Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissue (collagens type I and III, fibronectin). In this study we have analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix-degrading metalloproteinases (MMP-1, -2, -3 and -9) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in pancreatic cancer and control pancreatic tissue by Northern-blot analysis and mRNA in situ hybridization. Transcripts for MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) were not detectable in pancreatic cancer and control tissues. Steady-state levels of transcripts encoding extracellular matrix proteins, MMP-2 (72-kDa collagenase IV), MMP-9 (92-kDa collagenase type IV), TIMP-1 and TIMP-2 were elevated in the majority of pancreatic-cancer tissue samples as compared to control pancreatic tissue. A good correlation was seen between overexpression of these MMPs and TIMPs and the steady-state levels of transcripts coding for extracellular matrix proteins, the amount of collagen protein and the severity of the desmoplastic reaction. In situ hybridization studies localized transcripts coding for collagens type I and III to spindle-shaped stromal cells, whereas transcripts for MMP-2, MMP-9, TIMP-1 and TIMP-2 were found in both stromal and tumor cells. However, MMP-2 transcripts appeared to be more abundant in stromal cells, TIMP-1 and TIMP-2 transcripts were evenly distributed over tumor and stromal cells and relatively more MMP-9 transcripts were found in tumor cells. We conclude that, in human pancreatic cancer, MMP-2, MMP-9, TIMP-1 and TIMP-2 may be involved in processes leading to the strong desmoplastic reaction observed in these tumors. Both stromal and tumor cells appear to be the source of MMPs and TIMPs in human pancreatic cancer.
 ...
PMID:Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. 763 66

In the present study cultured human glomerular epithelial cells (HGEC) were used to examine the potential role for these cells in the turnover of the glomerular basement membrane (GBM) through the secretion of matrix metalloproteinases. The cells were shown by substrate gel electrophoresis to secrete gelatinase activity of molecular weights 72 kDa and 92 kDa. The gelatinolytic activity was inhibited by EDTA (10 mM), and by both TIMP-I and TIMP-II, but was not inhibited by PMSF (2.5 mM), indicating that the enzymes belonged to the metalloproteinase family. The identity of the enzymes was confirmed by the use of specific antisera to gelatinase A and gelatinase B. In addition, reverse transcription polymerase chain reaction (RT PCR) amplification of HGEC mRNA using specific primers to the two enzymes yielded single bands of amplified DNA and served to verify the identity of the enzymes. In supplementary experiments using both specific antiserum and PCR primers it was shown that HGEC express message and secrete both the specific metalloproteinase inhibitors TIMP-I and TIMP-II. These results indicate that the synthesis and secretion of degradative enzymes and their controlling inhibitors by HGEC have the potential to be involved in the turnover of the extracellular matrix.
 ...
PMID:Metalloproteinase generation by human glomerular epithelial cells. 764 37

The production and local release of various proteolytic enzymes, either by tumor cells or tumor-associated stromal cells, is thought to facilitate the malignant behavior of solid tumors. Human cutaneous melanoma offers an excellent clinical model to study the possible contribution of such proteases to solid tumor progression because melanoma goes through a series of well defined stages in its pathogenesis; moreover, permanent cell lines have been established from these various stages. As a first step to analyzing the gelatinolytic enzymes in melanoma pathology, we examined cell lines derived from early stage primary melanomas in which patients were cured of their disease and compared the results to those obtained with cell lines established from advanced stage primary lesions or metastases (i.e., from patients who eventually succumbed to the disease). We found that 80% of cell lines examined from early stage lesions constitutively produced only the 72-kDa gelatinase A but never the 92-kDa gelatinase B. In contrast, the majority of advanced stage cell lines examined produced both the 72-kDa gelatinase A and the 92-kDa gelatinase B. Advanced stage cell lines that did not constitutively produce the 92-kDa gelatinase B could be induced to do so with transforming growth factor beta, interleukin 1 beta or 12-O-tetradecanoyl-phorbol-13-acetate. In total, 0 of 5 early stage cell lines constitutively expressed the 92-kDa gelatinase B, and only 2 of 5 could be induced to produce this activity. In contrast, all advanced stage cell lines that were evaluated either constitutively or inducibly produced the 92-kDa gelatinase B. To analyze the mechanism by which 92-kDa gelatinase B production is switched on in the advanced stage melanoma cell lines, somatic cell hybrids were constructed using an advanced stage melanoma cell line as one partner and either one of two early stage cell lines as the other. Constitutive production of the 92-kDa gelatinase B in such hybrids was lost and could not be induced in such hybrids. Coculture of the early and advanced stage cell lines failed to recapitulate what was seen after somatic hybridization, and zymographic analysis of lysates from hybrid cell lines demonstrated no 92-kDa gelatinase B activity. Reverse transcription-PCR analysis demonstrated that the loss of 92-kDa gelatinase B production occurred at the level of steady-state mRNA for the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:The 92-kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. 766 94

