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Gene Review

TIMP3  -  TIMP metallopeptidase inhibitor 3

Homo sapiens

Synonyms: HSMRK222, K222, K222TA2, Metalloproteinase inhibitor 3, Protein MIG-5, ...
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Disease relevance of TIMP3

  • Differentiation expression of TIMP3 in choriocarcinoma may have potential application in clinical diagnosis and patient treatment [1].
  • These findings establish the potential of adenoviral gene delivery of TIMP3 as a therapeutic agent for selected lung cancers [2].
  • RESULTS: Methylation frequencies of TIMP3 in the breast cancer samples were 20.81 % [3].
  • CONCLUSION: The result demonstrated that hypermethylation of TIMP3 in IDC might be associated with high tumor grading and lymph nodes metastasis, and overexpression of ER, PR and c-erbB2, respectively [3].
  • DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma [3].

Psychiatry related information on TIMP3

  • Attention and memory for somatic symptom and IEI-trigger words was compared among participants with IEI (n = 54), somatoform disorders (SFD; n = 44) and control participants (n = 54) [4].

High impact information on TIMP3


Chemical compound and disease context of TIMP3


Biological context of TIMP3


Anatomical context of TIMP3


Associations of TIMP3 with chemical compounds

  • Low levels of endogenous TIMP3 protein expression were elevated using the natural polysaccharide calcium pentosan polysulfate (CaPPs) in combination with the cytokine IL-1alpha [10].
  • Because TIMP-3 is sequestered in the extracellular matrix, the presence of certain heparan sulfate proteoglycans could enhance its inhibitory capacity [15].
  • Thus the functional domain arrangement of TIMP-3 is analogous to that seen in TIMP-1 and -2, namely that the NH2-terminal domain is responsible for MMP inhibition whereas the COOH-terminal domain is most important in mediating the specific functions of the molecule [12].
  • The enhanced invasion capacity of MMP-13 expressing HT-1080 cells was dependent on MMP activity, as it was blocked by MMP inhibitor Batimastat (BB-94) and tissue inhibitor of metalloproteinases-3 (TIMP-3) [16].
  • We have cloned and sequenced a third human TIMP (hTIMP-3) from phorbol ester-differentiated THP-1 cells stimulated with bacterial lipopolysaccharide [17].

Physical interactions of TIMP3

  • We set out to delineate the basis for this specificity by examining the solvent accessibility of every epitope on the surface of a model of the truncated N-terminal domain form of TIMP-3 (N-TIMP-3) in a hypothetical complex with the crystal structure of TACE [18].
  • Further studies of the features of TIMP-3 that determine specific binding to both ADAM and glycosaminoglycan are required in order to understand these unique properties [19].

Regulatory relationships of TIMP3


Other interactions of TIMP3

  • The exchange of portions of the gelatinase A hemopexin domain with that of stromelysin revealed that residues 568-631 of gelatinase A were required for rapid association with TIMP-3 [15].
  • TIMP-1, TIMP-2, and TIMP-3 expression was low in all samples [24].
  • In addition, a prolonged effect of acrolein may be mediated by altering MMP9 and TIMP3 transcription [25].
  • In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA [26].
  • Moreover, patients with stages III/IV diseases tended to have higher concentrations of methylated APC (P = 0.08), TIMP3 (P = 0.005) and hMLH1 (P = 0.03) in the serum [27].

