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 Jun protein binds DNA and regulates transcription as a component of the AP-1 transcription factor complex. In its oncogenic form, Jun can transform cells in culture and cause tumors in animals. Both trans-activation and transformation require several functional domains of Jun, including an amino-terminal trans-activation domain. In this study, properties of Jun required for trans-activation and transformation were explored by replacing the trans-activation domains of c-Jun and its oncogenic counterpart, v-Jun, with the constitutively active trans-activation domain from the herpes simplex virus VP16 protein. The VP16-v-Jun chimera retained similar oncogenic properties to its parent, v-Jun. The VP16-c-Jun chimera, however, was considerably more oncogenic than c-Jun. Substitutions of a phenylalanine in the VP16 domain of the VP16-c-Jun chimera diminished or abolished transformation. Each of the chimeras bound to the AP-1 consensus recognition sequence from the collagenase promoter or from the human T-cell leukemia virus type I long terminal repeat in vitro. None of the VP16-Jun chimeras efficiently stimulated transcription from the collagenase promoter or an artificial promoter containing the human T-cell leukemia virus type I element in vivo. These results demonstrate that the Jun trans-activation domain can be replaced by a heterologous trans-activation domain with retention of oncogenic activity. However, this oncogenic activity is not reflected in the trans-activating properties of the chimeras.
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PMID:Chimeras of herpes simplex viral VP16 and jun are oncogenic. 824 Oct 24

The bone marrow stroma, represented in long-term marrow culture by cells of the adherent layer, is composed of a heterogenous mixture of macrophages and mesenchymal cells, including fibroblasts, endothelial cells and adipocytes, in association with a proteoglycan matrix. This matrix, which is synthesized by the stroma, is capable of binding hematopoietic growth factors, and likely plays a major role in hematopoietic regulation. Clonally-derived non-transformed bone marrow stromal cells, propagated in the presence of basic fibroblast growth factor, were studied for expression of collagenase, an enzyme whose substrate, collagen, is a major component of the extracellular matrix. Expression of steady-state collagenase mRNA was undetectable in both unstimulated dermal fibroblasts and non-transformed marrow stromal cells. However, stimulation with interleukin 1 alpha (10 U/ml) for 24 h resulted in marked accumulation of collagenase mRNA in dermal fibroblast cells, yet failed to elicit a similar response in bone marrow stromal cells. Both marrow stromal cells and dermal fibroblasts constitutively expressed transcripts of collagen I, and rhIL-1 alpha upregulated transcripts of interleukin 6 in both these cells as well. Although similar in morphology, these data indicate that bone marrow stromal cells differ from fibroblasts in their response to IL-1. In the marrow microenvironment, where IL-1 may be secreted by a variety of cell types, such suppression of collagenase expression may serve to prevent unwanted mobilization of collagen from the glycoprotein matrix by marrow stromal cells.
Leukemia 1994 Feb
PMID:Differential expression of collagenase by human fibroblasts and bone marrow stromal cells. 830 54

Many studies show a strong association between diabetes mellitus and risk for periodontal disease destruction. Patients with non-insulin-dependent diabetes mellitus have an increased risk of developing destructive periodontal disease. Under similar plaque conditions, adult patients with long-term, poorly controlled diabetes mellitus have more attachment and bone loss than controlled diabetic patients. Most patients with diabetes mellitus respond to conventional periodontal treatment, but in some cases the response may be related to the degree of metabolic control. Periodontal treatment may have a beneficial effect on the metabolic status of poorly controlled diabetes. Tetracycline therapy may be an effective adjunctive treatment in the management of periodontal disease in diabetic patients by blocking collagenase-dependent periodontal tissue destruction. Pyostomatitis vegetans is frequently associated with chronic inflammatory bowel disease and is a marker for the disease. Plaque control with chlorhexidine gluconate should be preceded by mechanical removal of plaque and calculus in patients with leukemia undergoing chemotherapy. A distinct gingival lesion is associated with Wegener's granulomatosis, a potentially fatal disease that, if detected early, has a favorable prognosis.
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PMID:Periodontal manifestations of systemic disease and management of patients with systemic disease. 840 43

The erythroid-potentiating activity (EPA) of the tissue inhibitor of metalloproteinase-1 (TIMP-1) was re-examined using ELM-I-1-3, a mouse erythroleukemia cell line, which responded well to erythropoietin. Depletion of pre-existing TIMP-1 from fetal calf serum in culture medium using monoclonal antibody suppressed erythropoietin-induced differentiation as measured by the induction of hemoglobin, commitment assay and globin mRNAs. The removal of TIMP-1 also suppressed the proliferation of ELM-I-1-3 as measured by cell number and de novo DNA synthesis. These changes were reversed by the addition of purified TIMP-1 to the culture medium. Anti-TIMP-1 antibody also blocked both hexamethylene bisacetamide (HMBA)-induced erythroid differentiation and the proliferation of both ELM-I-1-3 and Friend erythroleukemia cells. Considering previous reports analyzing the chemical induction of Friend mouse erythroleukemia cell differentiation, our results suggest that erythropoietin- or HMBA-induced erythroid differentiation might also be coupled with cell proliferation. Our 3H thymidine-uptake experiment shows that TIMP-1 removal was also effective in the inhibition of cell growth of various other cell lines in addition to erythroleukemia cell lines. These results suggest that EPA action of TIMP-1 on erythroid leukemia cell lines is closely related to its activity to promote the cell growth of various cell lines and cells including erythroleukemia cell lines.
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PMID:Erythroid potentiating activity of tissue inhibitor of metalloproteinases on the differentiation of erythropoietin-responsive mouse erythroleukemia cell line, ELM-I-1-3, is closely related to its cell growth potentiating activity. 841 53

