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)

Cleavage of the 45-kDa gelatin-binding fragment of human plasma fibronectin with fibronectinase resulted in the activation of two forms of metalloproteinase with different substrate specificities. The 40-kDa FN-type-IV collagenase A degrades heat-denatured type-I collagen, laminin and also native collagen type IV. The 27-kDa FN-type-IV collagenase B degrades native collagen type IV, but it does not cleave laminin and only poorly degrades gelatin. Both enzymes begin with the same N-terminal sequence VYQPQPH- (residues 262-268 of fibronectin) but, contrary to the FN-type-IV collagenase A, the FN-type-IV collagenase B has lost the C-terminal region of type I repeats, where the major gelatin-binding determinants of fibronectin are located. The FN-type-IV collagenases A and B are sequentially similar to the middle domain (domain II) of collagenase type IV, secreted by H-ras-transformed human bronchial epithelial cells. Substrate and inhibition specificity of FN-type-IV collagenase A and B are different from those of FN-gelatinase and FN-laminase, isolated previously from the central and C-terminal fibronectin domains, respectively. The substrate specificity of both enzymes, characterized in this study, is also different from that of already known matrix-degrading metalloproteinases.
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PMID:Collagen-binding domain of human plasma fibronectin contains a latent type-IV collagenase. 165 29

Insulin induces a rapid activation of p21ras in NIH 3T3 and Chinese hamster ovary cells that overexpress the insulin receptor. Previously, we suggested that p21ras may mediate insulin-induced gene expression. To test such a function of p21ras more directly, we studied the effect of different dominant inhibitory mutants of p21ras on the induction of gene expression in response to insulin. We transfected a collagenase promoter-chloramphenicol acetyltransferase (CAT) gene or a fos promoter-luciferase gene into NIH 3T3 cells that overexpressed the insulin receptor. The activities of both promoters were strongly induced after treatment with insulin. This induction could be suppressed by cotransfection of two inhibitory mutant ras genes, H-ras(Asn-17) or H-ras(Leu-61,Ser-186). In particular, insulin-induced activation of the fos promoter was inhibited completely by H-ras(Asn-17). These results show that p21ras functions as an intermediate in the insulin signal transduction route leading to the induction of gene expression.
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PMID:Two dominant inhibitory mutants of p21ras interfere with insulin-induced gene expression. 165 21

Extracellular matrix metalloproteases are secreted by the resident cells of the tissue in a proenzyme form, and their extracellular activity is regulated at the level of gene expression, proenzyme activation, and interaction with inhibitors. To understand the molecular mechanisms that control the activity of ECM metalloproteases and their effect on the cellular phenotype, we have established cell lines in which the transcription of the protease genes is repressed. We also have undertaken a detailed study of the pathway of extracellular activation of interstitial procollagenase. Stable transfection of three human tumor cell lines--H-ras-transformed bronchial epithelial cells TBE-1, fibrosarcoma cells HT1080, and melanoma cells A2058--with the adenovirus E1A gene dramatically repressed the expression of the secreted proteases, type IV and interstitial collagenases, and urokinase-type plasminogen activator. Concomitantly, E1A-expressing cells showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibody inhibited the invasive activity of parental tumor cell lines in the in vitro system, suggesting a possible causal relationship between the effect of E1A on the expression of secreted proteases and the reduced metastatic potential of the E1A-expressing transformants. We have also studied the mechanism of regulation of metalloprotease activity at the level of extracellular activation by investigating the cascade of proteolytic events that results in the activation of interstitial procollagenase. Cocultivation of the major cellular components of skin, dermal fibroblasts, and epidermal keratinocytes induces activation of interstitial procollagenase and prostromelysin in the presence of plasminogen. This activation occurs through a uPA-plasmin-dependent pathway in which plasmin catalyzes the first step in activation of both collagenase and stromelysin by amino-terminal processing. Activated stromelysin can in turn convert plasmin-activated collagenase into a fully active enzyme by removal of approximately 15 amino acid residues from the carboxyl end of the enzyme. This second step of activation results in a 5-8-fold further increase in specific activity of collagenase. This cascade of proteolytic events may constitute a major physiologic pathway of collagenase activation.
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PMID:Secreted proteases. Regulation of their activity and their possible role in metastasis. 215 52

