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 human T-cell leukemia virus type I (HTLV-I)-encoded Tax protein activates transcription from the viral promoter via association with the cellular basic leucine zipper factor cAMP-response element-binding protein-2. Tax is also able to induce cellular transformation of T lymphocytes probably by modulating transcriptional activity of cellular factors, including nuclear factor-kappaB, E2F, activator protein-1 (AP-1), and p53. Recently, we characterized in HTLV-I-infected cells the presence of a novel viral protein, HBZ, encoded by the complementary strand of the HTLV-I RNA genome (Gaudray, G., Gachon, F., Basbous, J., Biard-Piechaczyk, M., Devaux, C., and Mesnard, J.-M. (2002) J. Virol. 76, 12813-12822). HBZ is a nuclear basic leucine zipper protein that down-regulates Tax-dependent viral transcription by inhibiting the binding of cAMP-response element-binding protein-2 to the HTLV-I promoter. In searching for other cellular targets of HBZ, we identified two members of the Jun family, JunB and c-Jun. Co-immunoprecipitation and cellular colocalization confirmed that HBZ interacts in vivo with JunB and c-Jun. When transiently introduced into CEM cells with a reporter gene containing the AP-1 site from the collagenase promoter, HBZ suppressed transactivation by c-Jun. On the other hand, the combination of HBZ with Jun-B had higher transcriptional activity than JunB alone. Consistent with the structure of its basic domain, we demonstrate that HBZ decreases the DNA-binding activity of c-Jun and JunB. Last, we show that c-Jun is no longer capable of activating the basal expression of the HTLV-I promoter in the presence of HBZ in vivo. Our results support the hypothesis that HBZ could be a negative modulator of the Tax effect by controlling Tax expression at the transcriptional level and by attenuating activation of AP-1 by Tax.
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PMID:The HBZ factor of human T-cell leukemia virus type I dimerizes with transcription factors JunB and c-Jun and modulates their transcriptional activity. 1293 77

Degradation of the extracellular matrix by matrix metalloproteinases (MMPs) is a crucial step in tumour invasion and metastasis. In human carcinomas, tumour cell-fibroblast interactions (TFIs) have been demonstrated to play a role in the up-regulation of MMP levels in tumours, and emmprin is a surface molecule on tumour cells that stimulates nearby fibroblasts to produce MMP-1, 2, and 3. T-cell lymphomas frequently show extranodal organ involvement and skin invasion, but a role for TFIs in their invasion has not been examined in detail. This study investigated TFIs in T-cell lymphomas with special reference to emmprin expression and MMP production. Immunohistochemically, only germinal centre cells and some histiocytes expressed emmprin in non-neoplastic lymph nodes (ten cases), while all T-cell lymphomas [14 cases of adult T-cell leukaemia/lymphoma (ATLL), six cases of lymphoblastic lymphoma, seven cases of anaplastic large cell lymphoma, and nine cases of angio-immunoblastic T-cell lymphoma] expressed emmprin strongly and diffusely. FACS analysis of peripheral blood from normal individuals revealed that small fractions of B-cells, T-cells, and monocytes expressed emmprin, whereas emmprin-expressing T-cells were much increased in number, and expressed this protein to a higher level, in ATLL patients. In vitro co-cultures of emmprin-positive HTLV-1-transformed lymphocytes (MT-2) and emmprin-negative human fibroblasts enhanced the production of pro-MMP-2 (gelatinase A) and active MMP-2, compared with cultures of either cell type alone. This stimulation was inhibited by an activity-blocking peptide against emmprin. Moreover, in histopathological sections from patients with ATL skin involvement, MMP-2 was demonstrated in fibroblasts around infiltrating ATL cells, but not in fibroblasts in non-diseased areas. In conclusion, emmprin is overexpressed by T-lymphoma cells, when compared with normal counterparts, and facilitates MMP-2 production via interactions with fibroblasts, which could play a role in stromal invasion by lymphoma cells.
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PMID:Emmprin, a cell surface inducer of matrix metalloproteinases (MMPs), is expressed in T-cell lymphomas. 1499

