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)

Stromelysin gene expression is transcriptionally activated by a number of growth factors (e.g., EGF and PDGF), tumor promoters (e.g., TPA), and oncogenes (e.g., ras, src) through an AP-1-dependent mechanism. TGF-beta repression of stromelysin induction is mediated at the level of transcription by an element located at position -709 in the rat stromelysin promoter referred to as the TGF-beta inhibitory element (TIE). A TIE-binding protein complex is induced by treatment of rat fibroblasts with TGF-beta. This protein complex contains the protooncogene c-fos, and induction of c-fos by TGF-beta is required for the repressive effects of TGF-beta on stromelysin gene expression. Interestingly, c-fos induction is also required for stimulation of stromelysin expression by EGF in rat fibroblasts. Preliminary studies suggest that differential regulation of members of the jun family of early-response genes may explain this apparent paradox and determine whether stromelysin is induced or repressed by growth factors. TGF-beta stimulation therefore initiates a cascade of events that results in a specific pattern of gene expression: the direct stimulation of early-response genes can lead to subsequent induction or repression of other genes. Growth factor regulation of matrix metalloproteinases appears to play a role in embryonic development in the morphogenesis of the murine lung. Treatment of embryonic lungs in organ culture with the growth factors EGF or TGF-alpha results in stimulation of growth and inhibition of branching morphogenesis. A similar inhibition of branching was observed when these lung rudiments were treated with the matrix metalloproteinase collagenase. Most interestingly, the effects of EGF and TGF-alpha can be completely reversed by the tissue inhibitor of metalloproteinases, TIMP. TGF-beta has the opposite effect on growth of murine lung rudiments--growth is inhibited in a dose-dependent manner. This example illustrates a potential role for growth factor regulation of matrix-degrading metalloproteinases in complex developmental processes.
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PMID:Negative regulation of gene expression by TGF-beta. 163 49

The regulation of collagenase gene expression in the human osteosarcoma-derived osteoblastic cell lines MG-63, U2-OS and human fibroblast cell line IMR-90 was investigated by Northern blot analysis. Exposure of quiescent MG-63, U2-OS and IMR-90 cells to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and 10% fetal calf serum (FCS) resulted in the induction of mRNA encoding collagenase. Epidermal growth factor (EGF) induced collagenase mRNA in the IMR-90 cell but not in the MG-63 and U2-OS cells. In the IMR-90 and MG-63 cells, EGF stimulated the transcription of the c-fos and c-jun genes encoding the transcriptional factors which interact directly with the promoter region of the human collagenase gene. Parathyroid hormone and 1,25-dihydroxy-vitamin D3 did not increase the collagenase mRNA level in both osteosarcoma cells. Recombinant interleukin-1 beta (rIL-1 beta) induced collagenase and c-jun but not c-fos mRNA in the MG-63 cell. The induction by rIL-1 beta was blocked by cycloheximide and dexamethasone. Transforming growth factor beta 1 blocked the FCS-induced collagenase gene expression but partially inhibited the rIL-1 beta-induced gene expression in the MG-63 cell. These results suggest that the collagenase activity is regulated not only by post-translational modification but also at the transcriptional level by the various factors in bone.
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PMID:[Regulation of collagenase gene expression in human osteosarcoma-derived osteoblastic cell lines]. 164 84

Three cancer cell lines, IMC-2, IMC-3 and IMC-4, were established from a single tumor of a patient with maxillary cancer. We examined responses to epidermal growth factor (EGF) of these 3 cell lines with regard to cell growth and tumor invasion. The growth rate of IMC-2 in nude mice was markedly faster than that of the IMC-3 and IMC-4 cell lines. Assay for invasion through fibrin gels showed significantly enhanced invasive capacity of IMC-2 cells in response to EGF, but no change for IMC-3 and IMC-4 cells. We examined response to EGF of IMC-2 cells with regard to expression of a growth-related oncogene (c-fos), proteinases and their inhibitors. Expression of c-fos was transiently increased in IMC-2 cells at rates comparable to those seen in the 2 other lines in the presence of EGF. There was no apparent effect of EGF on the expression of urokinase-type plasminogen activator and 72-kDa type-IV collagenase in IMC-2 cells. In contrast, EGF specifically enhanced the expression of plasminogen activator inhibitor-I (PAI-I) and tissue inhibitor of metalloproteinases-I (TIMP-I) in IMC-2 cells. Our data suggest that proteinase inhibitors or other related factors may play an important role in tumor growth and invasion in response to EGF.
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PMID:The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors. 165 98

