Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) plays a major role in regulating connective tissue deposition by controlling both extracellular matrix production and degradation. In this study, we show that TGF-beta transcriptionally represses both basal and tumor necrosis factor-alpha-induced collagenase (matrix metalloprotease-1) gene expression in dermal fibroblasts in culture, whereas it activates its expression in epidermal keratinocytes. We demonstrate that this differential effect of TGF-beta on collagenase gene expression is due to a cell type-specific induction of distinct oncogenes of the Jun family, which participate in the formation of AP-1 complexes with different trans-activating properties. Specifically, our data indicate that the inhibitory effect of TGF-beta in fibroblasts is likely to be mediated by jun-B, based on the following observations: (a) TGF-beta induces high levels of jun-B expression and (b) over-expression of jun-B mimics TGF-beta effect in inhibiting basal collagenase promoter activity and preventing tumor necrosis factor-alpha-induced trans-activation of the collagenase promoter. In contrast, TGF-beta induction of collagenase gene expression in keratinocytes is preceded by transient elevation of c-jun proto-oncogene expression. Over-expression of c-jun leads to trans-activation of the collagenase promoter in both cell types, suggesting that c-jun is a ubiquitous inducer of collagenase gene expression. Transfection of keratinocytes with an antisense c-jun construct together with a collagenase promoter/reporter gene construct inhibits basal and TGF-beta-induced up-regulation of the collagenase promoter activity, implying that c-jun mediates TGF-beta effect in this cell type. Collectively, our data suggest differential signaling pathways for TGF-beta in dermal fibroblasts and epidermal keratinocytes, leading to cell type-specific induction of two AP-1 components with opposite transcriptional activities.
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PMID:Cell-specific induction of distinct oncogenes of the Jun family is responsible for differential regulation of collagenase gene expression by transforming growth factor-beta in fibroblasts and keratinocytes. 863 9

Patients with xeroderma pigmentosum (XP), a DNA repair disorder, run a large risk of developing skin cancer in sun-exposed areas. Cancer proneness in these patients correlates with a mammalian SOS-like response, "enhanced reactivation (ER) of viruses." Here, we report that radiation-induced activation of the ornithine decarboxylase (ODC) gene, a putative proto-oncogene, is required for this response. Various diploid fibroblast strains derived from a non-cancer-prone subclass of XP patients, which lack the ER response, were irradiated with 2 J/m2 and assessed for gene induction. In these fibroblasts, an absence of induction of ODC by UV-C was observed at the levels of mRNA, protein, and enzyme activity. This lack of induction is quite specific because the genes for fos and collagenase were induced as they were in normal XP cells. The apparent linkage between non-cancer proneness and a lack of ER and ODC induction was confirmed in a fibroblast strain derived from a patient with another DNA repair disorder, trichothiodystrophy, which does not lead to cancer proneness: in these cells, no induction of the ER response nor of ODC occurs after UV-C irradiation. Repair deficiency, however, is not essential because the simultaneous lack of ODC and ER induction after 10 J/m2 UV-C was found in at least one repair-proficient fibroblast. Next, a specific inhibitor of ODC, difluoromethylornithine, at a dose of 10 mM, completely blocked the ER response in cultured normal skin fibroblasts, suggesting that the ODC enzyme is in fact essential for the ER response. Difluoromethylornithine, although it did not affect other processes such as DNA repair, leads to a block in the cell division cycle at the G1-S transition. Interestingly, other blockers of this transition, wortmannin (500 nM) and mimosine (100 mM), also decreased the ER response. Finally, the ER and ODC responses also seem to be linked after treatment with X-irradiation (3 Gy), suggesting that both are part of a general response to DNA damage, at least in human skin fibroblasts. Apart from the abnormal ER and ODC responses, fibroblasts from non-tumor-prone XP patients react in the same way to radiation as do fibroblasts from tumor-prone XP patients with respect to other parameters. Thus, the lack of ODC induction after radiation may help to protect XP patients against skin carcinogenesis.
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PMID:A lack of radiation-induced ornithine decarboxylase activity prevents enhanced reactivation of herpes simplex virus and is linked to non-cancer proneness in xeroderma pigmentosum patients. 933 Nov 2

