Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simultaneous presence of gelatinase A (MMP-2) and MMP-2 messenger RNA (mRNA) in 30 malignant tumors with various degrees of differentiation and biological behavior was evaluated by immunohistochemistry and in situ hybridization. The series consisted of 10 gastric carcinomas, 10 colorectal carcinomas, five squamous skin carcinomas, and five basal cell skin tumors. MMP-2 was detected in all cases. MMP-2 mRNA was expressed in the stromal cells in all cases and was more marked in the less-differentiated gastric and colonic carcinomas; it was also detected in the neoplastic cells of poorly differentiated tumors, particularly in those of the signet-ring cell type, both in the colon and stomach. The study confirmed that stromal cells have a specific role in tumor invasion and suggests a direct relationship between neoplastic epithelium and stromal cells in the most aggressive varieties.
Diagn Mol Pathol 1994 Sep
PMID:Gelatinase A (MMP-2) and its mRNA detected in both neoplastic and stromal cells of tumors with different invasive and metastatic properties. 798 91

The matrix metalloproteinase enzymes have been implicated in tumor invasion and metastasis by a series of correlative immunohistochemical studies. In addition, direct evidence for the role of these enzymes in this pathologic process comes from studies using specific metalloproteinase inhibitors to block tumor invasion and metastasis formation, both in vitro and in vivo. Synthetic oligonucleotide primers for four metalloproteinases (MMP-1, MMP-2, MMP-9, MMP-10) and their tissue inhibitors (TIMP-1, TIMP-2) were selected, synthesized, and optimized in the reverse transcriptase-polymerase chain reaction (RT-PCR) to study the qualitative profile of these enzymes and inhibitors in cultured human tumor cells and tumor tissues. These primers are specific and generate unique amplification products for each appropriate enzyme and inhibitor. Slight enhancement in the amplification of cDNA products was achieved by adding dimethylsulfoxide to the reaction mixture, but commercial enhancement reagents were ineffective. Using this RT-PCR method, cDNA amplification was successful with RNA from as few as 20 cultured tumor cells. The RT-PCR analysis was done on three invasive human colon adenocarcinomas and their paired adjacent normal mucosa. The results show MMP-1 and MMP-2 products in all three tumors, and MMP-2 detected in one of the three normal mucosa samples; TIMP-2 expression was present in two of three patients and awaits quantitative assessment of RT-PCR products.
Diagn Mol Pathol 1993 Jun
PMID:Reverse transcription-polymerase chain reaction phenotyping of metalloproteinases and inhibitors involved in tumor matrix invasion. 826 80

Fibrillar collagens, essential for maintaining the structural integrity of the myocardium, are degraded by matrix metalloproteinase (MMP-1). In other tissues collagenolysis is an important component of wound healing. Here we examined collagen degradation in the myocardium after infarction. Collagenase activity, measured by zymography, and expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of metalloproteinase (TIMP) mRNA, detected by Northern blotting and in situ hybridization, in the rat heart 6 h to 28 days after left coronary artery ligation were studied. Sham-operated rats served as controls. Infarcted left ventricle was compared to non-infarcted right ventricle and interventricular septum and to sham-operated tissues. We found a transient increase in collagenase activity in the infarcted left ventricle, which began at day 2 (4.5-fold increase compared to controls), peaked at day seven (6.5-fold increase) and declined thereafter, together with a concomitant increase and contribution in collagenolytic activity of gelatinases (MMP-2 and MMP-9). An increase in collagenase mRNA was not seen until day 7 and only in the infarcted ventricle, while changes in MMP-1 activity or mRNA expression were not observed at remote sites or in sham-operated controls. Transcription of TIMP mRNA was observed at 6 h (two-fold increase) in the infarcted ventricle, peaked on day two after MI (eight-fold increase) and slowly decreased thereafter. No change in TIMP mRNA expression was observed at remote sites or in sham-operated controls. Cells responsible for transcription of MMP-1 and TIMP mRNA were fibroblast-like cells, not inflammatory or endothelial cells. At the site of infarction post-translational activation of latent collagenase (MMP-1) plays a greater role in the wound healing response than transcription of collagenase mRNA. Collagenase mRNA is synthesized when the latent extracellular pool of MMP-1 is reduced through the activation of latent collagenases and gelatinases. TIMP mRNA synthesis is regulated by the activation of MMPs with the balance between collagenase activation and TIMP inhibition determining the amount of collagenolysis in infarcted tissue.
J Mol Cell Cardiol 1995 Jun
PMID:Regulation of collagen degradation in the rat myocardium after infarction. 853 Dec 10