JEM-1 is a novel gene whose mRNA expression in acute promyelocytic leukemia (APL) is induced by retinoid treatments. The gene product, a 45 kDa basic nuclear factor containing a leucine repeat, was transiently expressed in HeLa or COS-7 cells and immunocharacterized within the nuclei in fine punctuated structures which increase in size after cell transfection. Jem-1 was not expressed in the nucleoli. Experimental deletion of peptide domains of Jem-1 (JemDelta331-400 and Jem DeltaL179-206) showed that its C-terminal sequence (Thr331 --> Leu400) is required for nuclear translocation, while the leucine repeat domain (Arg179 --> Glu206) has no influence on subcellular localization. The Jem-1 protein was not detected in the PML-containing nuclear bodies or in speckled structures containing the splicing factor SC-35. In contrast it was localized in the nucleus in structures containing activator protein-1 (AP-1). DNA mobility shift assays showed that the in vitro translated Jem protein interacts neither with the DNA binding site of AP-1, nor directly with in vitro co-translated c-Fos or/and c-Jun proteins bound to this specific sequence. Interestingly, Jem-1-1 increased substantially the transcriptional activity of c-Jun (three-fold) and more strongly that of ectopically co-expressed c-Fos and c-Jun (five- to six-fold), as measured by a CAT reporter gene driven by a heterologous promoter containing the AP-1 binding site of the human collagenase gene. These synergistic effects were strongly Jem-1 dose-dependent. However, Jem-1 alone showed no activity on the collagenase promoter. A deletion of the leucine repeat of Jem-1 (Arg179 --> Glu206) did not diminish the enhancer capacity of Jem-1 on AP-1 activity. In contrast, the enhanced AP-1 activity was abrogated when Jem-1 was deleted of its C-terminus (Thr331 --> Leu400). We conclude that the 45 kDa nuclear product of the JEM-1 gene has features of a novel transcription cofactor, which is enhancing AP-1 activity without directly interacting with c-Jun or c-Fos proteins. Possible implications of these findings for APL cell maturation are discussed.
Leukemia 1999 Dec
PMID:JEM-1, a novel nuclear co-factor: localisation and functional interaction with AP-1. 1060 19

Angiostatic substance TNP-470 displayed moderate cytotoxicity towards human leukemia HL-60, HL-60/ADR, HL-60/VCR and myeloma ARH77 cell lines with IC50 in the range 5-10 microM of concentrations and slightly higher IC50 for myeloma cell line U266. IC50 for ovarian CH-1, A2780 and A2780/ADR cell lines was in the range 10-15 microM with the exception of platinum-resistant SKOV3 cell line (more than 40 microM ). The IC50 values for MDA-MB-231 and MCF-7 breast carcinoma cell lines were 15 and 25 microM, respectively. In human hemopoietic neoplastic cell lines examined, TNP-470 induced the appearance of subpopulation with sub-G0 DNA content, suggesting the apoptosis-inducing potential of TNP-470 in these cells. No TNP-470-induced drug uptake modulation in drug-resistant leukemia cell line HL-60/VCR was observed. TNP-470 induced accumulation of cells in G0/G1 phase of cell cycle. There was no TNP-470-induced inhibition of MMP collagenase activity or MMP (MMP2 and MMP9) production in the human fibrosarcoma cells HT 1080 in vitro.
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PMID:Angiogenesis inhibitor TNP-470: cytotoxic effects on human neoplastic cell lines. 1066 43

Infiltrative capacity was found to distinguish separate T leukemia cell lines. Of seven T-cell lines four exhibited capacity to infiltrate Matrigel. Analysis of infiltration was performed at the single-cell level throughout the Matrigel using a depth meter. Further, we examined differences in migration capacity and metalloproteinase production between infiltrating and non-infiltrating T-cell lines. The capacity to infiltrate was not directly correlated to the capacity to adhere to the Matrigel or to migrate on/to extracellular matrix components. It is concluded that infiltration capacity does not simply reflect capacity to migrate but represents a distinct functional property. The production of metalloproteinases and their inhibitors by the separate T-cell lines was analyzed using rt PCR, biosynthetic labelling, zymography, immunoprecipitation and ELISA. All T-cell lines with capacity to infiltrate produced matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) while non-infiltrating cell lines did not express MMP-9. Expression of MMP-1, 2, 3, 10, 14 and 17 showed no correlation to capacity to infiltrate. Analysis of infiltration in the presence of a metalloprotease inhibitor showed an increased number of cells within the gel. This enhancement of infiltration suggests that the function of MMPs and/or their inhibitors in lymphocyte infiltration is more complex than previously thought.
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PMID:Infiltrative capacity of T leukemia cell lines: a distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). 1091 15