The expression of type IV collagenase (M(r) 72,000) has been examined in tissues from patients with benign prostatic hyperplasia (6 patients) and varying Gleason grades of malignant prostate cancer (18 patients). Immunoperoxidase labeling indicated that expression of the type IV collagenase was weak or nonexistent in benign tissue but consistently strong in the glandular and ductal epithelial cells of prostate tumors diagnosed at Gleason grades 1-8. In moderate to advanced cancer (i.e., Gleason grades 2 to 8), invasive tumor foci in the stromal tissue produced relatively modest amounts of type IV collagenase. The normal stromal tissue (i.e., fibroblasts) uniformly failed to produce detectable levels of type IV collagenase in the 24 patients examined. Northern and quantitative slot blot hybridization assays demonstrated that collagenase type IV mRNA levels were low in benign tissue and high in malignant tumors. In contrast, the stromal cells did not express significant amounts of type IV collagenase mRNA. Enzyme-linked immunosorbent assays demonstrated that the amounts of type IV collagenase protein correlated directly with the mRNA levels in the tumor tissue. The studies suggest that type IV collagenase may be selectively overexpressed by malignant, preinvasive prostatic epithelial cells.
 ...
PMID:Type IV collagenase (M(r) 72,000) expression in human prostate: benign and malignant tissue. 767 51

A 25-kDa protein was found to be associated with purified human neutrophil gelatinase. Polyclonal antibodies raised against gelatinase not only recognized gelatinase but also this 25-kDa protein. Specific antibodies against the 25-kDa protein were obtained by affinity purification of the gelatinase antibodies. Immunoblotting and immunoprecipitation studies demonstrated the 135-kDa form of gelatinase to be a complex of 92-kDa gelatinase and the 25-kDa protein, and the 220-kDa form was demonstrated to be a homodimer of the 92-kDa protein, thus explaining the 220-, 135-, and 92-kDa forms characteristic of neutrophil gelatinase. The 25-kDa protein was purified to apparent homogeneity from exocytosed material from phorbol myristate acetate-stimulated neutrophils. The primary structure of the 25-kDa protein was determined as a 178-residue protein. It was susceptible to treatment with N-glycanase, and one N-glycosylation site was identified. The sequence did not match any known human protein, but showed a high degree of similarity with the deduced sequences of rat alpha 2-microglobulin-related protein and the mouse protein 24p3. It is thus a new member of the lipocalin family. The function of the 25-kDa protein, named neutrophil gelatinase-associated lipocalin (NGAL), remains to be determined.
 ...
PMID:Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. 768 78

Intraepithelial lymphocyte migration is a biological process frequently observed in skin and tonsil. Using immunohistochemistry, we have studied the molecular bases of this process in seven skin biopsies involved by mycosis fungoides (MF) and in 12 tonsils, four involved by B-chronic lymphocytic leukaemia (B-CLL) and eight by lymphoid follicular hyperplasia (LH). In the skin, intraepidermal T-lymphocyte infiltration was associated with narrowing and fragmentation of the basement membrane, as shown by an anti-collagen type IV antibody. Immunostaining of serial sections with an anti-collagenase type IV antibody revealed that collagenase type IV was localized in the upper dermis and strictly co-distributed with collagen type IV, suggesting that enzymatic digestion played a role in the alterations of the basement membrane. Further migration through the epidermis was mediated by expression on keratinocytes of intercellular adhesion molecule-1 (ICAM-1) and of leukocyte-function associated antigen-1 (LFA-1) on infiltrating lymphocytes. In the tonsil, intraepithelial infiltration was mediated by the expression of vascular cell adhesion molecule-1 (VCAM-1) by epithelial cells and of very late antigen-4 (VLA-4) by infiltrating lymphocytes. Further intraepithelial lymphocyte migration was then established, as already shown in the skin, by ICAM-1/LFA-1 interaction. Lymphocyte recruitment from the systemic circulation was studied using antibodies directed against endothelial leukocyte adhesion molecule-1 (ELAM-1), ICAM-1, and VCAM-1. These adhesion molecules were highly expressed by blood vessels in the upper dermis of MF and the percentage of ELAM-1+/VCAM-1+ vessels was significantly higher than that observed in tonsils.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Molecular mechanisms involved in intraepithelial lymphocyte migration: a comparative study in skin and tonsil. 768 77

The actions of human recombinant stromelysins-1 and -2, collagenase, gelatinases A and B and matrilysin on neonatal human proteoglycan aggregates were examined. With the exception of gelatinase B, aggrecan was degraded extensively by most metalloproteinases studied, whereas link protein showed only limited proteolysis. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Cleavage at the former bond generated a link protein component with the same N-terminus as that isolated from newborn human cartilage. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.
 ...
PMID:Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. 769 69