Matrix metalloproteinases (MMP) are present in the latent form in normal myocardium. To examine the stringent balance between MMP and tissue inhibitor of metalloproteinase (TIMP) and to determine whether MMP are secreted simultaneously and in co-ordination with their inhibitors, we analysed MMP and TIMP by immunological, isolation by gel-permeation and affinity chromatography, and enzymatic assays in tissues and extracts. Using antibodies to MMP-1 and TIMP-1, we found strong in situ staining of MMP-1 and TIMP-1 in tissues. The staining was uniform in the endo- and subendomyocardium as well as in the interstitial space. TIMP-1 was present wherever MMP-1 was localized. From the tissue extract, proteins were separated on a gel-filtration column (Sephacryl S-200) and analysed for MMP and TIMP activity by zymography as well as by using succinyl-Gly-Pro-Leu-Gly-Pro-4-amido-7-methyl coumarin (Suc-GPLGP-AMC) as a selective fluorogenic substrate for collagenase. TIMP and MMP were further purified on collagen-Sepharose affinity column. The results indicated that MMP activity was co-eluted with TIMP activity. MMP-1, MMP-2 and TIMP-1 were further analysed by Northern blot for mRNA levels in the heart, skin, lung, liver and kidney. Results suggested co-expression of MMP-1 and TIMP-1 at the transcription level in all tissues. The level of MMP-2 mRNA was specifically higher in the heart tissue, which suggests a role of MMP-2 in the integrity of cardiovascular structure. The study indicated that myocardium as well as other tissue have an endogenous inhibitory system, suggesting that the MMPs activity is co-ordinated by their inhibitors at both the gene and protein levels. Furthermore, MMP and TIMP were co-expressed and were tightly regulated in maintaining the architecture of the interstitial tissue.
J Mol Cell Cardiol 1995 Oct
PMID:Co-expression of tissue inhibitor and matrix metalloproteinase in myocardium. 857 34

Extracellular matrix components as well as enzymes and enzyme-inhibitors controlling the turn-over of these components play an important role in the local control of testicular function. Zymographic analysis was used to study the secretion and the control of the secretion of gelatinase A (MMP-2) and B (MMP-9) by primary cultures of rat Sertoli cells and by subcultures of peritubular cells. Data on gelatinase A were complemented by measurement of the corresponding mRNA by Northern blot analysis. The agonists investigated included hormones (FSH, testosterone), second messengers (dbcAMP, phorbolester and a Ca(2+)- ionophore), interleukin-1 beta (IL-1 beta) and inducers of cytokine production (Concanavalin A: ConA; lipopolysaccharide: LPS; double stranded RNA: PIC). It is demonstrated that Sertoli cells originally secrete both gelatinase A and B. When maintained in serum-free medium, however, they rapidly lose the ability to secrete gelatinase B. After 3 days of culture gelatinase A remains the only measurable gelatinase in both Sertoli and peritubular cell cultures. The production in peritubular cells, however, exceeds that in Sertoli cells some 25-fold. This was confirmed by a 30-fold difference in the level of steady-state gelatinase A mRNA levels. Gelatinase A secretion and gelatinase A mRNA were stimulated by ovine FSH in Sertoli cells and by dbcAMP and ConA in both Sertoli and peritubular cells. IL-1 beta displayed measurable but limited stimulatory effects in both cell types. Interestingly, in peritubular cells but not in Sertoli cells, ConA stimulated the production of a lower MW species probably representing an activated form of gelatinase A. It is concluded that both the amounts of gelatinase A produced, the levels of the corresponding mRNA and the regulation differ in cultured peritubular cells and Sertoli cells. The lectin concanavalin A is a novel and potent inducer of gelatinase A. It resembles cytochalasin D in selectively inducing an activated form of gelatinase A in peritubular cells. The mechanism responsible for this selective effect warrants further investigation.
Mol Cell Endocrinol 1996 Apr 19
PMID:Gelatinase A secretion and its control in peritubular and Sertoli cell cultures: effects of hormones, second messengers and inducers of cytokine production. 873 89