The neutral zinc metalloendopeptidase (NEP, EC 3.4.24.11) is an integral membrane protein found in brain tissue, polymorphonuclear leukocytes, and many epithelia. We show here that NEP is expressed on rabbit synovial fibroblasts and on simian virus 40 (SV40) DNA- and H-ras-transformed rabbit mammary epithelial cells. Treatment of these cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 24 h decreased expression of NEP mRNA transcripts and decreased the biosynthetically labeled immunoprecipitable NEP antigen. In contrast to its effects on NEP, TPA treatment induced expression of the secreted metalloproteinase collagenase and the tissue inhibitor of metalloproteinases. TPA induced stromelysin, another secreted metalloproteinase, only in the fibroblasts. These data provide evidence that the expression of the membrane-bound NEP is regulated in several cell types.
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PMID:Phorbol diesters regulate expression of the membrane neutral metalloendopeptidase (EC 3.4.24.11) in rabbit synovial fibroblasts and mammary epithelial cells. 254 98

H-ras-transformed human bronchial epithelial cells (TBE-1) secrete a single major extracellular matrix metalloprotease which is not found in the normal parental cells. The enzyme is secreted in a latent form of 72 kDa, which can be activated to catalyze the cleavage of the basement membrane macromolecule type IV collagen. The substrates in their order of preference are: gelatin, type IV collagen, type V collagen, fibronectin, and type VII collagen; but the enzyme does not cleave the interstitial collagens or laminin. This protease is identical to gelatinase isolated from normal human skin explants, normal human skin fibroblasts, and SV40-transformed human lung fibroblasts. Based on its ability to initiate the degradation of type IV collagen in a pepsin-resistant portion of the molecule, it will be referred to as type IV collagenase. This enzyme is most likely the human analog of type IV collagenase detected in several rodent tumors, which has the same molecular mass and has been linked to their metastatic potential. Type IV collagenase consists of three domains. Two of them, the amino-terminal domain and the carboxyl-terminal domain, are homologous to interstitial collagenase and human and rat stromelysin. The middle domain, of 175 residues, is organized into three 58-residue head-to-tail repeats which are homologous to the type II motif of the collagen-binding domain of fibronectin. Type IV collagenase represents the third member of a newly recognized gene family coding for secreted extracellular matrix metalloproteases, which includes interstitial fibroblast collagenase and stromelysin.
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PMID:H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. 283 83

The appearance of gamma-glutamyl transpeptidase (GGT) in focal areas of hepatocytes is a widely used histochemical marker for the identification of preneoplastic cell populations. The characterization of these GGT-positive preneoplastic cells in relation to possible alterations in protooncogene expression may help define cellular changes occurring during the early stages of hepatocarcinogenesis. Female Sprague-Dawley rats were subjected to a two-thirds partial hepatectomy, followed 18 h later by a single intragastric administration of 30 mg of diethylnitrosamine per kg and subsequent feeding of a diet containing 0.05% phenobarbital for 6 or 11 mo. Primary cell suspensions were obtained after the perfusion of liver with collagenase. Cell debris and nonviable cells were removed with multiple washes and a Percoll gradient step. GGT-positive hepatocytes were enriched from the cell suspension by adherence to an affinity-purified GGT antibody affixed to Petri dishes. These dishes allowed the selective adherence and collection of up to 2.28 X 10(6) GGT-positive cells per liver. The starting cell population and the isolated GGT-positive and -negative cells were then used for subsequent analysis. RNA was prepared from the cell isolates and from hepatocellular carcinomas induced with the same diethylnitrosamine and phenobarbital regimen as that used to induce GGT-positive foci; 10 micrograms of total cellular RNA were used for Northern blot hybridizations. The blots were probed with 32P-labeled c-myc, H-ras, and albumin DNAs. The results indicate that GGT-positive hepatocytes do not differ from the other hepatocyte populations in either the size or amount of mRNA transcripts for the c-myc and H-ras protooncogenes. Increased expression of c-myc and H-ras was observed in some malignant lesions and may represent a secondary alteration occurring during the multistage process of hepatocarcinogenesis.
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PMID:Expression of H-ras and c-myc protooncogenes in isolated gamma-glutamyl transpeptidase-positive rat hepatocytes and in hepatocellular carcinomas induced by diethylnitrosamine. 287 Jul 98