Metabolism of the extracellular matrix (ECM) is a complex process that becomes disregulated in disease states characterized by chronic inflammation of joints, as is seen in rheumatoid arthritis or fibrosis of the lung. The participation of certain cytokines in this process is generally accepted (transforming growth factor-beta induces fibrosis), while the roles of other cytokines are less clear. Oncostatin M (OSM) is a member of the interleukin-6/leukaemia inhibitory factor (or gp130) cytokine family, and its participation in inflammation and the regulation of ECM metabolism is supported by a number of activities identified in vitro, including regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1. Local overexpression of transforming growth factor-beta has been shown to be fibrogenic in mouse lung, whereas local OSM overexpression via intra-articular administration has been shown to induce a pannus-like inflammatory response in the synovium of mouse knee joints. Here we examine the effects of OSM in the context of those of transforming growth factor-beta using an established adenovirus vector that expresses mOSM (AdmOSM). We administered the virus intra-nasally into Balb/C mice to achieve high expression of OSM in the lung, and examined the effects at various time points. AdmOSM resulted in a vigorous inflammatory response by day 7 which was characterized by an elevation of neutrophil and mononuclear cell numbers and a marked increase in collagen deposition. These data support the use of such systems to study the ECM in vivo, and indicate a potential role for OSM in inflammatory responses that can modulate steady-state ECM deposition in Balb/C mice.
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PMID:Modulation of extracellular matrix using adenovirus vectors. 1202 35

Arsenic trioxide (As2O3) has been implicated as a promising anticancer agent for treatment of many cancers including acute promylocytic leukemia. However, the molecular mechanisms are not yet fully defined in solid tumor cells, especially cervical cancer cells carrying human papillomavirus (HPV) genome. To analyze detailed mechanisms in vitro, we treated As2O3 to transformed HeLa cells, a well-studied cervical cancer cell line carrying HPV-18 sequence, and investigated its antiproliferative, antiviral and antimetastatic effects. As2O3 reduced survival and growth of HeLa cells in a dose- and time-dependent manner. Several indicatives of apoptosis were demonstrated by DNA fragmentation assay, DAPI nuclear staining and FACS analysis, respectively. Protein levels of p53 and cleavage of poly(ADP)-ribose polymerase were increased in a dose-dependent manner following treatment of As2O3. In parallel, semi-quantitative reverse transcription-polymerase chain reaction showed that the treatment inhibited HPV-18 E6/E7 viral gene expression in HeLa cells. Using transient transfection and CAT ELISA, we also found that AP-1 sites, located proximal to HPV-18 upstream regulatory region (URR) promoter, could be the major target sites for As2O3. Furthermore, As2O3-treated HeLa cells showed lesser capacity of invasion than those of untreated cells by in vitro invasion assay. Taken together, we proposed that antiviral effect, i.e. down-regulation of HPV E6/E7 oncogenes through targeting for AP-1 sites located in HPV URR might be associated with antiproliferative effect, i.e. induction of apoptosis as be resulted from the accumulation of p53, and that antimetastatic effect could be due to the targeted inactivation of AP-1, a transcription factor required for the expression of MMP-1 and -3. Therefore, our finding may provide a logical basis for the development of a new agent treating HPV-associated cervical neoplasia.
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PMID:Down-regulation of human papillomavirus E6/E7 oncogene by arsenic trioxide in cervical carcinoma cells. 1243 Jan 74

The U3 region of the LTR of oncogenic Moloney murine leukemia virus (Mo-MuLV) and feline leukemia viruses (FeLV) have been previously reported to activate expression of specific cellular genes in trans, such as MHC class I, collagenase IV, and MCP-1, in an integration-independent manner. It has been suggested that transactivation of these specific cellular genes by leukemia virus U3-LTR may contribute to the multistage process of leukemogenesis. The U3-LTR region, necessary for gene transactivational activity, also contains multiple transcription factor-binding sites that are essential for normal virus replication. To dissect the promoter activity and the gene transactivational activity of the U3-LTR, we conducted mutational analysis of the U3-LTR region of FeLV-A molecular clone 61E. We identified minimal nucleotide substitution mutants on the U3 LTR that did not disturb transcription factor-binding sites but abrogated its ability to transactivate the collagenase gene promoter. To determine if these mutations actually have altered any uncharacterized important transcription factor-binding site, we introduced these U3-LTR mutations into the full-length infectious molecular clone 61E. We demonstrate that the mutant virus was replication competent but could not transactivate cellular gene expression. These results thus suggest that the gene transactivational activity is a distinct property of the LTR and possibly not related to its promoter activity. The cellular gene transactivational activity-deficient mutant FeLV generated in this study may also serve as a valuable reagent for testing the biological significance of LTR-mediated cellular gene activation in the tumorigenesis caused by leukemia viruses.
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PMID:Mutations that abrogate transactivational activity of the feline leukemia virus long terminal repeat do not affect virus replication. 1275 76


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