Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q99542 (matrix metalloproteinase)
 15,999 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis (formation of new blood vessels) occurs in a number of diseases such as cancer and arthritis. The matrix metalloproteinase (MMP), gelatinase A, is secreted by endothelial cells and plays a vital role during angiogenesis. It is secreted as a latent enzyme and requires extracellular activation. We investigated whether activated protein C (APC), a pivotal molecule involved in the body's natural anti-coagulant system, could activate latent gelatinase A secreted by human umbilical vein endothelial cells (HUVEC). APC induced the fully active form of gelatinase A in a dose (100-300 nM)- and time (4-24 h)-responsive manner. The inactive zymogen, protein C, did not activate gelatinase A when used at similar concentrations. APC did not up-regulate membrane type 1 MMP (MT1-MMP) mRNA in HUVEC. In addition, the MMP inhibitor, 1, 10-phenanthroline (10 nM), was unable to inhibit APC-induced activation. These results suggested that MT1-MMP was not involved in the activation process. APC activation of gelatinase A occurred in the absence of cells, indicating that it acts directly. APC may contribute to the physiological/pathological mechanism of gelatinase A activation, especially during angiogenesis.
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PMID:Activated protein C directly activates human endothelial gelatinase A. 1073 39

The activation of the matrix metalloproteinase progelatinase A (MMP-2) has been of keen interest because an increase in MMP-2 activity has been implicated in disease states such as cancer and atherosclerosis. Activation of MMP-2 occurs on the surface of specific cell types in two steps. In the first step, primary cleavage of MMP-2 by a membrane-type matrix metalloproteinase generates an intermediate. A secondary cleavage and activation of the intermediate is thought to occur autocatalytically. Previous studies have shown that thrombin can also activate progelatinase A in the presence of endothelial cells. We show that this cell-dependent mechanism of MMP-2 activation also occurs with THP-1 cells and involves binding of thrombin to thrombomodulin present on the cell surface and generation of the anti-coagulant protein, activated protein C. We demonstrate that activated protein C is directly responsible for activation and cleavage of the gelatinase A intermediate. This work contributes new mechanistic insights into the activation of MMP-2 and provides a novel link between matrix metalloproteinase activation and anti-coagulation.
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PMID:Thrombin-thrombomodulin activation of protein C facilitates the activation of progelatinase A. 1129 49

Endothelial cell invasion is an essential event during angiogenesis (formation of new blood vessels). The process involves the degradation of the basement membrane and the underlying interstitium. The matrix metalloproteinase (MMP) family is considered to be primarily responsible for matrix degradation. Two members of the family, gelatinase A and B play an important role in angiogenesis. This review outlines recent findings on their regulation in human endothelial cells. Latent gelatinase B is secreted from endothelial cells. This enzyme can also accumulate in the cytosol as an active enzyme, free of TIMP-1. In contrast, latent gelatinase A is constitutively secreted from the cells. Unlike other MMPs, gelatinase A activation occurs on the cell membrane and is mediated by MT1-MMP. A number of physiological activators have recently been described. These include thrombin and activated protein C, both of which activate gelatinase A independent of the MT1-MMP pathway. These new findings may lead to therapeutic interventions for the treatment of angiogenic-dependent diseases such as cancer and arthritis.
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PMID:Human endothelial gelatinases and angiogenesis. 1147 Feb 30

We review recent developments in the diagnosis and treatment of colorectal cancer. In diagnosis, the detection of the APC gene mutation in stool samples has had a strong impact because of its practical usage for mass screening. Several reports have indicated that the molecular detection of a very small number of cancer cells in the peripheral blood, bone marrow, or lymph nodes yields adequate information on recurrent disease. Several new markers were reported as a significant indicators of cancer development, invasion, or metastasis. In treatment, determination of microsatellite instability may be useful to select good candidates for 5-fluorouracil-based chemotherapy. New molecular targets have been reported, including epidermal growth factor receptor inhibitor, matrix metalloproteinase inhibitors, etc. Gene therapy with p53 or FHIT had undergone successful clinical trials. Tumor-specific immunotherapy with dendritic cell vaccination has also been achieved. In conclusion, many efforts to overcome colorectal cancer will soon open new therapeutic windows.
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PMID:[Recent advances in the diagnosis and treatment of colorectal cancers]. 1209 97

The multiple intestinal neoplasia (Min/+) mouse, which carries a mutant adenomatous polyposis coli (Apc) allele, is a model for human familial colon cancer. Like the human syndrome caused by mutant APC, the Min/+ mouse syndrome shows susceptibility to tumors of other tissues, including the mammary gland. The matrix metalloproteinase (MMP) MMP-7 (matrilysin) gene is transcriptionally induced by signal transduction pathways resulting from loss of APC function, and contributes to the progression of benign and malignant intestinal epithelial cells. Mammary tumors that develop in Min/+ mice express MMP-7. To investigate whether mutant APC and MMP-7 can cooperate in mammary tumorigenesis, we compared N-ethyl-N-nitrosourea (ENU)-enhanced mammary tumor formation in Min/+ mice that were either wild-type or deficient in MMP-7. Min/+ mice lacking MMP-7 demonstrate a 60% reduction in the number of early focal lesions in the mammary gland at early, but not later, timepoints. We conclude that MMP-7 transiently influences early stage mammary tumorigenesis.
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PMID:The influence of matrix metalloproteinase-7 on early mammary tumorigenesis in the multiple intestinal neoplasia mouse. 1520 52

Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.
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PMID:Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing. 1595 48

