Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effects of ligation of the fibronectin receptor (FnR) on gene expression in rabbit synovial fibroblasts. Monoclonal antibodies to the FnR that block initial adhesion of fibroblasts to fibronectin induced the expression of genes encoding the secreted extracellular matrix-degrading metalloproteinases collagenase and stromelysin. That induction was a direct consequence of interaction with the FnR was shown by the accumulation of mRNA for stromelysin and collagenase. Monoclonal antibodies to several other membrane glycoprotein receptors had no effect on metalloproteinase gene expression. Less than 2 h of treatment of the fibroblasts with anti-FnR in solution was sufficient to trigger the change in gene expression, and induction was blocked by dexamethasone. Unlike other inducers of metalloproteinase expression, including phorbol diesters and growth factors, addition of the anti-FnR in solution to cells adherent to serum-derived adhesion proteins or collagen produced no detectable change in cell shape or actin microfilament organization. Inductive effects were potentiated by cross-linking of the ligand. Fab fragments of anti-FnR were ineffective unless cross-linked or immobilized on the substrate. Adhesion of fibroblasts to native fibronectin did not induce metallo-proteinases. However, adhesion to covalently immobilized peptides containing the arg-gly-asp sequence that were derived from fibronectin, varying in size from hexapeptides up to 120 kD, induced collagenase and stromelysin gene expression. This suggests that degradation products of fibronectin are the natural inductive ligands for the FnR. These data demonstrate that signals leading to changes in gene expression are transduced by the FnR, a member of the integrin family of extracellular matrix receptors. The signaling of changes in gene expression by the FnR is distinct from signaling involving cell shape and actin cytoarchitecture. At least two distinct signals are generated: the binding of fibronectin-derived fragments and adhesion-blocking antibodies to the FnR triggers events different from those triggered by binding of the native fibronectin ligand. Because the genes regulated by this integrin are for enzymes that degrade the extracellular matrix, these results suggest that information transduced by the binding of various ligands to integrins may orchestrate the expression of genes regulating cell behavior in the extracellular environment.
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PMID:Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. 254 5

A 140 000 D glycoprotein (140 kD gp), labelled radioactively with surface-specific techniques, remained as the major cell surface glycoprotein in the detergent-resistant cytoskeletal preparations of cultured human fibroblasts. The 140 kD gp was present also in trypsinized cells and was not affected by treatment of the cells either with collagenase, chymotrypsin or thrombin. In density gradient fractionation of whole cells the 140 kD gp was recovered in the plasma membrane fraction together with small amounts of cytoskeletal components. In fractionation of cytoskeletal preparations, on the other hand, the 140 kD gp could not be dissociated from cytoskeletal proteins and together with vimentin it formed the major component of the oligomeric polypeptide complex generated by treating the surface-labelled cytoskeletal preparations with bifunctional cross-linking reagent, dithiobis succinimidyl propionate (DTPS). Moreover, the 140 kD gp seemed to copurify with vimentin upon reconstitution of intermediate filaments from urea-solubilized cytoskeletal preparations. On the other hand, low ionic-induced degradation of vimentin led to a decrease in the amount of the detergent-resistant 140 kD gp on the cell surface. In electron microscopy, a close apposition between bilayer-like plasma membrane remnants of the adherent cytoskeletons and cytoskeletal elements could be seen. The results indicate that the 140 kD gp is a plasma membrane glycoprotein which closely interacts with the detergent-resistant cytoskeleton of cultured human fibroblast. Possible mechanisms of the association are discussed.
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PMID:140 000 Dalton surface glycoprotein. A plasma membrane component of the detergent-resistant cytoskeletal preparations of cultured human fibroblasts. 633 55

The effect on platelet function of a monoclonal platelet antibody to platelet membrane glycoprotein I was tested. This antibody, AN51, inhibited ristocetin or bovine factor VIII-induced aggregation but did not modify ADP, collagen type I or type III, thrombin or arachidonic acid induced aggregations. Furthermore, the adhesion-aggregation of platelets induced by microfibrils was also inhibited by the antibody. Platelet adhesion to rabbit aorta subendothelium was impaired by the antibody. The persistent adhesion of platelets to collagenase-treated subendothelium was also inhibited. These findings strongly suggested that platelet membrane glycoprotein I could interact with a non-collagenic microfibrillar component of subendothelium. The binding of factor VIII/von Willebrand factor to platelet membrane in the presence of ristocetin was decreased in the binding site for factor VIII/von Willebrand factor to allow platelet adhesion to subendothelium.
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PMID:Monoclonal antibody to human platelet glycoprotein I. II. Effects on human platelet function. 679 59

Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein belonging to the serine protease family. Human FAP is selectively expressed by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity, but its biological function in the tumor microenvironment is unknown. The modeled structure of murine FAP consists of a short cytoplasmic tail, a single hydrophobic transmembrane region, and a large extracellular domain. A seven-bladed beta-propeller domain is situated on top of the catalytic triad and may serve as a "gate" to selectively filter protein access to the catalytic site. HEK293 cells transfected to constitutively express murine FAP, when xenografted into scid mice, were 2-4 times more likely to develop s.c. tumors and showed a 10-40-fold enhancement of tumor growth compared with mock-transfected HEK293 cells. Rabbits immunized with recombinant murine FAP developed polyclonal anti-FAP antibodies that significantly inhibited murine FAP dipeptidyl peptidase activity in vitro. HT-29 xenografts treated with these inhibitory anti-FAP antisera exhibited attenuated growth compared with tumors treated with preimmunization rabbit antisera. These data demonstrate the ability of FAP to potentiate tumor growth in an animal model. Moreover, tumor growth is attenuated by antibodies that inhibit the proteolytic activity of FAP. These findings suggest a possible therapeutic role for functional inhibition of FAP activity.
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PMID:Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. 1218 36

We used a panel of monoclonal antibodies to characterize DCs in the dermis of normal human skin. Staining for the CD11c integrin, which is abundant on many kinds of DCs, revealed cells in the upper dermis. These cells were positive for blood DC antigen-1 (BDCA-1; also known as CD1c), HLA-DR, and CD45, markers that are also expressed by circulating myeloid DCs. A small subset of CD11c+ dermal cells expressed DEC-205/CD205 and DC-lysosomal-associated membrane glycoprotein/CD208 (DC-LAMP/CD208), suggesting some differentiation or maturation. When BDCA-1+ cells were selected from collagenase digests of normal dermis, they proved to be strong stimulators for T cells in a mixed leukocyte reaction. A second major population of cells located throughout the dermis was positive for factor XIIIA (FXIIIA), but lacked CD11c and BDCA-1. They expressed the macrophage scavenger receptor CD163 and stained weakly for HLA-DR and CD45. Isolated CD163+ dermal cells were inactive in stimulating T cell proliferation, but in biopsies of tattoos, these cells were selectively laden with granular pigments. Plasmacytoid DCs were also present in the dermis, marked by CD123 and BDCA-2. In summary, the normal dermis contains typical immunostimulatory myeloid DCs identified by CD11c and BDCA-1, as well as an additional population of poorly stimulatory macrophages marked by CD163 and FXIIIA.
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PMID:Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages. 1778 33

Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) is a multifunctional membrane glycoprotein overexpressed in many solid tumors, and involved in tumor invasion and angiogenesis. We investigated EMMPRIN expression in human prostate cancer (CaP) tissues and cells, and evaluated whether EMMPRIN expression is related to tumor progression and matrix metalloproteinase (MMPs) expression in human CaP. An immunohistochemical study using tissue microarrays of 120 primary CaPs of different grades and 20 matched lymph node metastases from untreated patients was performed. The association of EMMPRIN expression with clinicopathological parameters was evaluated. Co-immunolocalization for EMMPRIN and MMP-1, MMP-2 or MMP-9 in primary tumors was examined using confocal microscopy. Flow cytometry and immunoblotting were used to examine EMMPRIN expression in 11 metastatic CaP cell lines. Heterogeneous expression of EMMPRIN was found in 78/120 (65%) CaPs, correlated significantly with progression parameters including pre-treatment PSA level (P < 0.05) and increased with progression of CaP (Gleason score, P < 0.05; pathological stage, P < 0.01; nodal involvement, P < 0.05 and surgical margin, P < 0.05). Heterogeneous cytoplasmic MMP-1, MMP-2 and MMP-9 associated with EMMPRIN immunolabeling was observed, particularly in tumors with Gleason scores >3 + 4. Metastatic CaP cell lines, except DuCaP, expressed abundant EMMPRIN protein, indicating highly ( approximately 45 to approximately 65 kDa) and less ( approximately 30 kDa) glycosylated forms, although with no relationship to cells being either androgen responsive or nonresponsive. Our results suggest that EMMPRIN may regulate MMPs and be involved in CaP progression, and as such, could provide a target for treating metastatic CaP disease.
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PMID:The role of extracellular matrix metalloproteinase inducer protein in prostate cancer progression. 1827 14