Human heart matrix metalloproteinases (MMP) are present in the latent form and activated in the failing heart. To examine whether the MMP activation was due to gene and/or post-translational modification, we analysed tissue from 10 explanted hearts due to coronary heart disease (CHD) and five normal left atrial tissue from donor hearts. Based on in situ immunolabeling MMP-1, tissue inhibitor of metalloproteinase (TIMP-1) and collagen were co-localized in the interstitial tissue. Based on sandwich ELISA, TIMP-1 and MMP-1 levels were 37 +/- 8 ng/mg and 9 +/- 2 ng/mg in normal tissue (P < 0.01) and 12 +/- 5 ng/mg and 75 +/- 11 ng/mg in the infarcted tissue (P < 0.01), respectively. These levels suggest repression of TIMP-1 during myocardial infarction. Northern blot analysis indicated that the mRNAs for both MMP-1 and TIMP-1 were increased three-to four-fold in the infarcted tissue as compared to the normal tissue, suggesting upregulation of MMP and TIMP gene transcription following infarction. Based on in situ tissue overlay zymography, the generalized activation of MMP was observed in the interstitium of the infarcted heart. Zymographic and immunoblot analysis demonstrated the presence of one band at 66 kDa (MMP-2) in the normal tissue and several bands at 92 (MMP-9), 66 (MMP-2) and 54 kDa (MMP-1) in the infarcted heart. Incubation of the zymographic gel with metal chelator (phenanthroline) abolished bands at 92 kDa and 54 kDa but phenanthroline did not abolish the lytic band at 66 kDa. The 66 kDa band was completely abolished in the presence of phenanthroline and phenyl methyl sulfonyl fluoride (PMSF). 2D-zymographic analysis suggested that the lytic band at 66 kDa was a mixture of two neutral proteinases with different isoelectric point. Plasminogen/gelatin zymographic analysis of infarcted tissue extract indicated that the band at 66 kDa was plasmin generated due to increased expression of tissue plasminogen activator (tPA) activity. In relation to increased expression of gelatinase in the infarcted tissue, our data suggest that gelatinase B (92 kDa) is induced in diseased heart. The results suggest that tPA converts plasminogen to plasmin which, in turn, activates MMPs and inactivates TIMP-1 post-translationally following ischemic cardiomyopathy.
J Mol Cell Cardiol 1996 Jul
PMID:Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. 884 29

Heparin has been shown to stimulate angiogenesis in the border zones surrounding infarcted myocardium. Matrix metalloproteinases (MMP), which are involved in extracellular matrix (ECM) organization, have also been shown to be activated. Cholesterol is required for receptor signaling in the plasma membrane, but a role of MMPs for cholesterol in ECM remodeling has not yet been shown. To examine whether heparin and cholesterol induce MMP and tissue inhibitor of metalloproteinase (TIMP) in human heart fibroblast (HHF) cells, confluent HHF cells were treated with cholesterol (100 microM) or heparin (20 microM). MMP activity was measured using zymography and TIMP was measured by Western blot analysis. The number of HHF cells, measured by a hemocytometer, increased after heparin or cholesterol treatment. Gelatinase A (MMP-2) activity increased in heparin treated cells, and the TIMP-1 level increased in cholesterol-treated cells. Based on Northern blot analysis, we observed that both MMP-1 and MMP-2 were induced at the gene transcription level by heparin and that TIMP-1 was induced by cholesterol. To examine whether the effects of heparin and cholesterol were due to Ca2+ mobilization, we carried out Ca2+ transient assays using FURA-2/AM as a fluorescence probe in HHF cells. Heparin induced a slow rise in the Ca2+ transient with a slow decay, and cholesterol induced a rapid rise with a slow reversal to the baseline calcium level. This suggested that the effect of heparin on Ca2+ release from HHF may be secondary to the receptor binding on the cell membrane but that cholesterol may have a direct effect. Protein kinase inhibitor and Ca2+-channel blocker have been shown to inhibit MMP expression. To examine whether the effect of heparin on MMP expression is mediated through the collagenase promoter activity, we carried out gel-shift assays using a 21-oligonucleotide analogue to the MMP-1 promoter sequence. Results suggested that the increase in MMP promoter activity by heparin is due to a specific transcription factor binding to MMP-1 promoter sequence. The effect of cholesterol on fibroblast cell proliferation is due in part to the tissue inhibitor. This study demonstrated the role of heparin and cholesterol in ECM remodeling and has implications for angiogenesis and athersclerosis, respectively.
J Mol Cell Cardiol 1997 Jan
PMID:Differential regulation of extracellular matrix metalloproteinase and tissue inhibitor by heparin and cholesterol in fibroblast cells. 904 53

