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)

Tissue ablation by ultraviolet excimer lasers results in exposure of viable cells to subablative doses of radiation. To understand the potential biological consequences better, we have studied changes in gene expression in cultured human skin fibroblasts exposed to either 193- or 248-nm laser light. Northern blot analyses revealed that both treatments up-regulate a common set of genes, including interstitial collagenase, tissue inhibitor of metalloprotease, metallothionein, and the proto-oncogene c-fos. Dose-response and kinetic studies of collagenase induction by 193-nm radiation showed a maximal effect with 60 J/m2 and at approximately 24 h. The induction was still persistent 96 h later. In addition to the commonly affected genes, known to be activated also by conventional UV light (254 nm) and tumor-promoting phorbol esters, other genes were found to be selectively induced by the 193-nm radiation. The heat-shock hsp70 mRNA, undetectable in controls and in cultures irradiated at 248 nm, was transiently induced 8 h after exposure to 193-nm radiation. Furthermore, a selective up-regulation of collagen type I expression was observed. The results indicate that the 193- and 248-nm radiations by excimer lasers elicit specific and different cellular responses, in addition to an overlapping pathway of gene activation common also to UV radiation by germicidal lamps. The laser-induced genes could serve as molecular markers in evaluating cell injury in situ.
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PMID:Changes in gene expression by 193- and 248-nm excimer laser radiation in cultured human fibroblasts. 133 10

In view of the important role of fibroblast-type collagenase in the pathogenesis of periodontal disease (PD), we investigated the expression of this metalloproteinase in primary cultures of non-stimulated fibroblasts dissected from gingival tissues of patients with generalized moderate and localized severe chronic adult PD. Enhanced hybridization signals for collagenase RNA were observed in 8/8 PD-cases when compared with equivalent RNA amounts extracted from normal fibroblasts. Since both the proto-oncogene c-fos and the "early growth response" gene egr-1 might be involved in the transcriptional regulation of the collagenase gene expression in vivo, we also compared the relative expression of both potential transcriptional factors with collagenase RNA in the same fibroblast cytoplasmic extracts. Hybridization signals indicated elevated RNA amounts for c-fos in 8/8 PD-cases and for egr-1 in 7/8 PD-cases when compared with the cells from non-inflamed tissue. In periodontitis gingival tissue specimens, immunolocalization of collagenase could be confirmed in fibroblasts, macrophages and epithelial cells in situ. Collagenase label was not widely distributed within the tissues, but concentrated at the interface between epithelium and connective tissue. The data provide the first evidence that gingival fibroblasts producing elevated levels of collagenase RNA amounts express also c-fos and egr-1 indicating a crucial role for both genes in cellular proliferation and collagenase expression in gingival and periodontal tissue destruction in vivo.
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PMID:Expression of collagenase and potential transcriptional factors c-fos and egr-1 in periodontal gingival fibroblasts. 138 1

Phosphorylation events are major regulatory mechanisms of signal transduction pathways that control cell growth and differentiation. The potential involvement of serine/threonine-specific phosphoprotein phosphatases in pathways that regulate gene expression was analyzed. By use of okadaic acid, an inhibitor of protein phosphatases 1 (PP-1) and 2A (PP-2A), we present evidence that expression of distinct members of the jun family of genes, c-jun, junB, and junD, are regulated differentially by serine/threonine-specific phosphoprotein phosphatases. Treatment of cells with okadaic acid induces the expression of junB, and to a lesser extent c-jun, but has only a marginal effect on junD expression. This induction involves transcriptional as well as post-transcriptional mechanisms. An analysis of defined elements in different promoters suggests that serine/threonine phosphoprotein phosphatases are involved in the regulation of the c-jun and the collagenase 12-O-tetradecanoyl phorbol-13-acetate (TPA) response element (TRE) as well as the c-fos serum response element (SRE). Since inhibition of PP-1 and PP-2A leads to increased proto-oncogene expression, our results further support the view that certain protein phosphatases might act as negative regulators of growth.
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PMID:Differential regulation of jun family gene expression by the tumor promoter okadaic acid. 166 87

