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)

Matrix metalloproteinase-7 (MMP-7, matrilysin- 1) modulates crucial biological events by processing many epithelial cell surface-associated effectors. We addressed MMP-7 interaction with human epithelial cells and its resulting activity. In human endometrium, a model of controlled tissue remodeling, proMMP-7 was diffusely immunolocalized inside epithelial cells, whereas MMP-7 delineated their entire plasma membrane. Endometrial explants preferentially retained active MMP-7, but not proMMP-7. Endometrial epithelial cells and carcinoma cells from various tissues bound active MMP-7. Endometrial carcinoma-derived Ishikawa cells showed high affinity (K(D) of approximately 2.5 nM) and capacity (approximately 260,000 sites per cell) for MMP-7. MMP-7 binding decreased by extracting membrane sterols or interfering with heparan sulfate proteoglycans, and was abrogated by tissue inhibitors of metalloproteinase-2 (TIMP-2) or synthetic MMP inhibitors. Bound MMP-7 not only remained fully active towards a macromolecular substrate but also became resistant to TIMP-2. We conclude that MMP-7-selective targeting to the plasma membrane of epithelial cells promotes its activity by conferring resistance to TIMP-2.
Cell Mol Life Sci 2007 Mar
PMID:Binding of matrilysin-1 to human epithelial cells promotes its activity. 1731 Feb 81

Epithelial ovarian cancer (EOC) is asymptomatic at early stages and is often diagnosed late when tumor cells are highly metastatic. Lysophosphatidic acid (LPA) has been implicated in ovarian oncogenesis as levels of this lipid are elevated in patient ascites and plasma. Because the underlying mechanism governing LPA regulation of matrix metalloproteinase-2 (MMP-2) activation remains undefined, we investigated the relationship between LPA-induced changes in actin microfilament organization and MMP-2 enzymatic activity. We report that when cells were cultured at a high density, LPA mediated stress fiber and focal adhesion disassembly and significantly repressed RhoA activity in EOC cells. Inhibition of Rho-kinase/ROCK enhanced both LPA-stimulated loss of stress fibers and pro-MMP-2 activation. In contrast, expression of the constitutively active RhoA(G14V) mutant diminished LPA-induced pro-MMP-2 activation. LPA had no effects on membrane type 1-MMP or tissue inhibitor of metalloproteinase-2 expression, but up-regulated MMP-2 levels, contributing to the induction of MMP-2 activation. Interestingly, when cells were cultured at a low density, stress fibers were present after LPA stimulation, and ROCK activity was required for EOC cell migration. Collectively, these results were consistent with a model in which LPA stimulates the metastatic dissemination of EOC cells by initiating loss of adhesion and metalloproteinase activation.
Mol Cancer Res 2007 Feb
PMID:Lysophosphatidic acid down-regulates stress fibers and up-regulates pro-matrix metalloproteinase-2 activation in ovarian cancer cells. 1731 70

Epithelial-mesenchymal transition (EMT) events occur during embryonic development and are important for the metastatic spread of epithelial tumors. We show here that spontaneous differentiation of mouse embryonic stem (ES) cells is associated with an E- to N-cadherin switch, up-regulation of E-cadherin repressor molecules (Snail and Slug proteins), gelatinase activity (matrix metalloproteinase [MMP]-2 and -9), and increased cellular motility, all characteristic EMT events. The 5T4 oncofetal antigen, previously shown to be associated with very early ES cell differentiation and altered motility, is also a part of this coordinated process. E- and N-cadherin and 5T4 proteins are independently regulated during ES cell differentiation and are not required for induction of EMT-associated transcripts and proteins, as judged from the study of the respective knockout ES cells. Further, abrogation of E-cadherin-mediated cell-cell contact in undifferentiated ES cells using neutralizing antibody results in a reversible mesenchymal phenotype and actin cytoskeleton rearrangement that is concomitant with translocation of the 5T4 antigen from the cytoplasm to the cell surface in an energy-dependent manner. E-cadherin null ES cells are constitutively cell surface 5T4 positive, and although forced expression of E-cadherin cDNA in these cells is sufficient to restore cell-cell contact, cell surface expression of 5T4 antigen is unchanged. 5T4 and N-cadherin knockout ES cells exhibit significantly decreased motility during EMT, demonstrating a functional role for these proteins in this process. We conclude that E-cadherin protein stabilizes cortical actin cytoskeletal arrangement in ES cells, and this can prevent cell surface localization of the promigratory 5T4 antigen.
Mol Biol Cell 2007 Aug
PMID:E-cadherin inhibits cell surface localization of the pro-migratory 5T4 oncofetal antigen in mouse embryonic stem cells. 1750 57

