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)

We have identified and sequenced a cDNA encoding human neutrophil collagenase from a lambda gt11 cDNA library constructed from mRNA extracted from the peripheral leukocytes of a patient with chronic granulocytic leukemia. The library was screened with an oligonucleotide probe constructed from the putative zinc-binding region of fibroblast collagenase. Eleven positive clones were identified, of which the one bearing the largest insert (2.2 kilobases (kb)) was sequenced. From the nucleotide sequence of the 2.2-kb cDNA clone we have deduced a 467-amino acid sequence representing the entire coding sequence of the enzyme. The deduced protein was confirmed as neutrophil collagenase by conformity with the amino-terminal sequence analyses of three tryptic peptides of purified neutrophil collagenase. The cDNA clone hybridizes to a 3.3-kb mRNA present in RNA extracted from human bone marrow but did not hybridize with RNA isolated from U937 cells induced to differentiate with phorbol myristate acetate. Neutrophil collagenase was found to possess 57% identity with the deduced protein sequence for fibroblast collagenase with 72% chemical similarity. Certain regions of the molecule, including the putative zinc-binding region, are highly conserved. When compared with the published sequence for fibroblast collagenase, neutrophil collagenase contains four additional sites for glycosylation. Medium from COS-7 cells transfected with a pcDNA1 eucaryotic expression vector containing cDNA for neutrophil collagenase degraded type I collagen into the three-quarter, one-quarter fragments characteristic of mammalian interstitial collagenase activity. Thus, definitive evidence based on the cDNA sequence confirms the neutrophil collagenase is a distinct gene product and a member of the family of matrix metalloproteinases.
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PMID:Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. 216 2

Collagenase (matrix metalloproteinase 1) cleaves type I, II, and III collagen helices at a specific site between Gly-Ile or Gly-Leu bonds (residues 775 and 776, P1-P1'). To understand the mechanism of collagen processing, mutations around the cleavage site have been introduced into the cloned murine pro alpha 1(I) collagen (Col1a1) gene. These mutant constructs have been transfected into homozygous Mov13 fibroblasts that do not express the endogenous Col1a1 gene due to a retroviral insertion. Secreted triple-helical type I collagens containing substitutions of Pro for Ile (position 776) (P1') were not cleaved by human rheumatoid synovial collagenase, whereas those containing substitutions of Met for Ile (position 776) were cleaved. Type I collagens containing double substitutions of Pro for Gln-774 (P2) and Ala-777 (P2') were not cleaved regardless of whether they contained the wild-type residue Ile at position 776 or the substitution of Met for Ile at position 776. The wild-type alpha 2(I) chains derived from the endogenous Col1a2 gene were also resistant to enzyme digestion when they were complexed with the mutant alpha 1(I) chains, indicating that the presence of normal alpha 1(I) sequences is critical for cleavage of the alpha 2(I) chains in the type I heterotrimer.
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PMID:Generation of collagenase-resistant collagen by site-directed mutagenesis of murine pro alpha 1(I) collagen gene. 216 7

A series of tripeptidyl analogues carrying hydroxamic acid residue at the C-terminus of the molecule were synthesized, and their inhibitory activities against vertebrate collagenase and other metalloenzymes including bacterial collagenase were examined. Both Z-Pro-Leu-Ala-NHOH and Z-Pro-D-Leu-D-Ala-NHOH showed highly specific and potent inhibitory activity against tadpole and human skin collagenases with an IC50 of 10(-6) M order.
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PMID:Vertebrate collagenase inhibitor. I. Tripeptidyl hydroxamic acids. 216 73

A full-length complementary DNA (cDNA) for interstitial collagenase was isolated from an A2058 melanoma cDNA library using the pCD-X Okayama-Berg vector. The tumor interstitial collagenase cDNA was sequenced and compared to the published sequences for human fibroblast collagenase. The sequence for the tumor collagenase has two DNA base pairs which differ from the sequence of normal fibroblast collagenase. Restriction enzyme digestion of a specific DNA fragment produced by polymerase chain reaction amplification of genomic DNA from human placenta resolves a discrepancy in the previously reported DNA and amino acid sequences for the fibroblast collagenase. A high level of expression of interstitial collagenase message was found in human A2058 melanoma cells by Northern blot analysis, and this level was slightly increased by phorbol ester (phorbol myristate acetate) stimulation. Interstitial collagenase mRNA expression was significantly decreased by treatment with either transforming growth factor-beta 1 or retinoic acid in A2058 melanoma cells. A high level of the collagenase protein secreted into conditioned media was identified by Western blotting. As shown by gelatin zymogram analysis interstitial collagenase was one of at least two metalloproteinases secreted by this same cell line. Thus, human melanoma cells can directly produce interstitial collagenase without a requirement for host cell interaction.
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PMID:Cloning and characterization of human tumor cell interstitial collagenase. 216 56

