen, collagen-binding stress protein HSP47, interstitial collagenase (matrix metalloproteinase [MMP]-1), gelatinase A, and tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 expression by normal human lung fibroblasts. Heparin was used because it enhances the biologic activities of FGF-1. Fibroblasts were exposed either to 20 ng/ml FGF-1 plus 100 micrograms/ml heparin for 48 h or to FGF-1 or heparin alone. Messenger RNA (mRNA) expression was analyzed by Northern blot. Collagen synthesis was evaluated by digestion of [3H]collagen with bacterial collagenase, MMP-1 by Western blot, and gelatinolytic activities by zymography. Our results show that FGF-1 induced collagenase mRNA expression, which was strongly enhanced when FGF-1 was used with heparin. Likewise, both FGF-1 and FGF-1 plus heparin reduced by 70 to 80% the expression of type I collagen transcript, in part through effect on pro-alpha1(I) collagen mRNA stability. A downregulation of HSP47 gene expression was also observed. Synthesis of collagen and collagenase proteins paralleled gene expression results. FGF-1 activities were abolished with genistein, a tyrosine kinase inhibitor. Neither FGF-1 nor FGF-1 plus heparin affected the expression of TIMP-1, TIMP-2, and gelatinase A. These findings demonstrate that FGF-1, mostly in the presence of heparin, upregulates collagenase and downregulates type I collagen expression that might have a protective role in avoiding collagen accumulation during lung ECM remodeling.
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PMID:Acidic fibroblast growth factor induces an antifibrogenic phenotype in human lung fibroblasts. 1022 73

Angiotensin II is an established regulator of vascular tone and smooth muscle cell (SMC) growth. However, there are little data about its effect on collagen synthesis by SMCs and none regarding the mechanism of such an effect. We studied the effect of angiotensin II on collagen production by human arterial SMCs, using uptake of [(3)H]proline into collagenase-digestible proteins, and by ribonuclease protection assay for mRNA encoding the proalpha1 chain of type I collagen, the major collagen in arteries. This revealed a dose-dependent increase in relative collagen synthesis rate and a dose-dependent increase in proalpha1(I) collagen mRNA abundance, with the half-maximal effect at 1.7 nmol/L. Angiotensin II-stimulated collagen expression was associated with a 6-fold increase in transforming growth factor-beta (TGF-beta) production and was inhibited by a neutralizing antibody to TGF-beta. Both collagen production and TGF-beta release were inhibited by the AT(1)-specific antagonist, losartan, but not by the AT(2) receptor antagonist, PD123319. To determined if tyrosine phosphorylation was functionally linked to collagen synthesis, we studied the effect of 2 mechanistically distinct inhibitors of tyrosine kinase, genistein, and tyrphostin A25. These inhibitors abrogated angiotensin II-mediated procollagen mRNA expression and angiotensin II-mediated TGF-beta production, whereas the inactive homolog tyrphostin A1 had no effect. We conclude that angiotensin II stimulates collagen production in human arterial SMCs via the AT(1) receptor and an autocrine loop of TGF-beta, induction of which requires tyrosine phosphorylation.
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PMID:Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT(1) receptor, transforming growth factor-beta, and tyrosine phosphorylation. 1044 62