Proteolysis of extracellular matrix proteins by membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in tumor and endothelial cell migration. In addition to its proteolytic activity, several studies indicate that the proinvasive properties of MT1-MMP also involve its short cytoplasmic domain, but the specific mechanisms mediating this function have yet to be fully elucidated. Having previously shown that the serum factor sphingosine 1-phosphate stimulates MT1-MMP promigratory function through a process that involves its cytoplasmic domain, we now extend these findings to show that this cooperative interaction is permissive to cellular migration through MT1-MMP-dependent transactivation of the epidermal growth factor receptor (EGFR). In the presence of sphingosine 1-phosphate, MT1-MMP stimulates EGFR transactivation through a process that is dependent upon the cytoplasmic domain of the enzyme but not its catalytic activity. The MT1-MMP-induced EGFR transactivation also involves G(i) protein signaling and Src activities and leads to enhanced cellular migration through downstream extracellular signal-regulated kinase activation. The present study, thus, elucidates a novel role of MT1-MMP in signaling events mediating EGFR transactivation and provides the first evidence of a crucial role of this receptor activity in MT1-MMP promigratory function. Taken together, our results suggest that the inhibition of EGFR may represent a novel target to inhibit MT1-MMP-dependent processes associated with tumor cell invasion and angiogenesis.
Mol Cancer Res 2007 Jun
PMID:Membrane-type 1 matrix metalloproteinase stimulates cell migration through epidermal growth factor receptor transactivation. 1754 Oct 67

Membrane type 1 matrix metalloproteinase (MT1-MMP) is a protease produced by airway epithelial cells in various diseases. Since other MMPs are involved in bronchial epithelial repair, we investigated the role of MT1-MMP in naphthalene-induced small airway injury and repair in wild-type (WT) and MT1-MMP-knockout (KO) mice. The degree of injury was similar in both strains, but the MT1-MMP KO mice were unable to reconstitute a normal, fully differentiated airway epithelium 28 days after injury. MT1-MMP was required for the proliferative response in distal airway epithelial cells, resulting in decreased cell density and airway epithelial cell differentiation in MT1-MMP KO mice. Surprisingly, EGF-mediated signaling was unaltered in MT1-MMP KO mice and therefore unrelated to the proliferative response. However, keratinocyte growth factor receptor (KGFR) expression was significantly upregulated before the proliferative response and markedly less evident in the distal airway epithelium of MT1-MMP KO mice. These results indicate MT1-MMP is involved in KGFR expression and epithelial cell proliferation after acute airway injury.
Am J Physiol Lung Cell Mol Physiol 2007 Sep
PMID:Membrane type 1 matrix metalloproteinase is necessary for distal airway epithelial repair and keratinocyte growth factor receptor expression after acute injury. 1755 4