It is proposed that interferon may be an active agent in the treatment of patients with idiopathic myelofibrosis. In this disorder the megakaryocyte cell lineage plays a major role in the deposition of bone marrow collagen by the release of growth promoting factors, including platelet-derived growth factor, which are mitogenic for fibroblast proliferation. Interferon reduces collagen deposition in the bone marrow by suppressing the activity of the proto-oncogene, which is involved in the production of growth factors from abnormal megakaryocytes and platelets. A direct myeloid cytoreductive effect of interferon upon the megakaryocyte proliferation contributes to reducing growth factor activity in the bone marrow. Finally, interferon induces monocytoid differentiation, thereby increasing bone marrow collagenase-activity. Thus, interferon has several actions, which in concert might reduce bone marrow collagen in myelofibrosis.
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PMID:Hypothesis: a possible role for interferon in the treatment of idiopathic myelofibrosis. 322 65

The c-ets1 proto-oncogene encodes a transcription factor that binds a GGAA/T purine rich core DNA sequence. During normal as well as pathological development, the expression of c-ets1 is associated with the occurrence of invasive processes, either in invading cells or in the invaded tissue. Cellular regulatory sequences responsive to the c-Ets1 proteins include a urokinase-type plasminogen activator (u-PA) gene enhancer, the stromelysin-1 and the collagenase-1 gene promoters. Since invasive processes are thought to require the remodeling of the extra-cellular matrix, we investigate the relationships between c-Ets1 and the expression pattern of transcripts encoding these matrix degrading proteases, in embryos and in solid tumors.
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PMID:Does the transcription factor c-ets1 take part in the regulation of angiogenesis and tumor invasion? 753 26

Dimerization plays a pivotal role in modulating the activity of the c-Jun proto-oncogene product. Heterodimerization with activating transcription factor-2 (ATF-2) alters the DNA-binding specificity of c-Jun, allowing its targeting to several cAMP responsive element (CRE)-related sequences, which control a subset of AP-1-responsive genes. Here we show that a c-Jun/ATF-2 heterodimer binds to the AP-1 site (uPA 5'-TRE) essential for the activity of the human urokinase enhancer, conferring on this element several distinctive regulatory properties. The c-Jun/ATF-2 heterodimer was identified by binding competition assays, u.v. cross linking, and monospecific antibodies. In vitro binding studies revealed that the uPA 5'-TRE sequence is recognized by the cyclic AMP-unresponsive ATF-2 factor, but not by the cyclic AMP-inducible CREB. In addition, in vivo studies suggest that ATF-2 can mediate, at the same time, the activation of the c-Jun/ATF-2 site and the repression of the canonical collagenase AP-1 site. We report that heterodimerization with c-Fos does not increase the binding of c-Jun to the uPA 5'-TRE, in contrast to the increased binding at a consensus AP-1 site. Our data further suggest that c-Fos can act as a repressor of the c-Jun/ATF-2 binding site, revealing an important functional difference, with respect to canonical AP-1 elements.
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PMID:Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer. 762 51

The protein encoded by the c-ets1 proto-oncogene is a member of a new family of transcription factors. Cellular regulatory sequences responsive to the c-Ets1 proteins include a urokinase-type plasminogen activator (uPA) gene enhancer, the stromelysin 1 and the collagenase 1 gene promoters. During normal as well as pathological development, the expression of c-ets1 is associated with the occurrence of invasive processes, either in invading cells or in the invaded tissue. Since these invasive processes are thought to require the remodeling of the extracellular matrix, we investigate the relationships between c-Ets1 and the expression patterns of transcripts encoding the matrix-degrading proteases uPA, stromelysin 1 and collagenase 1, in embryos and in solid tumors.
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PMID:Expression of the transcription factor c-Ets1 correlates with the occurrence of invasive processes during normal and pathological development. 765 13

