Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excorporal bovine eye has been resuscitated and sustained with an aim of its development as an alternative to whole animal in evaluating acute retinal toxicity of xenobiotics. As indicated by the stable ERG response, such preparation is functionally reactive to photic stimuli over a span of 6-12 h. Moreover, after experienced a 20 min hypoxia the reperfused eyes recovered fully. This functionally responsive preparation was used to evaluate the influence of a highly purified bacterial collagenase (Nucleolysin) on the integrity of vitreoretinal junction. Nucleolysin at concentrations between 120-600 U/ml was injected into the posterior chamber for 15 min. Retinal surfaces were irrigated and eyes were perfusion fixed with glutaraldehyde. Ultrastructural analysis indicated that thinning of the internal limiting membrane occurred when enzyme exceeded 480 U. At 600 U concentration, the principle subcellular change involved the end-foot region of the Muller cells. These studies suggest that the isolated, perfused bovine eye is a suitable model for evaluating acute retinal toxicity of xenobiotics.
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PMID:Isolated, perfused bovine eye a model for acute retinal toxicity screening. 256 68

The transcription factors Fos, Jun, and Ets regulate the expression of human stromelysin-1 and collagenase-1 genes. Recently, we found that ERG, an Ets family member, activates collagenase-1 gene but not stromelysin-1 by physically interacting with c-Fos/c-Jun. Interestingly, ERG binds to stromelysin-1 promoter and represses its activation by ETS2. Here, to investigate the molecular mechanism of this regulation, we have used an in vitro protein-protein interaction assay and studied the transcription factor interactions of ETS2. We found that ETS2 could weakly associate with in vitro synthesized ETS1, c-Fos, and c-Jun and strongly with c-Fos/c-Jun complex and ERG via several distinct ETS2 domains including the C-terminal region that contains the DNA-binding domain. Strikingly, these interactions were stabilized in vitro by DNA as they were inhibited by ethidium bromide. Both the N-terminal region, comprising the transactivation domain, and the C-terminal region of ETS2 associated with ERG and, interestingly, the interaction of ERG through the transactivation domain of ETS2 was DNA-independent. The DNA-dependent interaction of ETS2 with c-Fos/c-Jun was enhanced by specific DNA fragments requiring two Ets-binding sites of the stromelysin-1 promoter. Using the two hybrid system, we also demonstrated that ETS2 interacts with c-Jun or ERG in vivo.
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PMID:The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner. 933 86

Ewing sarcoma is a malignant bone and soft tissue tumor of children and young adults, which is known to be highly aggressive and invasive. It expresses specific chimeric genes (EWS-FLI-1, EWS-ERG, EWS-ETV1, and EWS-E1AF), the 3' portions of which are all members of the ETS family. ETS-related proteins, such as FLI-1, ERG, and E1AF, transactivate the promoters of matrix metalloproteinase (MMP) genes, which play important roles in the processes of invasion and metastasis. Therefore, we hypothesize that the Ewing sarcoma-specific chimeric genes also transactivate the MMP genes, contributing to the tumor's invasiveness and propensity for metastasis. To verify this hypothesis, we investigated the expression of MMPs in eight Ewing sarcoma cell lines. Surprisingly, MMP-1 and MMP-3 were not expressed at all in any of the cell lines. MMP-9 was expressed in four out of the eight cell lines, and MMP-2 and MT1-MMP in all of the cell lines. Ewing sarcoma-specific chimeric genes have been shown to transactivate the promoter of the MMP-1 gene by the reporter assay, and bind to the putative recognition sites in the MMP regulatory elements by the gel shift assay. However, an in vivo formaldehyde cross-linking study revealed that the chimeric protein did not bind to the predicted ETS recognition sites in the regulatory elements of the MMPs. These results indicate that the absence of the MMP expression in the tumor cells is at least in part due to the loss of accessibility of the ETS recognition sites in the regulatory elements of the MMP genes. Therefore, we should be careful before theorizing simply that a putative binding site is essential for the transcription of critical genes, since the binding of this fusion protein was found to be modulated in tumor cells in this study.
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PMID:Lack of matrix metalloproteinase (MMP)-1 and -3 expression in Ewing sarcoma may be due to loss of accessibility of the MMP regulatory element to the specific fusion protein in vivo. 1205 64

Histone deacetylase inhibitors (HDACi) represent a promising new class of anticancer agents. In the current investigation, we examined the activity of the HDACi belinostat in preclinical models of prostate cancer. In vitro proliferation assays demonstrated that belinostat potently inhibited the growth of prostate cancer cell lines (IC(50) < 1.0 microM) and was cytotoxic to these cells. Washout experiments indicated that exposure to belinostat for relatively short periods of time (<12 hr) induced suboptimal growth-inhibition and that cells exposed to 1.0 microM belinostat for 48 hr retained the capacity for regrowth following drug withdrawal, while cells exposed to 4.0 microM belinostat were irreversibly growth-inhibited. Cell cycle analyses demonstrated that belinostat induced G2/M arrest and increased the percentage of cells with subG1 DNA content, thus confirming the growth-inhibitory and cytotoxic effects of this compound. Normal prostate epithelial cells were generally less susceptible to the effects of belinostat than were prostate cancer cells. In an orthotopic prostate cancer tumor model, belinostat inhibited tumor growth by up to 43%. Moreover, metastatic lung lesions were present in 47% of vehicle-treated animals but in none of the animals administered belinostat. Consistent with its observed antimetastatic activity, belinostat inhibited the migration of prostate tumor cells and increased the production of tissue inhibitor of metalloproteinase-1 (TIMP-1) by these cells, the latter effect being replicated by siRNA knockdown of HDAC3. Belinostat also increased the expression of p21 and decreased the expression of potentially oncogenic proteins (mutant p53 and ERG). These results support the clinical evaluation of belinostat for the treatment of prostate cancer.
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PMID:Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. 1894 5

In the process of angiogenesis, working of many transcription factors at the proper time is important to activate angiogenesis-related genes such as cytokine, matrix protease and adhesion molecules. In this study, we searched for Ets transcription factors and matrix metalloproteinases (MMPs) that respond to VEGF in endothelial cells. We first analyzed the expression of 27 human Ets factors and 15 human MMPs in VEGF-treated human umbilical vein endothelial cells (HUVEC) using quantitative RT-PCR. The most abundant Ets factors in HUVEC were ETS-1, Fli-1, ERP/NET/ELK3, and ERG. MMP-1, -2, -10, -11, -14, -15, and -16 were also detected in HUVEC. We also found that ETV-1, Fli-1, ERG, MMP-1, -3, -7, -8, -9, -10, -13, and -19 expression is up-regulated more than 1.5-fold in HUVEC after 2 h of VEGF treatment. In addition, the expression of MMP-10 induced by VEGF remained twofold higher for 24 h compared to non-treated control. The elevation of MMP10 mRNA and protein levels was confirmed to be both time- and dosage-dependent. In addition, MMP-10 transcription was mediated by Ets-1 but not ERP/NET/ELK3. The inhibition of PI3K and MAPK inhibited VEGF-induced MMP-10 expression. Furthermore, transfection of MMP-10 siRNA inhibited VEGF-induced migration and tube formation in HUVEC, and it also inhibited vessel formation in matrigel plugs in vivo. In conclusion, our study demonstrated induction of MMP-10 by VEGF in HUVEC and supports an angiogenic role for MMP-10 in response to VEGF stimulation in vitro and in vivo.
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PMID:Expression profiling of ETS and MMP factors in VEGF-activated endothelial cells: role of MMP-10 in VEGF-induced angiogenesis. 2043 69