The vertebrate Wnt-1 proto-oncogene is expressed transiently in embryonic brain and functions in the development of the central nervous system and neural crest. The role of Wnt-1 in neural crest development appears to be to increase the number of certain progenitor cells by preventing their premature differentiation. To study the mechanism by which this transient Wnt-1 expression inhibits differentiation we have constructed PC12 pheochromocytoma cells in which Wnt-1 expression levels were controlled by use of a tetracycline-responsive transactivator. Induction of Wnt-1 expression by tetracycline withdrawal was followed by activation of the Wnt-1 signalling pathway as shown by activation of the Lef-1/Tcf transcription factor. Wnt-1 expression by these cells resulted in reversible inhibition of NGF-induced neurite outgrowth, but it did not adversely affect the maintenance of previously formed NGF-induced neurites. Wnt-1 expression also partially blocked the ability of NGF to decrease the rate of cell multiplication. Wnt-1 decreased the NGF-induced expression of the late-response gene SCG10 but not of the immediate early genes, fos, Nur77 and UPAR (urokinase-type plasminogen activator receptor) nor of the late-response genes GAP-43 and collagenase. The Wnt-1 expressing PC12 cells multiplied at a greater rate when they expressed Wnt-1 than they did in the absence of Wnt-1 expression, a result that is consistent with the proposal that Wnt-1 may also act as a mitogen.
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PMID:Wnt-1 inhibits nerve growth factor-induced differentiation of PC12 cells by preventing the induction of some but not all late-response genes. 1083 18

The ets-1 proto-oncogene is a member of the transcriptional factor family and was identified by homology to the v-ets oncogene. It was recently demonstrated that Ets-1 protein interacts with the promoter region of the genes coding for proteinases, including matrix metalloproteinase-1 (MMP-1), MMP-3, and urokinase-type plasminogen activator, suggesting that it may play an important role in the regulation of MMP expression. The role of the ets-1 proto-oncogene in advanced glomerular diseases, where extracellular matrix accumulation is observed, remains undefined. In this study, the expression of ets-1 mRNA and protein during the progression of rat crescentic glomerulonephritis was examined using immunohistochemical analysis, reverse transcription-PCR, and in situ hybridization. Passive accelerated anti-glomerular basement membrane-induced nephritis was induced in rats by intravenous injection of nephrotoxic serum. Rats were euthanized on day 7, 14, 21, 28, or 42. Immunohistochemical analysis demonstrated significant upregulation of Ets-1 protein expression in glomeruli and the interstitium in anti-glomerular basement membrane-induced nephritis. The numbers of Ets-1-positive cells were increased 8.8-fold on day 21 in glomeruli (1.2+/-0.1 cells/glomerular cross-section, P<0.001) and sixfold on day 28 in the interstitium (21+/-1.3 cells/mm(2), P<0.001), compared with control samples. Ets-1 protein was predominantly localized in glomerular epithelial cells, endothelial cells, and interstitial cells. A small number of vascular endothelial cells, macrophages, and T cells also expressed Ets-1 protein. MMP-3 deposition was upregulated and positive cells in the interstitium often coexpressed Ets-1, whereas only a few glomerular cells were positive for both MMP-3 and Ets-1 protein. The expression of ets-1 mRNA was also markedly increased in diseased kidneys. The distribution of ets-1 mRNA was similar to that of the protein. These results indicate that overexpression of the ets-1 proto-oncogene by phenotypically altered renal cells might be associated with the pathogenesis of rat crescentic glomerulonephritis.
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PMID:Renal expression of the Ets-1 proto-oncogene during progression of rat crescentic glomerulonephritis. 1109 47

Collagenolytic enzymes control cell migration through connective tissues. They appear to be of crucial importance for angiogenesis, tumor metastasis or wound repair. A well-documented stimulation pathway of collagenase secretion, either by natural (cytokines) or synthetic (phorbol esters) molecules, acts through activation of the proto-oncogene activating protein 1 (AP-1). Interestingly, this nuclear factor enhances its own synthesis. It also modulates the activity of different genes, including the one coding for 92 kDa gelatinase. We developed a mathematical model to describe this pathway. It led us to conjecture the existence of an hysteresis cycle for PMA-stimulated collagenase secretion, which was experimentally demonstrated later in MDBK cells in culture. We also modified our model to simulate the behavior of tumoral cells expressing AP-1. In this case, the system becomes highly unstable and, once stimulated, cannot be brought back to rest. This approach paved the way for the understanding and the control of mammalian cell processes, connective tissue maintenance or metastasis dissemination.
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PMID:Control of 92 kDa collagenase secretion in mammalian cells by modulation of AP-1 activity: an experimentally based theoretical study. 1123 66