The production of tissue inhibitor of metalloproteinases (TIMP) in human uterine cervical fibroblasts was increased by human recombinant tumor necrosis factor alpha (hrTNF) at a low concentration (0.005 ng/ml) but the elevated synthesis was suppressed in a dose-dependent manner at higher concentrations (up to 50 ng/ml). In contrast, the production of collagenase (EC 3.4.24.7) and stromelysin was stimulated at all the corresponding concentrations. In contrast, human recombinant interleukin-1 alpha (hr IL-1, 10 ng/ml) coordinately induced these enzymes and TIMP production. The reduction of the elevated TIMP production by TNF was not due to the inhibition of TIMP secretion. These results suggest that TNF modulates the extracellular matrix degradation in human fibroblasts bifunctionally by the suppression of TIMP production in addition to the acceleration of matrix metalloproteinases production. Furthermore, the fact that TNF and IL-1 differently controlled the production of TIMP suggests that the signal pathway of TNF for TIMP production is different from that of IL-1.
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PMID:Tumor necrosis factor bifunctionally regulates matrix metalloproteinases and tissue inhibitor of metalloproteinases (TIMP) production by human fibroblasts. 216 46

We have recently presented biochemical evidence for collagen and gelatin degrading activities associated with plasma membranes of various human cancer cell lines. In this report we describe the localization of interstitial collagenase at the basal plasma membrane of the human pancreatic cancer cell line RWP-I, using immunofluorescence and ultrastructural immunogold labeling techniques. Collagenase was expressed on the extracellular face of the plasma membrane. Furthermore, the immunogold labeling was concentrated on the long, finger-like microvillous projections typically seen on the basal cell surface, while the short, brush-like projections characteristic of the apical cell surface were unlabeled. When the cytoplasmic face of the membrane was made accessible, the number of reactive sites increased markedly, indicating a high concentration of enzyme at the inner surface of the plasma membrane. When plasma membrane fractions of RWP-I cells were prepared by differential centrifugation, high salt washes virtually failed to extract collagenase activity from the membrane, while detergent extraction with n-octyl glucoside, a detergent used in the purification of integral membrane proteins, yielded soluble collagenase activity. When detergent extracted membrane fractions were passed over an anticollagenase immunoaffinity column, collagenase was specifically bound, as demonstrated by the TCA and TCB degradation of type I collagen by the bound material. Gelatinolytic activity did not bind to the column. Furthermore, immunoprecipitation of 125I-labeled detergent extracts of tumor membranes yielded a single Mr 55,000 band consistent with the zymogen form of the connective tissue collagenase. These morphological and biochemical findings suggest that collagenase is a tightly associated component of the basal plasma membrane, where it occupies a strategic location for directional proteolysis during cell migration and invasion.
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PMID:Localization of collagenase at the basal plasma membrane of a human pancreatic carcinoma cell line. 217 14

Interferon-gamma (IFN-gamma) is a lymphokine that activates mononuclear phagocytes. To test the hypothesis that IFN-gamma might have important effects upon the ability of human mononuclear phagocytes to degrade extracellular matrix, we have studied the action of this cytokine on the production of metalloproteinases and the counterregulatory tissue inhibitor of metalloproteinases (TIMP) by the human alveolar macrophage. We have found that IFN-gamma potently and selectively suppresses the lipopolysaccharide-induced production of two metalloproteinases--interstitial collagenase and stromelysin--by 50-90% at doses greater than or equal to 10 U/ml. The synthesis of TIMP and 92-kD type IV collagenase was also diminished by IFN-gamma, but these responses required 50- to 100-fold higher concentrations of the cytokine. All doses of IFN-gamma increased total and secreted protein synthesis slightly, indicating a highly specific effect on metalloenzyme biosynthesis. Inhibition of metalloproteinase expression occurred at a pretranslational level, as evidenced by parallel reductions in enzyme biosynthesis and collagenase-specific steady-state mRNA levels. Interestingly, the effect of IFN-gamma on metalloenzyme production was not readily reversible. Therefore, while IFN-gamma activates the macrophage and renders it tumoricidal, this enhanced function appears to be attained at the expense of the cell's capacity to degrade extracellular matrix.
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PMID:Immune modulation of metalloproteinase production in human macrophages. Selective pretranslational suppression of interstitial collagenase and stromelysin biosynthesis by interferon-gamma. 217 Apr 47