Chondrocyte-derived metalloproteases have been postulated to play a role in the degradation of articular cartilage during the development of chronic arthritic disorders. TNF alpha (tumor necrosis factor alpha), an inflammatory mediator released by activated macrophages, has been detected in the synovial fluid of patients with rheumatoid diseases. We have found that TNF alpha is a potent stimulator of collagenase and stromelysin mRNA accumulation, collagenase activity, and immunoprecipitable stromelysin in monolayer cultures of adult porcine articular chondrocytes. In contrast EGF (epidermal growth factor), which stimulates collagenase and/or stromelysin synthesis in fibroblast systems, stimulated minimal amounts of these enzymes at both the message and protein levels. Nuclear run-on transcription analysis demonstrated that the TNF alpha-stimulated increase in stromelysin and collagenase message levels was, at least partially, due to increased transcription. Elevated transcription of these genes, in response to TNF alpha, was apparent by at least 2 hours post-stimulation. The degree of c-fos and c-jun stimulation by TNF alpha or EGF did not correlate with the levels of collagenase and stromelysin message stimulated by these factors. EGF stimulated significant accumulation of both c-fos and c-jun mRNAs while only very low amounts of these messages were stimulated by TNF alpha. Our data suggests that TNF alpha may contribute to articular cartilage degradation by stimulating chondrocyte-derived matrix metalloproteases. In addition the regulation of metalloprotease genes in chondrocytes may be different from their regulation in fibroblasts.
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PMID:Tumor necrosis factor alpha and epidermal growth factor regulation of collagenase and stromelysin in adult porcine articular chondrocytes. 165 9

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

Although the incidence of, and deaths due to, malignant melanoma are rising at a rapid rate, few experimental models mimic the highly metastatic properties associated with the pathogenesis of the human disease, making study of the disease difficult. Thus, new human models are required to understand melanoma biology, especially its metastatic properties. Here we describe C8161, a highly invasive and spontaneously metastatic human melanoma cell line, which grows progressively in the subcutis of athymic nude mice with an average doubling time of approximately 6 days. By the time the tumor reaches a diameter of 1 cm, amelanotic metastases in lymph nodes, skin, peritoneal wall, spleen and lungs have formed. By comparing C8161 to variants from other well-characterized human malignant melanomas (A375 and MeWo) with differing metastatic traits, properties presumed to be involved in metastatic propensity were examined. C8161 showed a 2- to 14-fold higher ability to invade reconstituted basement membrane barriers in the MICS and correspondingly high type-IV collagenase mRNA levels and collagenolytic activity, as compared with other melanoma cell lines. Likewise, differential adhesion to immobilized RBM or HUVEC monolayers was observed, but did not correlate to rank orders of malignant properties. Recently, a correlation between surface expression of ICAM-1 and secondary tumor formation by human melanomas has been described in several laboratories. Basal levels of ICAM-1 on C8161, A375 and MeWo human melanomas were compared, but no correlation with metastatic potential was noted. Proto-oncogene expression in C8161 cells was compared with A375P and A375M variants using Northern blot analysis. c-myc expression was 6-fold greater than both A375 variants; c-fos expression was 3.4-fold less than A375P and 1.7-fold less than A375M; c-jun in C8161 cells was 2.5-fold and 2.1-fold greater than expression in A375P and A375M, respectively. Because C8161 is so highly malignant, amenable to experimental manipulation, and its behavior in nude mice mimics the clinical course of malignant melanoma, this cell line will prove valuable for studying properties associated with human melanoma tumor progression.
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PMID:Characterization of a highly invasive and spontaneously metastatic human malignant melanoma cell line. 167 Oct 30

Exposure of mammalian cells to DNA-damaging agents leads to activation of a genetic response known as the UV response. Because several previously identified UV-inducible genes contain AP-1 binding sites within their promoters, we investigated the induction of AP-1 activity by DNA-damaging agents. We found that expression of both c-jun and c-fos, which encode proteins that participate in formation of the AP-1 complex, is rapidly induced by two different DNA-damaging agents: UV and H2O2. Interestingly, the c-jun gene is far more responsive to UV than any other immediate-early gene that was examined, including c-fos. Other jun and fos genes were only marginally affected by UV or H2O2. Furthermore, UV is a much more efficient inducer of c-jun than phorbol esters, the standard inducers of c-jun expression. This preferential response of the c-jun gene is mediated by its 5' control region and requires the TPA response element, suggesting that this element also serves as an early target for the signal transduction pathway elicited by DNA damage. Both UV and H2O2 lead to a long-lasting increase in AP-1 binding activity, suggesting that AP-1 may mediate the induction of other damage-inducible genes such as human collagenase.
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PMID:Rapid and preferential activation of the c-jun gene during the mammalian UV response. 190 48

