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)

Part of the neurodegenerative cascade in AIDS dementia may involve overexpression of matrix metalloproteinases (MMPs). Here, we examined the possible effect of HIV-1 gp41, which has been shown as a key determinant associated with pathogenesis of AIDS dementia, on the activity of MMPs using human neuronal and glial cell lines. Zymographic analysis revealed that treatment with the gp41 peptide (aa 583-599) for 24 h markedly elevated the activity of MMP with Mr 66 kDa in the cultured media of glioblastoma cell line T98G in a concentration-dependent manner as well as of neuroblastoma cell line SK-N-SH despite of lower magnitude of the activity. In contrast, the immediately adjacent gp41 peptide (aa 598-613) as well as the reverse peptide (aa 598-583) had a little effect. Recombinant gp41 protein containing extracellular domain also elicited a similar effect, although with a lesser extent. This 66 kDa MMP was confirmed as gelatinase A (MMP-2) based on the results of its activity dependent on Ca2+ and inhibited in the presence of 1,10-phenanthroline or EDTA, as well as its specific immunoreactivity on the Western blot. N-acetyl cysteine (NAC) downregulated this gp41 peptide-induced MMP-2 activity in T98G. The soluble form of amyloid precursor protein (sAPP), which is synthesized in the Escherichia coli system, also inhibited the MMP-2 activity in vitro. Taken together, these results implicate that high production of HIV-1 gp41 or its metabolites containing aa 583-599 within central nervous system (CNS) could result in the increased activity of MMP-2 and that the extracellular deficiency of reducing agent or decreased level of sAPP within CNS could exacerbate this gp41-induced MMP-2 activity.
J Mol Neurosci 1998 Apr
PMID:Increased activity of matrix metalloproteinase-2 in human glial and neuronal cell lines treated with HIV-1 gp41 peptides. 969 54

Acidic fibroblast growth factor (FGF-1), a prototype member of the heparin-binding growth factor family, influences proliferation, differentiation, and protein synthesis in different cell types. However, its possible role on lung extracellular matrix (ECM) metabolism has not been evaluated. In this study we examined the effects of FGF-1 and FGF-1 plus heparin on type I collagen, collagen-binding stress protein HSP47, interstitial collagenase (matrix metalloproteinase [MMP]-1), gelatinase A, and tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 expression by normal human lung fibroblasts. Heparin was used because it enhances the biologic activities of FGF-1. Fibroblasts were exposed either to 20 ng/ml FGF-1 plus 100 micrograms/ml heparin for 48 h or to FGF-1 or heparin alone. Messenger RNA (mRNA) expression was analyzed by Northern blot. Collagen synthesis was evaluated by digestion of [3H]collagen with bacterial collagenase, MMP-1 by Western blot, and gelatinolytic activities by zymography. Our results show that FGF-1 induced collagenase mRNA expression, which was strongly enhanced when FGF-1 was used with heparin. Likewise, both FGF-1 and FGF-1 plus heparin reduced by 70 to 80% the expression of type I collagen transcript, in part through effect on pro-alpha1(I) collagen mRNA stability. A downregulation of HSP47 gene expression was also observed. Synthesis of collagen and collagenase proteins paralleled gene expression results. FGF-1 activities were abolished with genistein, a tyrosine kinase inhibitor. Neither FGF-1 nor FGF-1 plus heparin affected the expression of TIMP-1, TIMP-2, and gelatinase A. These findings demonstrate that FGF-1, mostly in the presence of heparin, upregulates collagenase and downregulates type I collagen expression that might have a protective role in avoiding collagen accumulation during lung ECM remodeling.
Am J Respir Cell Mol Biol 1999 May
PMID:Acidic fibroblast growth factor induces an antifibrogenic phenotype in human lung fibroblasts. 1022 73

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
Am J Respir Cell Mol Biol 1999 Jun
PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32

Experimental and clinical studies strongly suggest that gelatinase A plays a central role in the evolution of glomerular injury and sclerosis. The sequences of the 5' flanking regions of the human and rat gelatinase A genes do not share similarities with other members of the matrix metalloproteinase gene family and are regulated in a distinctive manner. The human and rat gelatinase A genes include regions of significant homology (r2 human; RE-1 rat), which have been shown to act as potent cis-activators of transcription. The rat RE-1 sequence interacts specifically with the developmentally regulated transcription factors AP2 and YB-1, resulting in a synergistic activation of gelatinase A transcription. Although the human r2 sequence specifically interacts with AP2 (Mol Cell Biol 10: 6524-6532, 1990), there is no clear evidence for the presence of a canonical YB-1 binding site (Y-box) within this sequence. This study demonstrates, despite the absence of a canonical Y-box sequence in the r2 element, that YB-1 and AP2 specifically interact with r2, yielding synergistic transactivation of the human gelatinase A gene. It is concluded that the r2 element is the conserved functional analog of the RE-1 element, and that interactions of AP2 and YB-1 govern human gelatinase A gene expression.
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PMID:YB-1 regulation of the human and rat gelatinase A genes via similar enhancer elements. 1058 85