We have compared the effects of a general matrix metalloproteinase (MMP) inhibitor (CT435) with those of a concentration-dependent specific gelatinase inhibitor (CT543; Ki < 20 nM) on bone resorption in vitro. The test systems consisted of measuring: (i) the release of 45Ca2+ from prelabelled mouse calvarial explants; (ii) the release of 45Ca2+ from prelabelled osteoid-free calvarial explants co-cultured with purified chicken osteoclasts; and (iii) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. Both CT435 and CT543 dose-dependently inhibited the release of 45Ca2+ from neonatal calvarial bones stimulated by either parathyroid hormone or 1,25-dihydroxyvitamin D3. Moreover, CT543 produced a 40% inhibition at a concentration (10(-8) M) selective for the inhibition of human gelatinases A and B. CT435 (10(-5) M) and CT543 (10(-5) M) partially inhibited the release of 45Ca2+ from osteoid-free calvarial explants by chicken osteoclasts with a maximum of approximately 25% for unstimulated cultures, and approximately 36% for cultures stimulated by interleukin-1 alpha (IL-1 alpha; 10(-10) M). Neither inhibitor prevented lacunar resorption on ivory by unstimulated rat osteoclasts, but the compounds produced a partial reduction in both the number and total surface area of lacunae in IL-1 alpha-stimulated cultures, with maximal action at 10(-5) M. Neither of the inhibitors affected protein or DNA synthesis, nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme beta-glucuronidase. Immunocytochemistry demonstrated that isolated rabbit osteoclasts constitutively expressed gelatinase A and synthesized gelatinase B, collagenase and stromelysin, as well as the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) following IL-1 alpha stimulation. These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption. They further suggest that MMPs produced by osteoclasts are released into the sub-osteoclastic resorption zone where they participate in bone collagen degradation.
 ...
PMID:The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts. 769 5

Several members of the matrix metalloproteinase family have been reported to cleave aggrecan in the interglobular domain between Asn-341 and Phe-342. An antiserum was prepared against a peptide conjugate corresponding to the C-terminal sequence of the matrix metalloproteinase-generated aggrecan G1 fragment (Phe335-Val-Asp-Ile-Pro-Glu-Asn341). A quantitative radioimmunoassay, with a limit of detection of about 80 pM, was developed using this antiserum. This antiserum requires the free carboxyl group of the C-terminal asparagine for optimal recognition. If the C-terminal asparagine is excised from the sequence, replaced with closely related amino acids, or extended across the matrix metalloproteinase cleavage site, there is a 40-10,000-fold loss in detection. Using peptides cleaved from the N-terminus, it was determined that the antiserum requires the entire Phe-Val-Asp-Ile-Pro-Glu-Asn sequence for optimal recognition. The radioimmunoassay detects matrix metalloproteinase-generated G1 fragments with similar sensitivity to the Phe-Val-Asp-Ile-Pro-Glu-Asn peptide, but it does not recognize intact aggrecan. Immunoreactive aggrecan G1 fragments of molecular mass 50 kDa are generated by the matrix metalloproteinases stromelysin and gelatinase A. In contrast, under identical conditions, the closely related metalloproteinases, gelatinase B and collagenase, as well as cathepsin G, cathepsin B and human leucocyte elastase, did not generate a G1 fragment recognized by the antiserum. The anti-Phe-Val-Asp-Ile-Pro-Glu-Asn serum detects stromelysin-generated aggrecan G1 fragments from mouse, guinea pig, rabbit and human, indicating that the detection is not species-specific. This antiserum and radio-immunoassay should be useful for quantifying and characterizing matrix metalloproteinase-generated aggrecan G1 fragments in articular cartilage and synovial fluids from humans and various animal models of articular-cartilage destruction.
 ...
PMID:Quantification of a matrix metalloproteinase-generated aggrecan G1 fragment using monospecific anti-peptide serum. 771 83

The M(r) 72,000 (MMP-2; gelatinase A) and M(r) 92,000 (MMP-9; gelatinase B) gelatinases are two members of the family of matrix metalloproteinases (MMPs). These proteinases are thought to play a critical role in tumor cell invasion and are frequently coexpressed in human cancers. Gelatinases are secreted in a latent inactive form, and their conversion to the active species can be accomplished by other proteolytic enzymes, including other MMPs. We report herein that organomercurial or plasma membrane-activated M(r) 72,000 gelatinase A activates progelatinase B to an M(r) 82,000 active form in a process inhibited by tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Progelatinase B activation was accomplished by the two active species of gelatinase A, the M(r) 62,000 and M(r) 45,000 forms, generated after plasma membrane or organomercurial activation of TIMP-2-free progelatinase A. The M(r) 45,000 species of gelatinase A lacks both the NH2-terminal profragment and the COOH-terminal domain known to play a role in plasma membrane activation and the regulation of TIMP-2 inhibition. These results suggest a novel mechanism of activation of progelatinase B mediated by gelatinase A species that may be localized in the surface of tumor cells and enhance matrix degradation during cancer metastasis.
 ...
PMID:Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). 778 Sep 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>