The c-fos proto-oncogene is believed to play a pivotal role in transducing growth factor-mediated signals from the extracellular milieu into the nucleus. c-fos protein dimerizes with c-jun and related proteins and mediates transcription via AP-1 sites. Using c-fos-deficient mice generated through gene knockout techniques, we derived 3T3-type cell lines from primary embryonic fibroblasts. The c-fos-deficient cells grow normally under optimal culture conditions and show only a slight reduction in growth rate in low serum culture compared with control cells. They also express mRNA for most of the Fos and Jun family members at normal levels. The overall levels of AP-1 DNA binding activity are normal and several genes (c-jun, MCP1, metallothionein) known to contain functional AP-1 sites are expressed normally in the c-fos-deficient and control cells. In contrast, mRNA for the metalloproteases stromelysin (MMP-3) and type I collagenase (MMP-1), which are often induced by oncogenes and growth factors and have been implicated in tumor invasiveness, cannot be induced by epidermal growth factor or platelet-derived growth factor in c-fos-deficient cells. Transformation of mutant cells with polyoma middle T oncogene essentially restores wild-type levels of stromelysin expression, while transformation with v-src leads to only a weak induction of the metalloprotease. These results clearly demonstrate that some AP-1-dependent genes require c-fos for full expression while others do not; oncogenes may activate expression of metalloproteases via either fos-dependent or fos-independent mechanisms. These results also imply that c-fos may play an important regulatory role in the invasive behavior of malignant tumors, independent of any role this proto-oncogene might play in cell growth per se.
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PMID:Targeted disruption of the c-fos gene demonstrates c-fos-dependent and -independent pathways for gene expression stimulated by growth factors or oncogenes. 803 3

The proto-oncogene transcription factors Fos and Jun form a heterodimeric complex that binds to DNA and regulates expression of specific target genes. Continuous expression of c-fos causes transformation of cultured fibroblasts and induces osteogenic sarcoma in mice. To investigate the molecular basis of fos-mediated oncogenesis, we developed a conditional cell transformation system in which Fos expression was regulated by isopropyl-beta-D-thiogalactopyranoside (IPTG). Synthesis or repression of Fos in L1-3c-fos cells occurred rapidly, within 30 min, after the removal or addition of IPTG to the culture medium. However, there was a significant delay between the induction of Fos expression and the appearance of morphological transformation. No effect was observed after 12 h of Fos expression, partial transformation was detected after 24 h, and full transformation required approximately 3 days of continuous Fos expression. Similarly, the transformed cell morphology persisted for at least 2 days after repression of Fos, and a normal phenotype was observed only after 3 days. Fos-Jun complexes, capable of binding to AP-1 sequences, were present continuously during the delay in morphological transformation. Furthermore, increased expression of several candidate Fos target genes, including those encoding Fra-1, transin (stromelysin), collagenase, and ornithine decarboxylase, was detected shortly after Fos induction. The induction of morphological transformation was not dependent on the cell cycle, as it occurred in both cycling and noncycling cells. Thus, the Fos-Jun complexes present before L1-3c-fos cells become fully transformed are transcriptionally active. These complexes disappeared, and the Fos target genes were repressed at least 2 days prior to reversion. Our results suggest that cell transformation by Fos requires increased expression of a target gene(s) with a long-lived product(s) that must reach a critical level.
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PMID:Cell transformation by c-fos requires an extended period of expression and is independent of the cell cycle. 819 66

Transgenic mice overexpressing the c-fos proto-oncogene in bone develop osteosarcomas, whereas mice overexpressing c-Jun are normal. In this study, we investigated whether Fos and Jun would cooperate in vivo and whether the threshold levels of Fos are important in osteosarcoma formation. Fos-Jun double-transgenic mice develop osteosarcomas at a higher frequency than single-Fos transgenic mice with no differences in the time of onset of tumor formation. Histological and histochemical analyses indicated that Fos-Jun tumors contained greater quantities of neoplastic bone, were more remodeled, and contained a greater number of multinucleated osteoclast-like cells than tumors isolated from age-matched, single transgenic littermates. In contrast, overexpression of Fos in knockout mice that lack endogenous Fos resulted in a decrease in the number of tumor-bearing mice; osteosarcomas were almost absent in c-fos -/- mice, whereas tumor incidence was reduced to approximately 50% in c-fos +/- mice. Cell lines isolated from Fos-Jun transgenic tumors expressed high levels of both transgenes but significantly lower levels of the jun-related gene junB compared with cells expressing only a c-fos transgene. Osteoblastic marker genes were expressed at varying levels in different cell lines, but expression of interstitial collagenase (matrix metalloproteinase-1) was enhanced in cells derived from Fos-Jun tumors. These studies demonstrate that coexpression of a c-jun transgene can enhance Fos-induced oncogenesis in vivo and suggest that a critical level of Fos is necessary for osteosarcoma development.
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PMID:c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. 852 21


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