This is a historical overview seen from a personal angle. It covers the insights made during the past 20 years into the destructive processes of rheumatoid arthritis (RA) related to cytokines. The biochemical knowledge of the matrix components (i.e. collagen) and enzymology (i.e. collagenase) available in the 1950s led to the identification of cells from synovial tissue producing collagenase (fibroblast-like cells) and their interaction with other immune cells, i.e. monocyte-macrophages (Mphi) and lymphocytes (1976-1979). This insight led to the isolation of soluble factors produced by Mphi, such as interleukin-1 (IL-1) and TNF, the principal cytokines inducing collagenase and PGE(2) in many target cells (i.e. synovial fibroblasts, chondrocytes, bone-derived cells) (1981-1985). Further advances resulted from observations that, in clinical conditions (i.e. leukaemia, juvenile RA), a remission of fever and inflammation may occur spontaneously and that tissue catabolism may persist despite the absence of systemic inflammation; this gave rise to the concept and identification of endogenous cytokine inhibitors (i.e. IL-1 receptor antagonist and TNF soluble receptor) (1984-1989). The fourth milestone was the observation that the production of IL-1 and TNF by Mphi was induced mainly by direct contact with lymphocytes, prompting studies of the ligands and counter-ligands on Mphi and lymphocytes as well as inhibitors involved in this cell-cell contact, some of these inhibitors being involved in lipid metabolism and acute-phase proteins (HDL-apo A-1).
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PMID:The process of identifying and understanding cytokines: from basic studies to treating rheumatic diseases. 1512 36

The oncoprotein Tax of human T-cell leukemia virus type I (HTLV-1) is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the human granzyme B promoter in mice results in a lymphoproliferative disorder resembling adult T-cell leukemia/lymphoma (ATL). Tax expression is associated with the production of high levels interferon-gamma (IFN-gamma) in HTLV-1-infected CD4(+) cells and Tax-transgenic tumors. We examined the role of IFN-gamma in tumorigenesis, by mating Tax-transgenic mice with a gene-specific knockout for IFN-gamma. IFN-gamma(-/-) Tax(+)-transgenic mice show accelerated tumor onset (median, 4 versus 6 months), dissemination (median, 5 versus 7 months), and death (median, 7 versus 10 months), compared with IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Pathologic and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced interleukin 2 receptor-beta (IL-2Rbeta) and suppressed intercellular adhesion molecule-1 (ICAM-1) expression on tumors from IFN-gamma(-/-) Tax(+) transgenic mice. IFN-gamma(-/-) tumors demonstrate enhanced CD31 (platelet-endothelial CAM-1 [PECAM-1]) staining compared with those from IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Angiogenesis-specific cDNA microarray analysis identified 4 mediators of angiogenic growth differentially expressed in tumors from Tax(+)IFN-gamma(-/-) mice compared with Tax(+)IFN-gamma(+/+) littermates. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), loss of IFN-gamma results in down-regulation of tumor necrosis factor-alpha (TNF-alpha) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) while up-regulating expression of vascular endothelial growth factor (VEGF) and tenascin C. These results provide insight into a possible mechanism by which IFN-gamma contributes to host resistance against HTLV-induced tumors through an angiostatic effect.
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PMID:Enhanced tumorigenesis in HTLV-1 tax-transgenic mice deficient in interferon-gamma. 1529 59

Aggressive tumor developing human TUR myeloid leukemia cells continued cell cycle progression in the presence of the differentiation-inducing phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Similar results were obtained after stable transfection of TUR cells with the pTracer control vector (pTracer TUR cells). In contrast, TUR transfectants containing a constitutively active poly(ADP-ribose) polymerase-1 (PARP-1) gene fragment in antisense orientation within the pTracer vector (asPARP TUR cells) demonstrated increasing cell attachment and differentiation after TPA treatment. Moreover, asPARP TUR cells ceased to divide upon TPA stimulation. Cell cycle analysis revealed a predominant G0/G1 arrest and a partial G2/M arrest in TPA-treated asPARP TUR cells, whereas little if any population was detectable in S phase. Microarray gene expression analysis exhibited a significant down-regulation of cell cycle genes in phorbol ester-stimulated asPARP TUR and markedly elevated levels of differentiation-associated factors in contrast to TPA-incubated wild-type TUR cells. Whereas PARP-1 can associate with the 20S proteasome in leukemia cells, a significant reduction of this proteolytic activity was observed in asPARP TUR cells. Conversely, protein levels of manganese superoxide dismutase and the matrix metalloproteinases MMP-1 and MMP-9 were progressively increased in TPA-treated asPARP TUR cells, respectively. These findings underscore an important function of PARP-1 in human leukemia cells to connect cell cycle progression and control of differentiation.
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PMID:Down-modulation of poly(ADP-ribose) polymerase-1 (PARP-1) in human TUR leukemia cells restores transcriptional responsiveness for differentiation and cell cycle arrest. 1632 85