One of the major causes of glomerular sclerosis which precedes renal failure is an increase in glomerular extracellular matrices (ECMs). Glomerular ECMs which are composed of mesangial matrix and basement membrane play an important role in physical, mechanical and structural functions of the glomerulus. Matrix metalloproteinases (MMPs) are the enzymes which degrade both the collagenous and noncollagenous components of the ECMs. Tissue inhibitors of metalloproteinases (TIMPs) are inhibitors of MMPs. The regulations by MMPs and TIMPs are considered to contribute to maintain homeostasis in the production and degradation of ECMs in the glomeruli. In the glomeruli of patients with glomerulonephritis, the imbalance between production and degradation of ECMs is supposed to cause the increase in ECMs and glomerular sclerosis. In this study, serum concentrations of MMP-1, -2, and -3, TIMP-1 and 2 and type IV collagen were measured in patients with IgA nephropathy, lupus nephritis and membranous nephropathy. In patients with IgA nephropathy and lupus nephritis which are mesangial proliferative glomerulonephritis, the levels of MMP-3 and TIMP-2 were increased. On the other hand, the levels of type IV collagen, MMP-2 and TIMP-1 were increased in patients with membranous nephropathy in which the thickening of basement membrane is characteristic. These differences may be caused by the difference of the pathogenesis of these diseases. The present results suggest that the imbalance between the metabolism of ECMs occurs in patients with glomerulonephritis and contributes to the progression of glomerulonephritis.
Res Commun Mol Pathol Pharmacol 1997 Feb
PMID:Changes in serum concentrations of matrix metalloproteinases, tissue inhibitors of metalloproteinases and type IV collagen in patients with various types of glomerulonephritis. 909 Jul 49

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) known to be fundamental to normal physiological processes, also contribute to several pathologies associated with uncontrolled tissue degradation. Recent observation of MMPs and TIMPs in the central nervous system suggest they could play a role in the neurodegenerative process following viral infection. We have investigated the expression of these molecules in human and rat glial cells infected with retrovirus HTLV-I, the causative agent of HTLV-I associated myelopathy (TSP/HAM). We report that cytokines secreted by infected glial cells are responsible for the increased expression of MMP-3, MMP-9 and TIMP-3, while MMP-2, TIMP-1 and TIMP-2 remained stable. The role of dysregulated MMPs/TIMPs in the pathogenesis of TSP/HAM may be related to various functions of these proteases, namely degradation of the blood-brain barrier, myelin constituent cleavage and conversion of inactive TNF-precursor to active form.
Mol Psychiatry 1997 Mar
PMID:Cytokines secreted by glial cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs): possible involvement in neurodegenerative processes. 910 28

Although increased deposition of collagen proteins has been described in cardiomyopathy, little is known of the temporal relationship between events in collagen gene transcription and the occurrence of cardiac fibrosis, the removal of collagen by matrix metalloproteinases (MMPs), or of the regulation of these events by angiotensin AT1 receptors in this disease. We sought to study steady-state collagen mRNA abundance and the deposition of specific collagen subtypes in right and left ventricular muscle of Syrian cardiomyopathic (CMP) hamsters at different stages of cardiomyopathy. Using zymography, we also investigated the gelatinolytic activities of different MMPs to gain some information about collagen removal in experimental hearts. Finally, we investigated the effect of AT1 receptor blockade (losartan) on collagen remodeling. We observed that the mRNA levels of types I and III collagens were significantly increased in all four experimental groups (35, 65, 120, and 200 day) in left ventricular tissue when compared to control (F1-beta strain) values. The mRNA levels of these collagen species in experimental right ventricular tissue samples were only elevated significantly in the 35 and 200 day experimental groups when compared to controls. Fibrillar collagen deposition was elevated in left and right ventricular CMP samples after a lag period from the occurrence of corresponding increases in mRNA abundance. Although 2-week losartan treatment of 65, 120 and 200 day experimental groups had no significant effect on left ventricular fibrillar collagen concentration or collagen mRNA abundance when compared to vehicle-infused CMP hamsters, AT1 receptor blockade was associated with complete regression of cardiac hypertrophy. Both MMP-1 (54 kDa band) and MMP-2 (58 and 62 kDa bands) activities were increased in left ventricular CMP tissues at 65, 120 and 200 days when compared to F1-beta controls. Losartan treatment was associated with significant attenuation of MMP activities in cardiomyopathic samples at 65 and 120 days. Thus, elevation of mRNA abundance of fibrillar collagen genes occurs at very early stages in this model of cardiomyopathy, and corresponding collagen proteins were subsequently deposited in the cardiac interstitium at later stages. As collagen concentration was significantly increased in later stages of cardiomyopathy studied herein (120 and 200 day groups), our data support the hypothesis that collagen synthesis exceeds the capacity of collagen removal during the progression of cardiomyopathy. Nevertheless, cardiac collagen remodeling may be facilitated by elevated MMP activity in cardiomyopathic stages in this experimental model, and we suggested that attenuation of MMP activity in the presence of losartan may be a cardioprotective mechanism of this agent.
J Mol Cell Cardiol 1997 Jul
PMID:Cardiac collagen remodeling in the cardiomyopathic Syrian hamster and the effect of losartan. 923 38


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