Activated protein C (APC) is a natural anticoagulant and inhibitor of inflammation that can stimulate keratinocyte wound repair in vitro and promote wound healing in vivo. The signaling mechanisms, however, are unknown and a keratinocyte receptor for APC has not been identified. Here, we show that cultured human keratinocytes from neonatal foreskins express the endothelial protein C receptor (EPCR). EPCR was also strongly expressed by lower epidermal layers of neonatal foreskin as determined by immunohistochemistry. In cultured keratinocytes, EPCR expression was upregulated by the addition of APC and inhibited by tumor necrosis factor-alpha. Addition of APC stimulated cell proliferation, production of matrix metalloproteinase-2, activation of ERK and p38 kinase signaling pathways, and expression of protease-activated receptor (PAR)-1. A monoclonal antibody, RCR252, which blocks APC binding to EPCR, or a blocking antibody to PAR-1, abolished APC's effects on keratinocytes. In summary, this study demonstrates that EPCR, a major receptor of protein C pathway, is expressed by human keratinocytes, and facilitates APC's function on keratinocytes via activation of PAR-1 pathway. Our findings highlight a possible new role for the protein C pathway in skin physiology and help elucidate the mechanisms of action by which APC promotes wound healing.
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PMID:Endothelial protein C receptor and protease-activated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C. 1635

The present study was designed to examine the effects of lifestyle modification on key contributing factors to atherogenesis, including oxidative stress, inflammation, chemotaxis, and cell adhesion. Obese men (n = 31), 15 of whom had metabolic syndrome, were placed on a high-fiber, low-fat diet in a 3-wk residential program where food was provided ad libitum and daily aerobic exercise was performed. In each subject, pre- and postintervention fasting blood was drawn for circulating levels of serum lipids, glucose and insulin (for estimation of insulin sensitivity), oxidative stress-generating enzyme myeloperoxidase and marker 8-isoprostaglandin F2alpha, the inflammatory protein C-reactive protein, soluble ICAM-1 as an indicator of endothelial activation, sP-selectin as a marker of platelet activation, the chemokine macrophage inflammatory protein-1alpha, and total matrix metalloproteinase-9. Using subject sera and human aortic endothelial cell culture systems, we measured VCAM-1 cell surface abundance and monocyte chemotactic protein-1, nitric oxide, superoxide, and hydrogen peroxide production in vitro by fluorometric detection. Also determined in vitro was serum-induced, monocyte adhesion and monocyte chemotactic activity. After 3 wk, significant reductions (P < 0.05) in body mass index, all serum lipids and lipid ratios, fasting glucose, insulin, homeostasis model assessment for insulin resistance, myeloperoxidase, 8-isoprostaglandin F2alpha, C-reactive protein, soluble ICAM-1, soluble P-selectin, macrophage inflammatory protein-1alpha, and matrix metalloproteinase-9 were noted. In vitro, serum-stimulated cellular VCAM-1 expression, monocyte chemotactic protein-1 production, and fluorometric detection of superoxide and hydrogen peroxide production decreased, whereas a concomitant increase in NO production was noted (all P < 0.01). Additionally, both monocyte adhesion (P < 0.05) and MCA (P < 0.01) decreased. Nine of 15 were no longer positive for metabolic syndrome postintervention. Intensive lifestyle modification may ameliorate novel coronary artery disease risk factors in men with metabolic syndrome factors before reversal of obesity.
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PMID:Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors. 1661 61

Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. We show here that APC upregulates the angiogenic promoters, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8) or matrix metalloproteinase-2 (MMP-2) in cultured human skin fibroblasts (HF), keratinocytes (HK) or umbilical vein endothelial cells (HUVE). In the chick embryo chorio-allantoic membrane assay, APC promoted angiogenesis. In a full-thickness rat skin healing model, a single topical application of APC enhanced wound healing compared to saline control. In summary, our results demonstrate that APC promotes cutaneous wound healing at least partly by stimulation of angiogenesis.
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PMID:Activated protein C stimulates expression of angiogenic factors in human skin cells, angiogenesis in the chick embryo and cutaneous wound healing in rodents. 1654 31

Colorectal carcinogenesis is initiated mainly by aberrant activation of the Wnt signaling pathway, caused by mutation of either APC or beta-catenin (CTNNB1) gene. Poly(ADP-ribose) polymerase-1 (PARP-1) is a highly conserved nuclear enzyme, which binds tightly to DNA and plays a role in DNA repair, recombination, proliferation and genomic stability. It has recently been shown that PARP-1 is a novel co-activator of TCF-4/beta-catenin-evoked gene transactivation and may play a role in colorectal carcinogenesis. The aim of this study was to examine the PARP-1 expression and determine whether it is correlated with the expression of beta-catenin and its target genes such as c-myc, cyclin D1 and matrix metalloproteinase (MMP)-7 in the early stage of sporadic colorectal carcinogenesis. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), 91 colorectal tumours, including 65 adenomas and 26 submucosal (pT1) cancers, were analysed for the expression of PARP-1, beta-catenin, c-myc, cyclin D1 and MMP-7. Immunohistochemical analysis of PARP-1 and beta-catenin was also performed. PARP-1 mRNA overexpression was detected in 64 (70.3%) of the 91 tumours. PARP-1 overexpression was significantly correlated with tumour size and histopathology. Overexpression of beta-catenin, c-myc, cyclin D1 and MMP-7 mRNA expression was observed in 39.6%, 78.0%, 83.5% and 72.5% of the 91 tumours, respectively. PARP-1 overexpression was correlated significantly with overexpression of beta-catenin, c-myc, cyclin D1 and MMP-7. Correlation of PARP-1 expression with beta-catenin overexpression was also demonstrated by immunohistochemistry. The results suggest that PARP-1, in conjunction with beta-catenin, c-myc, cyclin D1 and MMP-7, plays an important role in the early stage of colorectal carcinogenesis.
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PMID:Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis. 1680 31


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