Tissue inhibitors

Tissue inhibitor of metalloproteins (TIMP, from human blood plasma), Mr -30,000. 

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. 

Morgunova E, Tuuttila A, Bergmann U et al (2002) Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci USA 99 7414—7419... 

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. 

Plasminogen activator Plasminogen activator inhibitor-1 Tissue inhibitor of metalloproteinase... 

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 UMP Tissue inhibitors of metalloproteinase... 

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... 

Moreau M, Brocheriou I, Petit L, Ninio E, Chapman MJ, Rouis M. Interleukin-8 mediates downregulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages relevance to stability of atherosclerotic plaque. Circulation 1999 99(3) 420-426. 

Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N. Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. Lab Invest 1998 78(6) 687-698. 

Expression of matrix metalloproteinases (MMPs) and their inhibitors is an important function of the RPE, particularly with respect to the maintenance of appropriate permeability of the Bruch s membrane (Ahir et al., 2002). This function can be tested in vitro (Marin-Castano et al., 2006). For example, it has been shown that the expression of MMP-2, TIPM-2s (tissue inhibitor of MMP-2), and type IV collagen by cultured ARPE-19 cells is affected by repetitive exposures to nonlethal oxidant injury with hydroquinone (Marin-Castano et al., 2006). Oxidative stress decreases MMP-2 activity and increases collagen type IV accumulation. 

Current evidence suggests that the cells of the IVD are themselves the primary culprits responsible for the destruction of the IVD ECM via the increased production of numerous proteinases (Table 2) [26, 27, 41, 42]. In most cases, production of tissue inhibitors of MMPs (TIMPs) increases in parallel with MMP synthesis however, TIMP-3 (an inhibitor of ADAMTS-4) may not, thus potentially... 

Burger, D. et al., Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes Involvement of membrane-associated cytokines, Arthr. Rheum., 41, 1748, 1998. 

A1. Alvarez, O. A., Carmichael, D. F., and DeClerck, Y. A., Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J. Natl. Cancer Inst. 82, 589-595 (1990). 

K4. Khokha, R., and Denhardt, D. T., Matrix metalloproteinases and tissue inhibitors of metal-loproteinases A review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 9, 391-405 (1989). 

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). 

George, S.J., C.T. Lloyd, G.D. Angehni,A.C. Newby, and A.H. Baker, Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation, 2000.101(3) 296-304. 

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... 

Murphy G, Willenbrock F, Ward RV, Cockett MI, Eaton D, Docherty AJP. The C-terminal domain of 72 kDa gelatinase A is not required for catalysis, but is essential for membrane activation and modulates interactions with tissue inhibitors of metalloproteinase. J. Biochem. 1992 328 637-641. 

The authors reported the preparation of polymers imprinted with kallikrein (47) as a template, a known tissue inhibitor, which, after template removal, were used to allow direct coupling between a di-chloro-triazine (48) and a series of aromatic amines. The first substrate was used to resynthesise the compound that was used as template and the yield of this was four times higher than with the corresponding control polymer. Moreover, the same reaction performed in free solution in the same conditions gave no product. The polymer was then tested against the other substrates to verify whether it was possible to synthesise compounds with slightly different properties. This experiment resulted in compounds with lower yields, 21 % for one and 34% for another, whilst using a bulkier substrate it was not possible to obtain any product. 

Hickey M, Higham J, Sullivan M, Miles L, Fraser IS. Endometrial bleeding in hormone replacement therapy users preliminary findings regarding the role of matrix metalloproteinase 9 (MMP-9) and tissue inhibitors of MMPs. Fertil Steril 2001 75(2) 288-96. 

Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, Park IC, Kim MS, Rhee CH, Hong SI. 2006. Transforming growth factor-betal induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Spl in human fibrosarcoma cells. Mol Cancer Res 4 209-220. 

Matrix Metal loproteinases, Tissue Inhibitors of Metalloproteinases... 

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