TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3

School of Biological Sciences, University of East Anglia, Norwich, UK.
FEBS Letters (Impact Factor: 3.17). 10/1998; 435(1):39-44.
Source: PubMed

ABSTRACT TNF-alpha converting enzyme (TACE; ADAM-17) is a membrane-bound disintegrin metalloproteinase that processes the membrane-associated cytokine proTNF-alpha to a soluble form. Because of its putative involvement in inflammatory diseases, TACE represents a significant target for the design of specific synthetic inhibitors as therapeutic agents. In order to study its inhibition by tissue inhibitors of metalloproteinases (TIMPs) and synthetic inhibitors of metalloproteinases, the catalytic domain of mouse TACE (rTACE) was overexpressed as a soluble Ig fusion protein from NS0 cells. rTACE was found to be well inhibited by peptide hydroxamate inhibitors as well as by TIMP-3 but not by TIMP-1, -2 and -4. These results suggest that TIMP-3, unlike the other TIMPs, may be important in the modulation of pathological events in which TNF-alpha secretion is involved.

16 Reads
  • Source
    • "Among these genes, DAB2 (expressed in various tissues), which is detected at an early myogenic differentiation state [67], has lost or reduced expression in hyperproliferative cells [96]. Another gene in this group that is significantly down-regulated is a member of the tissue inhibitors of matrix metalloproteinases (TIMP) family, TIMP3, or metalloproteinase inhibitor 3. TIMP3 complexes with MMPs and is the only TIMP capable of inhibiting membrane bound MMP, transmembrane MMP and sheddases such as TNF-α converting enzyme (TACE), which is also known as disintegrin and metalloproteinase (ADAM-17) [97], [98]. Conversely, all MMPs detected in this study were highly up-regulated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of myogenic regulatory factors (MRFs) consisting of MyoD, Myf5, myogenin (MyoG) and MRF4 characterizes various phases of skeletal muscle development including myoblast proliferation, cell-cycle exit, cell fusion and the maturation of myotubes to form myofibers. Although it is well known that the function of MyoG cannot be compensated for other MRFs, the molecular mechanism by which MyoG controls muscle cell differentiation is still unclear. Therefore, in this study, RNA-Seq technology was applied to profile changes in gene expression in response to MyoG knock-down (MyoGkd) in primary bovine muscle satellite cells (MSCs). About 61-64% of the reads of over 42 million total reads were mapped to more than 13,000 genes in the reference bovine genome. RNA-Seq analysis identified 8,469 unique genes that were differentially expressed in MyoGkd. Among these genes, 230 were up-regulated and 224 were down-regulated by at least four-fold. DAVID Functional Annotation Cluster (FAC) and pathway analysis of all up- and down-regulated genes identified overrepresentation for cell cycle and division, DNA replication, mitosis, organelle lumen, nucleoplasm and cytosol, phosphate metabolic process, phosphoprotein phosphatase activity, cytoskeleton and cell morphogenesis, signifying the functional implication of these processes and pathways during skeletal muscle development. The RNA-Seq data was validated by real time RT-PCR analysis for eight out of ten genes as well as five marker genes investigated. This study is the first RNA-Seq based gene expression analysis of MyoGkd undertaken in primary bovine MSCs. Computational analysis of the differentially expressed genes has identified the significance of genes such as SAP30-like (SAP30L), Protein lyl-1 (LYL1), various matrix metalloproteinases, and several glycogenes in myogenesis. The results of the present study widen our knowledge of the molecular basis of skeletal muscle development and reveal the vital regulatory role of MyoG in retaining muscle cell differentiation.
    PLoS ONE 03/2014; 9(3):e92447. DOI:10.1371/journal.pone.0092447 · 3.23 Impact Factor
  • Source