Active matrix metalloproteinases and degraded collagen are observed in disease states, such as atherosclerosis. To examine whether degraded collagen fragments have distinct effects on vascular smooth muscle cells (SMC), collagenase-digested type I collagen was added to cultured human arterial SMC. After addition of collagen fragments, adherent SMC lose their focal adhesion structures and round up. Analysis of components of the focal adhesion complex demonstrates rapid cleavage of the focal adhesion kinase (pp125(FAK)), paxillin, and talin. Cleavage is suppressed by inhibitors of the proteolytic enzyme, calpain I. In vitro translated pp125(FAK) is a substrate for both calpain I- and II-mediated processing. Mapping of the proteolytic cleavage fragments of pp125(FAK) predicts a dissociation of the focal adhesion targeting (FAT) sequence and second proline-rich domain from the tyrosine kinase domain and integrin-binding sequence. Coimmunoprecipitation studies confirm that the ability of pp125(FAK) to associate with paxillin, vinculin, and p130cas is significantly reduced in SMC treated with degraded collagen fragments. Further, there is a significant reduction in the association of intact pp125(FAK) with the cytoskeletal fraction, while pp125(FAK) cleavage fragments appear in the cytoplasm in SMC treated with degraded collagen fragments. Integrin-blocking studies indicate that integrin-mediated signals are involved in degraded collagen induction of pp125(FAK) cleavage. Thus, collagen fragments induce distinct integrin signals that lead to initiation of calpain-mediated cleavage of pp125(FAK), paxillin, and talin and dissolution of the focal adhesion complex.
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PMID:Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. 1054 5

Neutral matrix metalloproteinases (MMPs) are responsible for the pathological features of rheumatoid arthritis (RA) such as degradation of cartilage. We herein show the up-regulation of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin) mRNAs of cultured synovial fibroblasts retrieved from rheumatoid arthritis (RA) patients in response to macrophage migration inhibitory factor (MIF). The elevation of MMP-1 and MMP-3 mRNA was dose-dependent and started at 6 h post-stimulation by MIF, reached the maximum level at 24 h, and was sustained at least up to 36 h. Interleukin (IL)-1beta mRNA was also up-regulated by MIF. These events were preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1, a common inhibitor of these proteases, was slightly up-regulated by MIF. Similarly, mRNA up-regulation of MMP-1 and MMP-3 was observed in the synovial fibroblasts of patients with osteoarthritis. However, their expression levels were much lower than those of RA synovial fibroblasts. The mRNA up-regulation by MIF was inhibited by the tyrosine kinase inhibitors genestein and herbimycin A, as well as the protein kinase C inhibitors staurosporine and H-7. On the other hand, the inhibition was not seen after the addition of the cyclic AMP-dependent kinase inhibitor, H-8. The mRNA up-regulation of MMPs was also inhibited by curcumin, an inhibitor of transcription factor AP-1, whereas interleukin-1 receptor antagonist, an IL-1 receptor antagonist, failed to inhibit the mRNA up-regulation. Considering these results, it is suggested that 1) MIF plays an important role in the tissue destruction of rheumatoid joints via induction of the proteinases, and 2) MIF up-regulates MMP-1 and MMP-3 via tyrosine kinase-, protein kinase C-, and AP-1- dependent pathways, bypassing IL-1beta signal transduction.
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PMID:Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. 1061 37

Constitutive activation of the Met tyrosine kinase results in transformation of cells of diverse origin. Recent studies have demonstrated a role for the c-Jun N-terminal kinase (JNK) in Met-induced transformation, but little is known about the molecular mechanisms that connect Met to JNK activation. Our studies show that activated Met associates with, and phosphorylates, the docking protein Gab1, which in turn binds to the src homology 2 (SH2)-domain of the adapter protein Crk and recruits Crk to the Met signaling complex. Formation of the Gab1 - Crk complex correlates with Met-induced JNK activation, and mutant forms of Met that fail to induce the complex formation also fail to activate JNK. Importantly, expression of a loss-of-function mutant of Crk severely impairs activation of the JNK pathway by Met. We also show here that Met controls the transcription of the matrix metalloproteinase-1 (MMP-1) gene in carcinoma cells and that this transcriptional regulation occurs in a Crk - JNK-dependent manner through an AP-1 element in the MMP-1 promoter. Taken together, our data implicate the Gab1 - Crk signaling complex in Met-induced JNK activation and suggest that the Gab1 - Crk complex formation may be an important event in regulating the tumorigenic phenotype of Met-transformed cells.
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PMID:Met-induced JNK activation is mediated by the adapter protein Crk and correlates with the Gab1 - Crk signaling complex formation. 1061 18


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