We have studied the enzymatic gelatinolytic activity of matrix metalloproteinases (MMPs) present in cerebrospinal fluid (CSF) of samples obtained from 67 individuals, twenty-one nonneurological patients (considered controls) and 46 subjects with various neurological disorders e.g., vascular lesions, demyelination, inflammatory, degenerative and prion diseases. Biochemical characterization of MMPs, a family of neutral proteolytic enzymes involved in extracellular matrix modeling, included determination of substrate specificity and Ca+2 dependency, as well as the effects of protease inactivators, carboxylic and His (histidine) residue modifiers, and antibiotics. Whereas all CSF samples expressed MMP-2 (gelatinase A) activity, it corresponded in most cases (normal and pathological samples) to its latent form (proenzyme; pMMP-2). In general, inflammatory neurological diseases (especially meningitis and neurocisticercosis) were associated with the presence of a second enzyme, MMP-9 (or gelatinase B). Whereas MMP-9 was found in the CSF of every tropical spastic paraparesis patient studied, its presence in samples from individuals with vascular lesions was uncommon. Patients blood-brain barrier damage was ascertained by determining total CSF protein content using both, the conventional polyacrylamide gel electrophoresis procedure under denaturing conditions and capillary zone electrophoresis.
Res Commun Mol Pathol Pharmacol 1999
PMID:Gelatinase activity of matrix metalloproteinases in the cerebrospinal fluid of various patient populations. 1060 77

The cellular mechanisms underlying fetal membrane repair are poorly understood. Matrix metalloproteinases (MMP) and the endogenous tissue inhibitors of metalloproteinases (TIMP) play a key role in the control of turnover of extracellular matrix in fetal membranes at normal parturition and preterm prelabour rupture of the fetal membranes (PPROM). The time course of secretion of MMP-2 (72 kDa, gelatinase A) and MMP-9 (92 kDa, gelatinase B) and TIMP into extra-embryonic coelomic, allantoic and amniotic fluids in a rabbit model was examined. Furthermore, to evaluate their role in fetal membrane repair, the changes induced by fetoscopy at mid-gestation (23 days; gestation length is 32 days) were investigated. Zymography showed predominantly secretion of latent MMP-2 at 18, 23 and 30 days of gestation in all gestational compartments. Reverse zymography detected a broad range of TIMP activity with molecular weights of 27-30 kDa (TIMP-1, glycosylated TIMP-3 and TIMP-4), 24 kDa (unglycosylated TIMP-3) and 21 kDa (TIMP-2). Following fetoscopy, both MMP-2 and TIMP increased significantly in amniotic fluid and extra-embryonic coelomic fluid, but not in allantoic fluid, as demonstrated by densitometric analyses. These findings indicate a modulating role for MMP and TIMP in the repair processes following a surgically induced fetal membrane defect.
Mol Hum Reprod 2000 May
PMID:Matrix metalloproteinases -2 and -9 and their endogenous tissue inhibitors in fetal membrane repair following fetoscopy in a rabbit model. 1077 54

NGF has anti-proliferative and anti-invasive effects in neuroendocrine tumors. In the present work we examined the effects of NGF and retinoic acid on cell proliferation and invasion in thyroid carcinoma cells. We found that NGF and retinoic acid do not affect cell proliferation on their own but in combination they produce a strong inhibition. We also found that retinoic acid regulates the matrix metalloproteinase 2 activity and invasion. In contrast, NGF inhibited invasion and reverted the effect of retinoic acid. This effect of NGF is likely mediated by an increase in adhesion to laminin and collagen IV and the inhibition of cell migration. NGF also induced the expression of the p75 NGF receptor. In conclusion, NGF and retinoic acid in combination inhibit proliferation and invasion of thyroid papillary carcinoma cells. These data open the possibility of a potential combined therapy for thyroid papillary carcinomas.
Mol Cell Endocrinol 2000 Sep 25
PMID:Nerve growth factor and retinoic acid inhibit proliferation and invasion in thyroid tumor cells. 1100 May 24