Fra-2, one of the Fos-related antigens, is promptly expressed after the growth stimulation of fibroblasts, but its induction peak is later than that of c-Fos. In this report, we examined biochemical properties of Fra-2 and compared them with those of two other Fos family proteins, c-Fos and Fra-1. Like c-Fos and Fra-1, Fra-2 formed stable heterodimers with c-Jun, JunB or JunD in vitro and all these complexes had specific DNA-binding activity to AP-1-binding sites (AP-1 sites) or related sequences. When transiently introduced into a mouse embryonic carcinoma cell line, F9, with reporter genes containing the AP-1 site from the collagenase gene, fra-2 plus c-jun suppressed the transactivation by c-jun alone. This property of Fra-2 is in clear contrast to that of c-Fos, which stimulates the transcriptional activity of c-Jun by forming a stable heterodimer. Analysis of chimeric proteins between c-Fos and Fra-2 indicated that this difference is mainly attributable to their C terminal-half regions. Interestingly, this suppressive effect of Fra-2 was not observed in the combination with JunD: fra-2 plus junD, like c-fos plus junD, had higher transcriptional activity than junD alone. Fra-1 showed essentially the same transcriptional regulatory properties as Fra-2. These differential properties greatly expand the potential range of regulatory functions of the Fos family proteins.
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PMID:Difference in transcriptional regulatory function between c-Fos and Fra-2. 194 31

Human collagenase gene expression is regulated transcriptionally and is inducible by various mitogens in many cell types. To investigate the molecular mechanisms of this response, we examined the effects on collagenase gene expression of okadaic acid, a non-12-O-tetradecanoyl-phorbol-13-acetate (TPA)-type tumor promoter, which induces apparent "activation" of protein kinases by inhibition of protein phosphatases. Steady state levels of collagenase mRNA were markedly increased by okadaic acid treatment. We show that the AP-1 consensus sequence in the collagenase promoter is required for the induction of collagenase gene expression by okadaic acid, even though sequences upstream of the AP-1 consensus site have an additive effect. We also examined the regulation by okadaic acid of expression of the components of the AP-1 complex, c-fos and c-jun. c-fos expression is dramatically stimulated by okadaic acid, whereas c-jun expression is stimulated to a lesser extent. Induction of c-fos gene mRNA occurs through a region known to contain multiple regulatory elements. These results suggest that phosphorylation regulates collagenase gene expression mediated by an AP-1 binding site.
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PMID:Regulation of collagenase gene expression by okadaic acid, an inhibitor of protein phosphatases. 196 42

The hypothesis that activation of the signal transduction pathways by environmental stress may lead to genetic instability was tested. Mouse T-lymphoma cells, GRSL13, were treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The induction of transcription of c-fos, fosB, c-jun, junB and collagenase was studied as well as the mutation rate in the progeny of treated cells. It was found that mRNA levels of fosB, junB and collagenase, all known to be involved in the growth factor signal transduction pathway, were enhanced. No transcription of c-fos and c-jun was observed in control and TPA-treated cells. These results suggest that transcription of c-fos is not a prerequisite for the induction of transcription of collagenase. The degree of induction of the signal transduction pathway was dependent on culture conditions of the treated cells, growing cells having less response than stationary cells. The mutation rate was significantly enhanced in the progeny of TPA-treated cells from 4.2 X 10(-7) to 9.8 X 10(-7)/cell/generation. Fluctuation analysis showed that TPA leads to a temporary enhancement of the mutation rate up to the eighth generation after treatment. The enhancement of the mutation rate is less apparent in growing cells than in stationary cells (1.8- and 2.9-fold respectively) which, because the signal transduction pathways are less induced in growing cells than in stationary cells, is in agreement with the hypothesis that induction of the signal transduction pathway leads to genetic instability.
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PMID:Concomitant induction of signal transduction pathways and genetic instability by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 200 94


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