Several members of the ETS family of transcription factors contribute to tumorigenesis in many different tissues, including breast epithelium. The ESX gene is an epithelial-specific Ets member that is particularly relevant to breast cancer. ESX is amplified in early breast cancers, it is overexpressed in human breast ductal carcinoma in situ, and there may be a positive feedback loop between the HER2/neu proto-oncogene and ESX. Despite this progress in our understanding of ESX, its ability to regulate tumor-related gene expression and to modulate breast cell survival, remain unknown. Here we show that HA-ESX stimulates the collagenase and HER2/neu promoters, but fails to activate an intact stromelysin promoter. However, HA-ESX activates, in a dose-dependent manner, a heterologous promoter containing eight copies of the Ets binding site derived from the stromelysin gene (p8Xpal-CAT). Analysis of the ability of constructs encoding nine Ets family members to activate the HER2/neu promoter revealed three patterns of gene activation: (1) no effect or repressed promoter activity (Elk-1 and NET); (2) intermediate activity (ER81, GABP, ESX, and HA-Ets-2); and, (3) maximal activity (Ets-1, VP-16-Ets-1, and EHF). Based on these observations, we also determined whether ESX is capable of conferring a survival phenotype upon immortalized, but nontransformed and ESX negative MCF-12A human breast cells. Using a colony formation assay, we found that HA-ESX and HA-Ets-2, mediated MCF-12A cell survival rates that approached those generated by oncogenic V12 Ras, whereas empty vector resulted in negligible colony formation. By contrast, in immortalized and transformed T47D breast cancer cells, which express both HER2/neu and ESX, we found that antisense and dominant-negative HA-ESX inhibited T47D colony formation, whereas control vector allowed formation of many colonies. These results are significant because they show that HA-ESX is able to differentially activate several malignancy-associated gene promoters, and that ESX expression is required for cellular survival of nontransformed MCF-12A and transformed T47D human mammary cells.
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PMID:The epithelial-specific ETS transcription factor ESX/ESE-1/Elf-3 modulates breast cancer-associated gene expression. 1271 34

The constitutive activation of signal transducer and activator of transcription 3 (Stat3) is frequently detected in breast cancer tissues and cell lines. Stat3 has been classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumor formation in nude mice. Since Stat3 may play an important role in breast cancer, it is of interest to investigate the expression of phosphorylated Stat3, an activated form of Stat3, and its downstream mediators specifically in breast cancer, and to explore the possible mechanisms of Stat3 signaling pathway in oncogenesis of breast cancer. We analyzed Stat3 phosphorylation and expression of Stat3-regulated genes in breast cancer cell lines as well as invasive breast cancer tissues using tissue microarray slides. Our results showed that elevated levels of phosphorylation of Stat3 protein (Tyr705) were detected in 48 out of total 136 invasive breast tumors (35%) whereas normal breast tissues express much lower levels of Stat3 phosphorylation. The increased levels of Stat3 phosphorylation were associated with the metastasis in regional lymph nodes (P=0.042) and the expression of progesterone receptor (P=0.028) but not with distant metastasis, nor the expression of estrogen receptor. Our results also indicate that elevated levels of Stat3 phosphorylation were significantly associated with increased expression of potential downstream targets of Stat3 which include apoptosis inhibitors (Survivin, Mcl-1, HSP27, Adrenomedullin, and Bcl-xL), cell-cycle regulators (c-Fos, MEK5, and c-Myc), and inducer of tumor angiogenesis (VEGF, COX-2, MMP-2, MMP-10, and MMP-1) in invasive breast cancer tissues. Therefore, our findings suggest that constitutive Stat3 signaling may be one of the key upstream regulators to induce these downstream proteins, which may play important roles in Stat3-mediated oncogenesis in breast cancer.
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PMID:Evaluation of potential Stat3-regulated genes in human breast cancer. 1608 Oct 48