Once prostate cancer has metastasized, current treatment methods are generally ineffective. Due to the reported anti-tumor properties of specific nutrients, we investigated the effect of a unique formulation (NS) of lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate on human prostate cancer cell lines: PC-3, DU145 (androgen insensitive) and LNCaP (androgen sensitive), by measuring cell proliferation, MMP expression, and invasion potential. Cell lines DU145, PC-3, and LNCaP were treated at near confluence with NS at various concentrations. Cell proliferation was measured by MTT assay after 24 hours, MMP expression was measured by gelatinase zymography in condition media, and invasion activity was measured by Matrigel. The nutrient mixture did not significantly inhibit PC-3 cell proliferation at 50 microg/ml, but showed significant antiproliferative effect at 500 ug/ml. When treated with NS, proliferation of LNCaP cells was inhibited by 80% of control at 100 microg/ml. NS showed dose-dependent inhibition of DU145 cell proliferation with 47% reduction at 1000 microg/ml. NS showed a dose-dependent inhibition of both MMP-2 and MMP-9 expression by PC-3 cells and MMP-9 expression by PMA-treated (200 ng/ml) DU145 cells. Neither MMP-2 nor MMP-9 gelatinolytic activity was detected in LNCaP cell culture. Invasion of DU145 and LNCaP cells through Matrigel was completely inhibited at 500 microg/ml and PC-3 at 1000 microg/ml. Inhibition of MMP expression and invasion suggests the mixture of nutrients studied is a potent, natural anticancer agent for the treatment of prostate cancer.
Res Commun Mol Pathol Pharmacol 2004
PMID:Anti-tumor effect of ascorbic acid, lysine, proline, arginine, and epigallocatechin gallate on prostate cancer cell lines PC-3, LNCaP, and DU145. 1756 22

Mycobacterium tuberculosis (MTb) kills approximately 2 million people each year. MTb must drive host tissue destruction to disseminate and also to cause pulmonary cavitation. Matrix metalloproteinase-9 (MMP-9, gelatinase B) is implicated in this Tb-related immunopathology. We demonstrate that conditioned media from MTb-infected monocytes (CoMTb), but not direct infection with MTb, up-regulates MMP-9 gene expression and secretion from primary human bronchial epithelial cells (NHBE). MMP-9 secretion was increased 8.7-fold by CoMTb (P < 0.05) as assayed by gelatin zymography. A549 and 16HBE14o epithelial cell MMP secretion was significantly less than primary NHBE secretion. MMP-9 secretion was decreased 53.2% by inhibition of the p38 mitogen-activated protein kinase (MAPK) by SB203580 (P < 0.01) and 48.3% by inhibition of extracellular signal-regulated kinase with PD98059 (P < 0.05). MMP-9 secretion was prostaglandin independent. TNF-alpha was necessary but not sufficient for MMP-9 up-regulation by the monocyte-epithelial cell network. Soluble factors derived from Tb culture synergized with TNF-alpha to increase MMP-9 secretion by NHBE 6-fold (P < 0.01 compared with either stimulus alone). Together, these data reveal a new mechanism by which host- and pathogen-derived factors act together in MTb infection to drive MAPK-dependent MMP-9 secretion from respiratory epithelial cells.
Am J Respir Cell Mol Biol 2007 Oct
PMID:Synergistic up-regulation of epithelial cell matrix metalloproteinase-9 secretion in tuberculosis. 1757 75

The development of atrial fibrillation (AF) is associated with electrical and structural remodeling. The aim of this study was to assess the contribution of electrical and structural remodeling to the development of AF in a rapid atrially paced ovine model with and without His bundle ablation and to determine the role of the angiotensin pathway and matrix metalloproteinases in this process. Thirty-five sheep were rapidly paced in the atrium and were randomized to undergo His bundle ablation (HBA) (21 sheep; HBA sheep) or not (14 sheep; non-HBA sheep). After HBA the ventricles were paced at 80 bpm. Both groups were subdivided to receive active treatment (quinapril+losartan) or placebo. Sheep were followed for 15 weeks. Inducible AF was defined as a rapid irregular atrial rhythm lasting >1 min. Inducible AF was considered to be persistent if during further follow-up no sinus rhythm (SR) was documented anymore. The inducibility of AF with atrial tachypacing was not different between the 4 groups. On the other hand, non-HBA sheep developed persistent AF significantly earlier than HBA sheep (p=0.028). They had elevated ventricular rates, diminished atrial MMP-2, increased TIMP-2 expression, and more extensive atrial fibrosis. Active treatment in these sheep significantly lowered AT-II (p=0.018), prevented atrial fibrogenesis (p<0.001) and slowed the development of persistent AF (p=0.049). Electrical remodeling is sufficient to induce AF, while structural changes are needed for persistent AF. Fibrosis development in our model is the result of an increased expression of AT-II in combination with changes in MMP expression. Inhibition of the angiotensin pathway suppresses atrial fibrosis and the development of persistent AF.
J Mol Cell Cardiol 2007 Aug
PMID:Self-terminating AF depends on electrical remodeling while persistent AF depends on additional structural changes in a rapid atrially paced sheep model. 1759 47

