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)

The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on matrix metalloproteinases (MMP) and metalloproteinase inhibitors was studied in a variety of human cell lines. Expression of the mammalian collagenase (MMP-1), 72-kD gelatinase/type IV collagenase (MMP-2), stromelysin (MMP-3), 92-kD gelatinase/type IV collagenase (MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) was assessed by zymography and Northern blot analysis. MMP-2 and TIMP-2 activities were refractory to TPA, IL-1 and TNF-alpha treatment in most of the cell lines. In contrast, MMP-3, MMP-9 and TIMP-1 activities were markedly stimulated by TPA in most of the tumor cell lines and human umbilical vein endothelial cells (HUVEC), whereas the fibroblast lines were minimally stimulated or unresponsive to TPA. The MMP-3, MMP-9 and TIMP-1 stimulation in response to IL-1 and TNF-alpha treatment was detected in some of the tumor cell lines and HUVEC. The increase in activity was less marked than in TPA. A breast carcinoma cell line, MDA-MB-231, which did not express MMP-2, had high expression of MMP-3 and MMP-9 which were unaffected by TPA and cytokine treatment. Northern blot analysis of MMP and TIMP mRNA expression reflected the zymogram findings for most of the cell lines. TPA-mediated stimulation of MMP-1 was similar to that of MMP-3 and MMP-9. Exceptions were the fibroblast cell lines which showed either a much more marked mRNA response of MMP-9 to TPA than observed at protein level, or a high constitutive MMP-9 mRNA when MMP-9 activity was not detectable by zymography. TPA-mediated stimulation of MMP-9 and TIMP-1 activity was blocked by staurosporine, an inhibitor of protein kinase C (PKC). A non-PKC-activating phorbol ester, 4 alpha-phorbol-12,13-didecanoate, did not stimulate MMP-9 and TIMP-1 activity. TPA treatment caused the increased expression of c-fos containing AP-1-specific binding activity in selected tumor cell lines. This activity was maximal at 6 h. An association was observed between AP-1 binding activity and increased expression of MMP-1, MMP-3 and MMP-9, which possess TPA-responsive elements (TRE). TPA-sensitive MMPs and TIMP-1 were variably stimulated by biologically relevant cytokines, such as IL-1 and TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. 128 26

Endothelins (ET) are potent vasoconstrictor peptides that also function as mitogens for numerous cell types. Although regulation of second messenger pathways by ET peptides has been extensively investigated, little is known about the pathways of nuclear signaling by which ET controls gene expression. The present experiments investigated whether fos and jun contribute to nuclear signaling and gene regulation by ET isopeptides. ET isopeptides induced a subset of fos and jun mRNAs in mesangial cells, including c-fos, fra-1, c-jun, and JunB. fos and jun mRNAs were induced as members of the immediate-early gene response. Activation of the high affinity ET receptor moderately increased c-fos and fra-1 mRNA, whereas activation of the low affinity receptor markedly induced both fos and jun mRNAs. Thus, different ET receptor subtypes evoke distinct patterns of fos and jun induction. Prominent isopeptide- and cell-specific differences in the magnitude and kinetics of fos and jun expression were observed. Most striking was the marked elevation of c-fos steady-state mRNA and protein by ET-1, as compared with ET-3. In addition, ET-1, but not ET-3, increased transcriptional activity conferred by an AP-1 cis-element and directed collagenase gene expression. These results suggest that differential regulation of fos and jun expression and of AP-1 cis-element activity by ET isopeptides contributes to regulation of gene expression by ET. Furthermore, a role for AP-1 in mitogenic signaling by ET is suggested by the close correlation between AP-1 cis-element activity and cell growth.
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PMID:Differential regulation of fos and jun gene expression and AP-1 cis-element activity by endothelin isopeptides. Possible implications for mitogenic signaling by endothelin. 131 33

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

Typical erosions of articular joint structures in rheumatoid arthritis and in the spontaneous destructive hind-limb arthropathy of autoimmune MRL-lpr/lpr (MRL/l) mice occur predominantly in areas contiguous with proliferating synovial lining cells, suggesting release of proteolytic enzymes from these cells. Synovial lining cells were isolated from arthritic MRL/l mice, and the spontaneous expression of the interstitial procollagenase and its potential transcriptional factors, egr-1 and c-fos, was examined in vitro. The data indicate that basal collagenase RNA expression was stronger in MRL/l cells than in virus-transformed cells. Moreover, elevated RNA levels of the c-fos gene could be detected in the collagenase-expressing synovial lining cells in vitro. In a related immunohistochemical study, collagenase was detected in situ in proliferating synovial lining cells as well as in chondrocytes of the first stage of pathological changes in the MRL/l mouse arthropathy.
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PMID:Expression of collagenase and potential transcriptional factors in the MRL/l mouse arthropathy. 137 11