Most advanced glomerular diseases are characterized by abnormal extracellular matrix (ECM) accumulation in the glomeruli, and matrix metalloproteinases (MMPs) play a pivotal role in ECM remodeling in various glomerular diseases. The proto-oncogene, ets-1, is a transcription factor regulating the expression of various matrix proteinases, including MMP-1, MMP-3, and MMP-9. The goal of the present study was to characterize the role of Ets-1 in the progression of glomerular diseases. Overexpression of Ets-1 in cultured mesangial cells prevented transforming growth factor (TGF)-beta-induced inhibition of DNA-binding activity and TGF-beta-induced type I collagen production. In addition, exogenous Ets-1 abolished TGF-beta-induced collagen gel contraction. The in vivo transfection of the ets-1 gene into nephritic kidney resulted in the increases in glomerular MMP-1, MMP-3, and MMP-9 mRNA, decreases in mesangial ECM deposition, and attenuation of fibronectin extradomain A (EDA) and type I collagen expression. In contrast, knockdown of Ets-1 in glomeruli resulted in severe ECM deposition in diseased glomeruli. In conclusion, Ets-1 promotes degradation of ECM proteins and is critical for integral glomerular reorganization.
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PMID:Transcription factor Ets-1 is essential for mesangial matrix remodeling. 1673 37

c-Met proto-oncogene, which is a receptor of ligand hepatocyte growth factor (HGF), has been associated with cancer cell invasion. There have been no reports on the relationship between the expression of c-Met and tumor invasion and metastasis in small (T(1-2)) squamous cell carcinoma of the oral tongue (SCCOT). We analyzed the relationship between c-Met expression and tumor invasion depth and lymph node metastasis in 71 surgically treated patients with small SCCOT using immunohistochemistry. Furthermore, we investigated the associations between the c-Met expression status and patient survival. In addition, we explored whether overexpression of c-Met enhances tumor growth and invasion of tongue cancer cells in vitro and in vivo. Positive immunohistochemical staining of c-Met was observed in 39 (55%) samples. Presence of neck metastasis, and >4mm depth of tumor invasion, strongly correlated with c-Met expression in small SCCOT both by the univariate and multivariate analysis (p<.05). The survival rates with c-Met expression were significantly shorter than for patients without c-Met expression (p<.05). Constitutive activation of c-Met enhanced migration and invasion of tongue cancer cells in vitro through the expressions of matrix metalloproteinase-1, -2, and -9, and promoted tongue cancer cell growth in vitro and in vivo. The results support the association of c-Met with the invasiveness and metastasis of small SCCOT.
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PMID:Overexpression of c-Met promotes invasion and metastasis of small oral tongue carcinoma. 2270 61

The phenomenon of vasculogenic mimicry in melanoma has been recently described to be an important factor relating to melanoma progression. Large scale gene expression profiling by real-time quantitative RT-QPCR of a panel of 40 normal tissues and 54 cancer cell lines revealed that two genetically related melanoma cell lines, one derived from a primary lesion Hs.688(A) and one derived from a lymph node metastasis Hs.688(B), displayed a unique expression pattern when compared to other cancer cell lines and tissue samples in the panel. Quantitative-RT-PCR data indicated that these melanoma cells expressed a number of activated endothelial cell-associated genes such as tissue inhibitors of matrix metalloproteinases TIMP-2, matrix metalloproteinase (MMP-1, MMP-2), thrombospondin 1 (TSP1), proto-oncogene c-MET and vascular endothelial growth factor (VEGF). To examine the gene expression profile of these unique melanoma cells in greater depth, cDNA libraries were made from isolated microsome complexes to enrich those transcripts that were destined to be translated into cell surface or secreted proteins. High throughput sequencing analysis revealed that this library contained over 7000 cDNAs and was enriched by over 80% of secreted or membrane-bound proteins. The presence in the cDNA library of genes such as acetyl LDL receptor, tumor endothelial markers-1, 5 and 8 (TEMs), flow-induced endothelial G protein coupled receptor-1 and VEGF-related protein (VRP), all of which are known to be expressed uniquely by endothelial cells, supported the hypothesis that Hs.688(A) and Hs.688(B) cells were mimicking an activated vascular phenotype. Ultimately the goal is to investigate the biological roles of endothelial cell-associated genes in the behavior of Hs.688(A) and Hs.688 (B) melanoma cells.
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PMID:The Melanoma Vascular Mimicry Phenotype Defined in Gene Expression and Microsome Sequencing Analysis. 3139 28


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