Stratifin is a member of 14-3-3 protein family, a highly conserved group of proteins constituted by seven isoforms. They are involved in numerous crucial intracellular functions such as cell cycle and apoptosis, regulation of signal transduction pathways, cellular trafficking, cell proliferation and differentiation, cell survival, and protein folding and processing, among others. At epidermal level, stratifin (also called 14-3-3 sigma) has been described as molecule with relevant functions. For instance, this isoform is a marker associated with keratinocyte differentiation. In this maturation process, the presence of dominant negative molecules of p53 induces a "stemness condition" of keratinocyte precursor cells and suppression of stratifin expression. In addition, the recently described keratinocyte-releasable form of stratifin is involved in dermal fibroblast MMP-1 over-expression through c-Fos and c-Jun activity. This effect is mediated, at least in part, by p38 mitogen-activated protein kinase (MAPK). Other MMP family members such as stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), neutrophil collagenase (MMP-8), and membrane-type MMP-24 (MT5-MMP) are also up-regulated by stratifin. Within fibroproliferative disorder of skin, hypertrophic scar and keloids exhibit a high content of collagen, proteoglycans, and fibronectin. Thus, the MMP profile induced by stratifin is an interesting starting point to establish new therapeutic tools to control the process of wound healing. In this review, we will focus on site of synthesis and mode of action of stratifin in skin and wound healing.
Mol Cell Biochem 2007 Nov
PMID:The role of stratifin in fibroblast-keratinocyte interaction. 1764 30

Extracellular matrix (ECM) molecules and growth factors, such as fibroblast growth factor (FGF), play a crucial role in Alzheimer's disease (AD). The purpose of this investigation was to determine whether phenotypic alterations in ECM production are present in non-neuronal AD cells associated with different FGF expression and response. Synthesis of glycosaminoglycans (GAG) and collagen were measured in skin fibroblasts from patients with familial, sporadic AD (FAD and SAD respectively), and from age-matched controls by radiolabeled precursors. Proteoglycans (PG), metalloprotease (MMP)-1, and FGF gene expressions were measured by reverse transcription-polymerase chain reaction. The results showed different ECM neosynthesis and mRNA levels in the two AD fibroblast populations. FAD accumulated more collagen and secreted less GAG than SAD. Biglycan PG was upregulated in FAD while betaglycan, syndecan, and decorin were markedly downregulated in SAD fibroblasts. We found a significant decrease of MMP1, more marked in FAD than in SAD fibroblasts. Constitutive FGF expression was greatly reduced in both pathological conditions (SAD>FAD). Moreover, an inverse high affinity/low affinity FGF receptor ratio between SAD and FAD fibroblasts was observed. FGF treatment differently modulated ECM molecule production and gene expression in the two cell populations. These observations in association with the changes in FGF gene expression and in the FGF receptor number, suggest that cellular mechanisms downstream from FGF receptor binding are involved in the two different forms of AD.
Mol Med
PMID:Differences in extracellular matrix production and basic fibroblast growth factor response in skin fibroblasts from sporadic and familial Alzheimer's disease. 1766 Aug 61


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