In the present study we developed an enzymatic approach (through the use of collagenase and dispase) to isolate bovine intestinal epithelial cells. Using this method, freshly isolated jejunocytes could be distinguished from simultaneously isolated colonocytes, as the jejunocytes specifically exhibited the small intestinal peptidase gene transcript, as well as an active alkaline phosphatase. The transformation of both types of cell suspension was performed by retroviral infection, using reproduction-defective viruses bearing the gene coding for the large T antigen of the leukaemia simian virus (SV40). The success of the transfection was demonstrated by (1) a significant increase in cell passage numbers (52-53 vs. 7 passages for non-transfected cells), (2) the detection of both the large T transcript and the large T antigen in transformed cells. Possible contamination and progressive substitution of bovine primocultures by non-bovine lineages available in the laboratory was excluded, as the transformed cells presented a bovine typical karyotype. Most transfected cells kept an epithelial morphology after transformation. They also maintained the expression of FABP and enterocyte specific enzymes (brush-border associated maltase and IAP). However, levels of specific activity of these enzymes were low, suggesting that cell differentiation is not completely achieved under the applied culture conditions.
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PMID:Preliminary characterization of jejunocyte and colonocyte cell lines isolated by enzymatic digestion from adult and young cattle. 1916 86

Cartilage degradation is mediated by matrix metalloproteinases (MMPs) and their inhibitors, tissue metalloproteinases (TIMPs), which are transcriptionally regulated by a variety of growth factors and cytokines. The levels of various MMPs as well as TIMPs have been shown to increase in response to certain cytokines. These include leukaemia inhibitory factor (LIF) and Oncostatin M (OSM), both of which have been detected in the synovial fluids of patients with rheumatoid arthritis (RA). However, the role of LIF and OSM in the regulation of various MMPs and TIMPs is still incompletely understood. The aims of this study were to examine the effects of LIF and OSM on MMP-1, MMP-3, and TIMP-1 production. In addition, the capacity of the LIF antagonist, MH35-BD, to block LIF and OSM induced MMP expression was examined. Primary chondrocytes, isolated from porcine metacarpophalangeal cartilage, were cultured in the presence and absence of LIF and OSM, with and without a predetermined concentration of the LIF antagonist. We analysed the levels of MMP-1, MMP-3 and TIMP-1 expression using qRT-PCR, Northern blot, and ELISA assays. The results indicate that LIF and OSM increase the expression of MMP-1, MMP-3, and TIMP-1 several fold. Furthermore their expression is reduced to basal levels in the presence of the LIF antagonist MH35-BD.
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PMID:Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes. 1934 53