    • "Interestingly, the levels of TIMP-3 in group 2 and group 3 did differ significantly. TIMP-3 was found to be a strong inhibitor of TACE among other TIMPs [36] and TACE. Diabetic conditions can increase the expression of markers of systemic inflammation and Monroy et al. [37] showed that insulin-resistant conditions were associated with the increased level of TACE activity and such conditions were correlated with the down-regulation of TIMP-3 in human skeletal muscle. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to analyze the expression of inducible nitric oxide synthases (iNOS), tissue inhibitors of metalloproteinase (TIMP)-3, and TIMP-4 in the gingival tissues of periodontal patients with or without type 2 diabetes mellitus (DM). Depending on the patient's systemic condition and clinical criteria of the gingiva, each gingival sample was classified into one of three groups. Sixteen clinically, systemically healthy patients (group 1), 16 periodontal patients (group 2), and 16 periodontal patients with DM (group 3) were included. Tissue samples in each group were collected, prepared, and analyzed by western blotting. Quantification of the relative amount of TIMP-3, TIMP-4, and iNOS was performed. The expression levels of iNOS and TIMP-3 both increased in group 1, group 2, and group 3 in increasing order, and were significantly higher in both group 2 and group 3 as compared to group 1 (P<0.05). The expression levels of TIMP-4 increased in the same order, but significantly increased in group 2 as compared to group 1, in group 3 as compared to group 1, and group 3 as compared to group 2 (P<0.05). This study demonstrated that iNOS, TIMP-3, and TIMP-4 might be involved in the progression of periodontal inflammation associated with type 2 DM. It is thought that further study of these factors can be applied practically for the diagnosis and control of periodontitis in diabetics.
    Journal of periodontal & implant science 04/2013; 43(2):87-95. DOI:10.5051/jpis.2013.43.2.87 · 1.15 Impact Factor
  • Source
    • "In general, all four TIMPs are broad-spectrum inhibitors of the MMP family, with some differences in specificity. TIMP-3 has been demonstrated to have a broader range of metalloproteinase substrates being particularly effective in uniquely inhibiting several members of the ADAM (a disintegrin and metalloprotease) and ADAMTS (ADAM with thrombospondin motifs) family [1], [2], [3], [4], [5], [6]. Although originally characterized for their functional property to inhibit MMP activity, TIMPs have more recently been shown to have additional biological activities that may be independent of their MMP-inhibitory functions [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tissue inhibitors of metalloproteinases (TIMPs) while originally characterized as inhibitors of matrix metalloproteinases (MMPs) have recently been shown to have a wide range of functions that are independent of their MMP inhibitory properties. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a potent inhibitor of VEGF-mediated angiogenesis and neovascularization through its ability to block the binding of VEGF to its receptor VEGFR-2. To identify and characterize the anti-angiogenic domain of TIMP-3, structure function analyses and synthetic peptide studies were performed using VEGF-mediated receptor binding, signaling, migration and proliferation. In addition, the ability of TIMP-3 peptides to inhibit CNV in a mouse model was evaluated. We demonstrate that the anti-angiogenic property resides in the COOH-terminal domain of TIMP-3 protein which can block the binding of VEGF specifically to its receptor VEGFR-2, but not to VEGFR-1 similar to the full-length wild-type protein. Synthetic peptides corresponding to putative loop 6 and tail region of TIMP-3 have anti-angiogenic properties as determined by inhibition of VEGF binding to VEGFR-2, VEGF-induced phosphorylation of VEGFR-2 and downstream signaling pathways as well as endothelial cell proliferation and migration in response to VEGF. In addition, we show that intravitreal administration of TIMP-3 peptide could inhibit the size of laser-induced choroidal neovascularization lesions in mice. Thus, we have identified TIMP-3 peptides to be efficient inhibitors of angiogenesis and have a potential to be used therapeutically in diseases with increased neovascularization.
    PLoS ONE 03/2013; 8(3):e55667. DOI:10.1371/journal.pone.0055667 · 3.23 Impact Factor
Show more