Thrombospondin 2 (TSP2)-null mice, generated by disruption of the Thbs2 gene, display a variety of connective tissue abnormalities, including fragile skin and the presence of abnormally large collagen fibrils with irregular contours in skin and tendon. In this study we demonstrate that TSP2-null skin fibroblasts show a defect in attachment to a number of matrix proteins, and a reduction in cell spreading. To investigate the molecular mechanisms responsible for these abnormal cell-matrix interactions, we compared the levels of matrix metalloproteinases (MMPs) in wild-type and mutant fibroblasts. Isolation and analysis of gelatinases from conditioned media by gelatin-agarose affinity chromatography and gelatinolytic assays demonstrated that TSP2-null fibroblasts produce a 2-fold increase in gelatinase A (MMP2) compared with wild-type cells. The adhesive defect was corrected by treatment of TSP2-null fibroblasts with soluble TSP2, with the MMP inhibitors BB94 and tissue inhibitor of metalloproteinase-2, and with a neutralizing antibody to MMP2. Moreover, stable transfection of TSP2-null fibroblasts with mouse TSP2 cDNA corrected both the adhesive defect and the altered expression of MMP2. Finally, MMP2 was shown to interact with TSP2 in a direct-binding plate assay. We conclude that TSP2 plays an important role in cell-matrix interactions, and that a deficiency in the protein results in increased levels of MMP2 that contribute to the adhesive defect in TSP2-null fibroblasts and could play a role in the complex phenotype of TSP2-null mice.
Mol Biol Cell 2000 Oct
PMID:Matricellular proteins as modulators of cell-matrix interactions: adhesive defect in thrombospondin 2-null fibroblasts is a consequence of increased levels of matrix metalloproteinase-2. 1102 41

The purpose of this study was to determine the role of CREB and its associated proteins in melanoma progression. We used MeWo human melanoma cells transfected with a dominant negative construct of CREB, KCREB. KCREB has a mutation in its DNA-binding domain and can not bind the CRE element. Expression of KCREB yields proper heterodimerization with CREB and its associated proteins, but the proteins associated with KCREB do not confer the same degree of transcriptional activity as they would in the case of wild-type CREB. Here, we demonstrate that expression of KCREB in MeWo melanoma cells leads to a decrease in their tumorigenicity and metastatic potential in nude mice. We identified two mechanisms that explain at least partially this effect of KCREB. The first, is one in which CREB and its associated proteins play an essential role in invasion. We showed that the invasive properties of KCREB-transfected MeWo cells were reduced due to the downregulation of the CRE-dependent expression of the type IV collagenase MMP-2 and the adhesion molecule MCAM/MUC18. In the second mechanism, CREB and its associated proteins act as survival factors for human melanoma cells. Here we demonstrated that expression of KCREB in MeWo cells rendered them susceptible to apoptosis induced by thapsigargin, which in turn increased the intracellular level of Ca2+. Thapsigargin induced CREB and ATF-1 phosphorylation and activated CRE-dependent transcription in MeWo cells. Collectively, our data demonstrate that CREB and its associated proteins play an important role in tumor growth and metastasis of human melanoma.
Mol Cell Biochem 2000 Sep
PMID:Regulation of tumor growth and metastasis of human melanoma by the CREB transcription factor family. 1110 32

We have recently shown that the adhesive defect observed in dermal fibroblasts derived from thrombospondin 2 (TSP2)-null mice results from an increase in matrix metalloproteinase 2 (MMP2) levels (Yang, Z., Kyriakides, T. R., and Bornstein, P. (2000) Mol. Biol. Cell 11, 3353-3364). Adhesion was restored by replacement of TSP2 and by inhibitors of MMP2 activity. In pursuing the observation that TSP2 and MMP2 interact, we now demonstrate that this interaction is required for optimal clearance of extracellular MMP2 by fibroblasts. Since TSP2 is known to be endocytosed by the scavenger receptor, low density lipoprotein receptor-related protein (LRP), we determined whether interference with LRP function affected fibroblast adhesion and/or extracellular MMP2 levels. Addition of heparin, which competes for the binding of TSP2 to LRP coreceptor proteoglycans, inhibited adhesion of control but not TSP2-null cells, and a blocking antibody to LRP as well as the LRP inhibitor, receptor-associated protein, also inhibited adhesion and increased MMP2 levels only in control fibroblasts. TSP2 did not inhibit active MMP2 directly and did not inhibit the activation of pro-MMP2. Finally, the internalization of 125I-MMP2 was reduced in TSP2-null compared with control fibroblasts. We propose that clearance of MMP2-TSP2 complexes by LRP is an important mechanism for the regulation of extracellular MMP2 levels in fibroblasts, and perhaps in other cells. Thus, some features of the phenotype of TSP2-null mice, such as abnormal collagen fibrillogenesis, accelerated wound healing, and increased angiogenesis, could result in part from increased MMP2 activity.
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PMID:Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. 1111 33


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