In recent years, evidence has emerged supporting the hypothesis that cancer is a stem cell disease. The cancer stem cell field was led by the discovery of leukemia stem cells (Tan, B.T., Park, C.Y., Ailles, L.E., and Weissman, I.L. (2006) The cancer stem cell hypothesis: a work in progress. Laboratory Investigation. 86, 1203-1207), and within the past few years cancer stem cells have been isolated from a number of solid tumor including those of breast and brain cancer among others (Al-Hajj M., Wicha M.S., Benito-Hernandez A., Morrison, S.J., and Clarke, M.F. (2003) Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983-3988; Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J., and Dirks, P.B. (2003) Identification of a Cancer Stem Cell in Human Brain Tumors. Cancer Research. 63, 5821-5828). Cancer stem cells exhibit far different properties than established cells lines such as relative quiescence, multidrug resistance, and multipotency (Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H.M., Jones, D.L., Visvader, J., Weissman, I.L., and Wahl, G.M. (2006) Cancer Stem Cells-Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells. Cancer Research. 66, 9339-9344). In addition, our laboratory has demonstrated that breast cancer stem cells exhibit a strong metastatic phenotype when passaged in mice. Since stem cells exhibit these somewhat unique properties, it will be important for endocrinologists to evaluate hormonal action in these precursor cells for a more thorough understanding of cancer biology and development of more effective treatment modalities. A relatively easy and low cost method was developed to isolate breast cancer stem cells from primary needle biopsies taken from patients diagnosed with primary invasive ductal carcinoma during the routine care of patients with consent and IRB approval. Fresh needle biopsies (2-3 biopsies at 2 cm in length) were enzymatically dissociated in a collagenase (300 U/ml)/hyaluronidase (100 U/ml) solution followed by sequential filtration. Single cell suspensions were cultured on ultra low attachment plastic flasks in defined medium and formed non-adherent tumorspheres. The tumorspheres exhibited surface marker expression of CD44(+)/CD24(low/-)/ESA(+), previously defined as a "breast cancer stem cell" phenotype by Al Hajj et al. (Al-Hajj M., Wicha M.S., Benito-Hernandez A., Morrison, S.J., and Clarke, M.F. (2003) Prospective identification of tumorigenic breast cancer cells.
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PMID:Breast tumor-initiating cells isolated from patient core biopsies for study of hormone action. 1976 16

The ability of embryonic germinal cells (EG) to differentiate into primordial germinal cells (PGCs) and later into gametes during early developmental stages is a perfect model to address our hypothesis about cancer and infertility. This protocol shows how to isolate primordial germinal cells from developing gonads in 10.5-11.5 days post coitum (dpc) mouse embryos. Developing gonadal ridges from mouse embryos (C57BL6J) were dissociated by mechanical disruption with collagenase, then plated in a mouse embryo fibroblast feeder layer (MEF-CF1) that was previously mitotically inactivated with mitomycin C in the presence of knockout media and supplemented with Leukemia Inhibitor Factor (LIF), basic Fibroblast Growth Factor (bFGF), and Stem Cell Factor (SCF). Using these optimized methods for PCG identification, isolation, and establishment of culture conditions permits long term cultures of EG cells for more than 40 days. The embryonic germinal cell lines showed embryonic phenotype and expression of common used markers of the pluripotent state. Isolation and derivation of germinal cells in culture provide a tool to understand their development in vitro and offer the opportunity to monitor cumulative damage at genetic and epigenetic levels after exposure to oxidative stress.
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PMID:Isolation and derivation of mouse embryonic germinal cells. 1985 Dec 76

Matrix metalloproteinase (MMP) comprises a family of zinc-dependent endopeptidases that degrade various components of the extracellular matrix (ECM) and basement membrane. MMPs are involved in solid and hematological malignancy through modification of cell growth, activation of cancer cells and modulation of immune functions. Several polymorphisms of different MMPs such as MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A) & MMP-9 (-1562 C/T) and their expression levels have been well documented in different types of solid cancer. These polymorphic variations were found to be associated with angiogenesis, cancer progression, invasion and metastasis. There is paucity of data available in the field of hematological malignancies. Hence the field of matrix biology of hematological malignancies is an area of active exploration. A number of MMP inhibitors (MMPIs) have been developed for the cancer treatment. The most extensively studied classes of MMP inhibitors include Batimastat, Marismastat, Salimatat, Prinomastat and Tanomastat. However, their efficacy and action have not been confirmed and more data is required. The application of one or more selective targeted MMPIs in combination with conventional anti-leukemic treatment may represent a positive approach in combat against hematopoietic malignancies. Balance of MMPs and TIMPs is altered in different malignancies and biochemical pathways. These alternations will add another dimension in the matrix biology of both solid tumor and leukemia. MMP and TIMP singly and in combination are increasingly being recognized as an important player in basic cellular biology. Exploration and exploitation of MMP and TIMP balance in various malignant and nonmalignant lesions is going to be one of the most interesting facets of future use of this system for human health care.
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PMID:Matrix metalloproteinase and its drug targets therapy in solid and hematological malignancies: an overview. 2337 Apr 82


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