In order to investigate the role of collagenase in cancer invasion and metastasis, two collagenase activities of interstitial collagenase and type IV collagen degrading enzyme (type IV collagenase) were determined in 40 cases of human stomach cancer tissue. Elevated cancers which are known to have a propensity to cause blood-borne metastases showed higher activities of both interstitial collagenase and type IV collagenase than flat or ulcerous type of cancer. Using the parameters of lymph node metastasis vs tumor size or vs depth of cancerous invasion into the stomach wall, classification of the cases was attempted according to the degree of malignancy. In the cases with marked lymph node metastases in spite of small tumor size and/or shallow cancerous invasion into the stomach wall, type IV collagenase activity was higher than that in the cases with lower malignancy (p less than 0.025, p less than 0.05, respectively). These results suggest that collagenase in stomach cancer tissue play an important role in the invasion and metastasis of cancer cells. Type IV collagenase activity in stomach cancer tissue could be one of the useful biological markers for the degree of malignancy.
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PMID:The collagenase activities, interstitial collagenase and type IV collagenase, in human stomach cancer: with special reference to local spreading and lymph node metastasis. 217 1

We demonstrated previously that growth promoting factors in general could induce the secretion of interstitial collagenase into the medium of human fibroblast cells (HF). In this study, the effect of tumor necrosis factor-alpha (TNF-alpha) on the induction of collagenase and tissue inhibitor of metalloproteinases (TIMP) was examined. Stimulation of quiescent HF cells with 10 ng/ml TNF-alpha induced the secretion of Mr 57,000, 52,000 procollagenases into the medium. The collagenase activity was elevated 2.8-fold after TNF-alpha treatment. Northern blot analysis of the steady-state mRNA indicated a tenfold elevation of collagenase transcript after 24 h treatment with 10 ng/ml TNF-alpha. The increase in collagenase mRNA was due to transcriptional activation of collagenase gene activity. TIMP mRNA level increased three-fold after TNF-alpha treatment. The activity of TNF-alpha on collagenase and TIMP induction may play an important role in tissue inflammatory, repair and remodeling processes after wound and injury.
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PMID:Tumor necrosis factor-alpha induces mRNA for collagenase and TIMP in human skin fibroblasts. 217 94

In human placentation, events of implantation and early blastocyst development are mediated by fetal trophoblastic cells which penetrate into the maternal endometrium and myometrium. Although highly regulated in its biological behavior, trophoblast simulates a malignant neoplasm by virtue of invading the uterine wall and uterine spiral arteries and by embolizing throughout the systemic circulation. This process is at least in part dependant on the regulated production of proteolytic enzymes to degrade extracellular matrix. The most abundant extracellular protein is connective tissue type (interstitial) collagen. The uterine remodeling during the establishment of the embryo requires collagenase which catalyzes the initial step in the breakdown of collagen. This study demonstrates the presence of interstitial collagenase in villous and extravillous trophoblast of first trimester placenta using immunocytochemical methods on light microscopic and ultrastructural levels. Intracytoplasmic staining for interstitial collagenase was present in cyto- and syncytiotrophoblast covering the chorionic villi as well as in extravillous intermediate trophoblast invading spiral arteries in the placental bed. Furthermore, outgrowth cultures of chorionic villi were studied with the immunogold method. Gold labelling was associated with the cell surface of trophoblastic cells as well as with fibrillary collagen like proteins of newly synthesized extracellular matrix. We speculate that interstitial collagenase plays a role in the degradation of uterine collagen within the developing human placenta.
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PMID:Proteolytic activity of first trimester human placenta: localization of interstitial collagenase in villous and extravillous trophoblast. 217 59


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