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

In view of the important role of interstitial collagenase in the pathogenesis of rheumatoid arthritis (RA), we studied the expression of fibroblast-type collagenase in rheumatoid synovium and searched for its potential transcription factors, namely the oncoprotein c-fos and the early-growth-response gene-1 (egr-1), an inducible zinc-finger encoding gene. Elevated levels of RNA sequences complimentary to c-fos and egr-1 cDNA probes could be detected in cytoplasmic extracts of collagenase-expressing synovial fibroblast-like cells when compared to equivalent RNA amounts isolated from control fibroblasts. Utilizing immunocytochemistry, immunoreactivity for c-fos oncoprotein was found in 13 of 19 joint specimens obtained from patients with active RA. These oncoprotein data were positively correlated to the collagenase expression in the same specimens. Moreover, immunohistochemical analysis confirmed the localization of both oncoprotein c-fos and fibroblast-type collagenase within synovial fibroblast-like cells attached to bone erosions.
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PMID:Spontaneous expression of immediately-early response genes c-fos and egr-1 in collagenase-producing rheumatoid synovial fibroblasts. 141 Oct 83

PTH is a potent regulator of osteoblast gene expression, yet the nuclear events that mediate PTH action are poorly understood. We were interested in identifying immediate early genes which may regulate PTH-altered gene expression in the osteoblast. Therefore, we examined the effects of PTH on c-fos and c-jun gene expression in a rat osteoblastic cell line (UMR 106-01). Under control conditions, c-fos and c-jun mRNAs were present at low basal levels. After PTH treatment, c-fos mRNA abundance dramatically increased, with a maximal and transient response at 30 min. PTH also stimulated an increase in c-jun mRNA, but in a biphasic manner, with maximal levels at 30 min and 2 h. These responses were dose dependent, not altered by cotreatment with the protein synthesis inhibitor cycloheximide, and preceded PTH-induced expression of matrix metallo-proteinase-1 mRNA. Nuclear run-on assays demonstrated an increased rate of c-fos and c-jun transcription after PTH exposure. To determine the signal transduction pathways involved, second messenger analogs were tested for their ability to mimic the effects of PTH. 8-Bromo-cAMP and phorbol 12-myristate 13-acetate (PMA) caused increases in the abundance of c-fos and c-jun transcripts. Ionomycin had no effect on the expression of these genes. Pretreatment of the cells with PMA resulted in a decrease in basal c-jun expression, but did not alter the PTH-mediated increase in c-fos, c-jun, or matrix metalloproteinase-1 mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone induces c-fos and c-jun messenger RNA in rat osteoblastic cells. 148 Jan 73

To clarify the contribution of c-fos DNA to bone formation, the effect of constitutive expression of the c-fos gene in collagen synthesis was examined by introducing c-fos DNA into osteoblastic MC3T3-E1 cells. The [3H] proline incorporation into the collagenase digestible protein(CDP) and the percent collagen synthesis were significantly decreased in the c-fos transfectants which constitutively express c-fos mRNA as compared with control transfectants. Transcription of type 1(alpha 1) collagen gene was also specifically decreased in the c-fos transfectants. This indicates that constitutive expression of c-fos DNA interferes with bone formation by inhibiting collagen synthesis in osteoblasts.
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PMID:Constitutive expression of c-fos gene inhibits type 1 collagen synthesis in transfected osteoblasts. 154 Jan 82

In HeLa cells transcription of the c-jun gene is activated strongly and rapidly by ultraviolet (UV) irradiation and, to a somewhat lesser extent, by treatment with phorbol ester tumor promoters. In the same cells UV and phorbol esters only marginally enhance the abundance of RNA transcribed from the jun D gene and from the gene coding for the serum response factor (which in turn acts on the UV and phorbol ester response element of the c-fos gene). In contrast to c-jun, jun B transcription is induced more efficiently by phorbol ester than by UV irradiation, suggesting that the members of the jun family are differently regulated. The promoter of c-jun carries two enhancer elements resembling AP-1 binding sites: the jun1 UV response element (URE-71 TGACATCA -64) and the jun2 URE (-190 TTACCTCA-183). These elements act independently in the UV induced expression of c-jun. In the context of the complete c-jun promoter they seem not to be required for c-jun induction by phorbol esters. When fused to the Herpes simplex thymidine kinase promoter, however, the isolated elements mediate induction by both UV and phorbol esters. UV and phorbol ester treatment of cells increases the binding of transcription factors to both elements. Both elements bind factors different in modification or/and constitution from AP-1, the heterodimeric transcription factor composed of c-Fos and c-Jun that controls the activity of the UV and phorbol ester response element (-72 TGAGTCA-66) of the human collagenase gene.
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PMID:Ultraviolet-radiation induced c-jun gene transcription: two AP-1 like binding sites mediate the response. 156 Dec 39

Normal and osteoarthritic (OA) human articular cartilage chondrocytes, released enzymatically in the presence of 0.5% fetal calf serum, display constitutive expression of early response activating protein (AP-1) genes; c-fos, c-jun and jun-B. Among the late AP-1 responsive genes, total metallothionein (MT) and stromelysin mRNAs were expressed at high levels in both normal and OA chondrocytes, while collagenase and hMT-IIA mRNA levels were elevated only in OA individuals. Despite the common AP-1 sequences present in their promoter regions, the three late genes were differentially expressed.
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PMID:Expression of c-fos, c-jun, jun-B, metallothionein and metalloproteinase genes in human chondrocyte. 163 72


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