Tissue inhibitor metalloproteinase 2 TIMP

Increase matrix metalloproteinase (MMP-1) relative to tissue inhibitor metalloproteinase (TIMP-1) (54, 55). 

The enzymatic activity of these potentially harmful enzymes is tightly controlled. Once transcribed into protein, MMPs are expressed as inactive zymogens and require distinct activation processes to convert them into active enzymes. After secretion, MMP-activity is regulated by the noncovalent binding of tissue inhibitors of metalloproteinases ( TIMPs) as shown in Fig. 2 for MMP-2 and TIMP-2. Four TIMPs have been identified so far TIMP-1, TIMP-2, TIMP-3, and TIMP-4. All known MMPs can be inhibited by at least one of the four known TIMPs. Nevertheless, individual differences with regard to bond strength and thus the magnitude of inhibition of a particular MMP do exist. 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

TIMP-1, TIMP-2 Tissue inhibitors of metalloproteinases 1 and 2 Ha Thymus leukaemia antigen TLC TTiin-layer chromatt raphy TLCK Tosyl-lysyl-CHiCl TLP Tumour-like proliferation Tm T memory... 

KI3. Kossakouska, A. E., Urbanski, S. J., Huchcroft, S. A., and Edwards, R. R., Relationship between clinical aggressiveness of large cell immunoblastic lymphomas and expression of 92 kDa gelatinase (type IV collagenase) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Oncol. Res. 4, 233-240 (1992). 

TIMP Tissue inhibitor of metalloproteinase family. E(M) 0(0) 1(1) 1BR9... 

Although much has been learned ftom in vitro assays, we do not yet fully understand the predominant migratory mechanisms used by cancer cells in vivo. It is important that any molecular mediators (or their inhibitors) identified in one assay are tested in complementary assays and validated in appropriate in vivo models before they can be assumed to play a significant role in invasion and metastasis. There are several examples where a molecule can have either positive or negative regulatory roles in key cellular functions depending on the cellular/microenvironmental context (e.g., tissue inhibitors of matrix metalloproteinases TIMPs (12)). Thus, care needs to be taken to avoid undesirable activities or, as in the example of some angiogenic inhibitors, compensatory mechanisms that result in adverse events (13). 

The MMPs are secreted as inactive proenzymes, which are activated by proteolytic cleavage. Once activated they are subject to control by tissue inhibitors of metalloproteinases (TIMPs). It is the imbalance between the active enzymes and the TIMPs that leads to destructive tissue degradation that potent directed pharmaceuticals can overcome. These enzymes have been the target of... 

Another possible strategy that, to our knowledge, has not been studied is to increase the concentration or effect of matrix metalloproteinases, compounds that are responsible for controlled, ongoing degradation of collagen. One such method would be to block tissue inhibitors of metalloproteinases (TIMPs). Such a method would have... 

Abbreviations CEL, cellulose DXM, dexamethasone EIPA, ethylisopropylamiloride FIB, fibrin MR methylprednisolone NA, not available Neo-R, neointima reduction PC, phosphorylcholine PCL, polycaprolactone PFM-P75, polyfluoroalkoxyphosphazene PLLA(PLA), poly-L-lactic acid POP, polyorganophosphazene PU, polyurethane Q-DL, Quanam drug eluting stent Q-M, Quanam metal stent SNR sodium nitroprusside TIMP, tissue inhibitors of metalloproteinase. 

The MMPs are a family of zinc-dependent neutral endopep-tidases that share structural domains but differ in substrate specificity, cellular sources, and inductivity (Table I). All the MMPs are important for remodeling of the extra cellular matrix and share the following functional features (/) they degrade extracellular matrix components, including fibronectin, collagen, elastin, proteoglycans, and laminin, (//) they are secreted in a latent proform and require activation for proteolytic activity, (///) they contain zinc at their active site and need calcium for stability, (/V) they function at neutral pH, and (v) they are inhibited by specific tissue inhibitors of metalloproteinases (TIMPs). 

Cultured cells secrete hyaluronidases into the culture media, away from the cells. Such a phenomenon does not occur within tissues. The production of unopposed hyaluronidase activity would cause great havoc in tissues. Simultaneous deposition of hyaluronidases and their inhibitors is a reasonable scenario, one that parallels control of the matrix metalloproteinases by their TIMPs (tissue inhibitors of MMPs). 

Stetler-Stevenson, W. G., Brown, P. D., Onisto, M., Levy, A. T. and Liotta, L. A. (1990). Tissue inhibitor of metalloproteinase-2 (TIMP-2). mRNA expression in tumor cell lines and human tumor tissues. J. Biol. Chem. 265,13933-13938. 

The functions of the extracellular matrix are manifold (1.) stabilization of the tissue and organ structure, (2.) structural linkage of cells, (3.) transmission of information between the various types of cells within the tissue and the extracellular milieu, (4.) adhesion or migration of cells, and (5.) influence on the development and differentiation of cells and their polarity. In fibrogenesis, collagen fibres build the framework in which the other components of the extracellular matrix are embedded. In line with this wide scop>e of functions, the extracellular matrix is not only organ-sp>ecific as regards its architecture, but it also displays variations at different locations within the liver, e.g. in Disse s space, in the periportal fields and within the acinus zones. The extracellular matrix is a dynamic structure, i. e. there is a constant equilibrium between build-up (by matrix-metalloproteinases = MMP) and break-down (by tissue inhibitors of matrix metaUoproteinases = TIMP). 

However, the augmentation of intracellular sialic acid pools by the introduction of ManNAc was found to be ineffective in increasing the overall level of sialylation of human tissue inhibitor of metalloproteinases 1 (TIMP-1) produced by CHO cells and mouse NSO cells [3]. Therefore, the overexpression of nucleotide sugar transporters, particularly the CMP-sialic acid transporter (CMP-SAT), was investigated as a means of improving the sialylation process in CHO cells. Increasing cellular CMP-SAT levels by recombinant means results in increased transport of CMP-sialic acid into the Golgi, and subsequent increase in the CMP-sialic acid intra-lumenal pool affords increased sialylation of the proteins expressed [4]. 

THP-1 Human monocytic leukaemia Thy 1+ Murine T cell antigen t.i.d. Ter in die (three times a day) TIL Tumour-infiltrating lymphocytes TIMP Tissue inhibitors of metalloproteinase... 

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