Expression of the T24ras oncogene induces malignancy (tumor growth, invasion and metastasis) in cloned rat embryo fibroblasts (CREF T24). In CREF T24, the rate of phosphorylation of eukaryotic translation initiation factor 4E (eIF-4E) is increased, resulting in increased protein synthesis rates. We have recently shown that reducing the protein levels of eIF-4E in CREF T24 (AS4E line) markedly decreases soft-agar colonization, increases tumor latency periods and increases tumor doubling times without significantly altering monolayer growth. In this study, cells with reduced eIF-4E had delayed and reduced invasiveness and decreased experimental metastasis. Furthermore, reduced eIF-4E levels correlated with decreased expression of the metastasis-associated 92-kDa collagenase type-IV and exon-6 variants of the CD44 adhesion molecule [CD44(6v)]. Reduced eIF-4E levels correlated inversely with increased levels of the putative metastasis-suppressor protein nm23. Cell lines established from AS4E tumors and lung metastases exhibited increased levels of eIF-4E protein and protein synthesis rates compared to the AS4E line. Tumor-derived AS4E had the shortened tumor latency periods of CREF T24 but displayed the slow tumor-growth rates of AS4E. Tumor-derived AS4E exhibited the metastatic capacity of CREF T24 controls. Furthermore, tumor- and lung-nodule-derived AS4E expressed levels of CD44 (6v) and the 92-kDa collagenase type IV comparable to CREF T24 and displayed reduced levels of nm23 relative to AS4E. These results demonstrate that eIF-4E is an important effector molecule involved in oncogenic p21ras-induced malignant transformation.
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PMID:Reduction of translation initiation factor 4E decreases the malignancy of ras-transformed cloned rat embryo fibroblasts. 782 25

We have used reconstituted basement membrane molecules which have formed into barriers in order to investigate the invasive potential of malignant bone and soft tissue tumour cells in vitro. A number of cell lines established from human malignant tumours demonstrated a high degree of invasiveness, although fibroblasts showed no ability to penetrate the basement membrane barrier. H-ras oncogene transfected cells into the fibroblasts were much more invasive than the parent lines. Primary cultures of malignant tumour cells demonstrated invasiveness, while those of nonmetastatic cells and fibroblasts did not. The binding of tumour cells to laminin in the basement membranes was found to induce secretion of collagenase and motility which are crucial factors for invasion. A synthetic peptide, Tyr-Ile-Gly-Ser-Arg, was able to suppress the invasiveness of HT1080 human fibrosarcoma cells, and also reduced lung colonisation in vitro. The results suggest that the in vitro assay was useful, firstly to determine the invasive potential, secondly to investigate the mechanism of invasion, and finally to development treatment against invasion and metastases.
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PMID:In vitro assay of the invasive potential of malignant bone and soft tissue tumours through basement membranes. 800 14

Rat embryo fibroblasts (REFs) are inefficiently transformed by the T24-ras oncogene. A contributing factor to cellular resistance to transformation is the limited tolerance to p21-ras oncoprotein expression. Here we present data suggesting that long-term glucocorticoid treatment of ras oncogene-transfected REFs results in increased tolerance to p21-ras oncoproteins, leading to expression of the transformed phenotype. Stably transformed cell lines that expressed high levels of H-ras and could be maintained in the absence of hormone were isolated. In three out of four lines studied, the AP-1-dependent collagenase gene was expressed at a low level. In one of these lines, low collagenase expression was paralleled by lack of c-jun mRNA. Immunochemical analysis revealed that progression to hormone independence was not paralleled by mutations in the p53 gene. We propose that a decreased expression of AP-1-driven genes may result in increased tolerance to p21-ras oncoprotein.
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PMID:Lack of c-jun expression in a transformed cell line isolated by glucocorticoid promotion of ras-transfected rat embryo fibroblasts. 847 51

(+)-Limonene (d-limonene) and related monoterpenes show chemopreventive activity against rodent mammary carcinoma and inhibit the growth of cancer cells in vitro. One suggested mechanism for the anti-tumorigenic effect of (+)-limonene is inhibition of the post-translational isoprenylation of growth controlling Ras oncoproteins. We have here examined the growth inhibitory effect of (+)-limonene and other related monoterpenes on PANC-1 pancreas carcinoma cells (carrying a K-ras mutation) and on 12V-H-ras-transformed rat fibroblasts. (+)- and (-)-perillyl alcohol, 7-methyl-perillyl alcohol, (+)-limonene oxide and (+)-perillic acid methyl ester were all found to efficiently inhibit cell growth at 1 mM, whereas (+)-limonene caused an approximately 50% growth reduction at 5 mM. Whereas BZA-5B, an inhibitor of Ras farnesyl transferase, was found to induce morphological reversion of 12V-H-ras-transformed cells, (+)-perillyl alcohol and (+)-limonene did not induce reversion. Furthermore, monoterpenes did not decrease MAP kinase enzyme activity or collagenase promoter activity in PANC-1 cells, two functions known to be down-stream from Ras. We conclude that although effective in inhibiting the growth of tumor cells harboring activated ras oncogenes, limonene and (+)-perillyl alcohol are unlikely to act by inhibiting Ras function.
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PMID:Inhibition of tumor cell growth by monoterpenes in vitro: evidence of a Ras-independent mechanism of action. 882 11


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