Analytical, diagnostic and therapeutic context of TIMP3


  1. Down-regulation and promoter methylation of tissue inhibitor of metalloproteinase 3 in choriocarcinoma. Feng, H., Cheung, A.N., Xue, W.C., Wang, Y., Wang, X., Fu, S., Wang, Q., Ngan, H.Y., Tsao, S.W. Gynecol. Oncol. (2004) [Pubmed]
  2. In vitro susceptibility to the pro-apoptotic effects of TIMP-3 gene delivery translates to greater in vivo efficacy versus gene delivery for TIMPs-1 or -2. Finan, K.M., Hodge, G., Reynolds, A.M., Hodge, S., Holmes, M.D., Baker, A.H., Reynolds, P.N. Lung Cancer (2006) [Pubmed]
  3. DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Lui, E.L., Loo, W.T., Zhu, L., Cheung, M.N., Chow, L.W. Biomed. Pharmacother. (2005) [Pubmed]
  4. Selective attention, memory bias, and symptom perception in idiopathic environmental intolerance and somatoform disorders. Witthöft, M., Gerlach, A.L., Bailer, J. Journal of abnormal psychology. (2006) [Pubmed]
  5. Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration. Mohammed, F.F., Smookler, D.S., Taylor, S.E., Fingleton, B., Kassiri, Z., Sanchez, O.H., English, J.L., Matrisian, L.M., Au, B., Yeh, W.C., Khokha, R. Nat. Genet. (2004) [Pubmed]
  6. Night blindness in Sorsby's fundus dystrophy reversed by vitamin A. Jacobson, S.G., Cideciyan, A.V., Regunath, G., Rodriguez, F.J., Vandenburgh, K., Sheffield, V.C., Stone, E.M. Nat. Genet. (1995) [Pubmed]
  7. Tissue inhibitors of metalloproteinase expression in human breast cancer: TIMP-3 is associated with adjuvant endocrine therapy success. Span, P.N., Lindberg, R.L., Manders, P., Tjan-Heijnen, V.C., Heuvel, J.J., Beex, L.V., Sweep, C.G. J. Pathol. (2004) [Pubmed]
  8. Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. Karan, D., Lin, F.C., Bryan, M., Ringel, J., Moniaux, N., Lin, M.F., Batra, S.K. Int. J. Oncol. (2003) [Pubmed]
  9. Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia. Nuttall, R.K., Silva, C., Hader, W., Bar-Or, A., Patel, K.D., Edwards, D.R., Yong, V.W. Glia (2007) [Pubmed]
  10. Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby's fundus dystrophy patients. Arris, C.E., Bevitt, D.J., Mohamed, J., Li, Z., Langton, K.P., Barker, M.D., Clarke, M.P., McKie, N. Biochim. Biophys. Acta (2003) [Pubmed]
  11. Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis. García-Alvarez, J., Ramirez, R., Checa, M., Nuttall, R.K., Sampieri, C.L., Edwards, D.R., Selman, M., Pardo, A. Exp. Lung Res. (2006) [Pubmed]
  12. Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby's fundus dystrophy mutation. Langton, K.P., Barker, M.D., McKie, N. J. Biol. Chem. (1998) [Pubmed]
  13. Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes. Steen, B., Sejersen, S., Berglin, L., Seregard, S., Kvanta, A. Invest. Ophthalmol. Vis. Sci. (1998) [Pubmed]
  14. Cytokine stimulated vascular cell adhesion molecule-1 (VCAM-1) ectodomain release is regulated by TIMP-3. Singh, R.J., Mason, J.C., Lidington, E.A., Edwards, D.R., Nuttall, R.K., Khokha, R., Knauper, V., Murphy, G., Gavrilovic, J. Cardiovasc. Res. (2005) [Pubmed]
  15. Human tissue inhibitor of metalloproteinases 3 interacts with both the N- and C-terminal domains of gelatinases A and B. Regulation by polyanions. Butler, G.S., Apte, S.S., Willenbrock, F., Murphy, G. J. Biol. Chem. (1999) [Pubmed]
  16. Expression of collagenase-3 (MMP-13) enhances invasion of human fibrosarcoma HT-1080 cells. Ala-Aho, R., Johansson, N., Baker, A.H., Kähäri, V.M. Int. J. Cancer (2002) [Pubmed]
  17. Cloning and characterization of human tissue inhibitor of metalloproteinases-3. Wilde, C.G., Hawkins, P.R., Coleman, R.T., Levine, W.B., Delegeane, A.M., Okamoto, P.M., Ito, L.Y., Scott, R.W., Seilhamer, J.J. DNA Cell Biol. (1994) [Pubmed]
  18. Mapping and characterization of the functional epitopes of tissue inhibitor of metalloproteinases (TIMP)-3 using TIMP-1 as the scaffold: a new frontier in TIMP engineering. Lee, M.H., Maskos, K., Knäuper, V., Dodds, P., Murphy, G. Protein Sci. (2002) [Pubmed]
  19. Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail. Murphy, G., Knäuper, V., Lee, M.H., Amour, A., Worley, J.R., Hutton, M., Atkinson, S., Rapti, M., Williamson, R. Biochem. Soc. Symp. (2003) [Pubmed]
  20. The role of matrilysin (MMP-7) in leukaemia cell invasion. Lynch, C.C., McDonnell, S. Clin. Exp. Metastasis (2000) [Pubmed]
  21. Expression of the ETS transcription factor ELF3 in the retinal pigment epithelium. Jobling, A.I., Fang, Z., Koleski, D., Tymms, M.J. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  22. Tissue inhibitor of metalloproteinase-3 expression is upregulated during human cytotrophoblast invasion in vitro. Bass, K.E., Li, H., Hawkes, S.P., Howard, E., Bullen, E., Vu, T.K., McMaster, M., Janatpour, M., Fisher, S.J. Dev. Genet. (1997) [Pubmed]
  23. An immunohistochemical study of TIMP-3 expression in oesophageal squamous cell carcinoma. Miyazaki, T., Kato, H., Nakajima, M., Faried, A., Takita, J., Sohda, M., Fukai, Y., Yamaguchi, S., Masuda, N., Manda, R., Fukuchi, M., Ojima, H., Tsukada, K., Kuwano, H. Br. J. Cancer (2004) [Pubmed]
  24. Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn's disease. Kirkegaard, T., Hansen, A., Bruun, E., Brynskov, J. Gut (2004) [Pubmed]
  25. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Deshmukh, H.S., Case, L.M., Wesselkamper, S.C., Borchers, M.T., Martin, L.D., Shertzer, H.G., Nadel, J.A., Leikauf, G.D. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  26. Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms. Ogata, T., Shibamura, H., Tromp, G., Sinha, M., Goddard, K.A., Sakalihasan, N., Limet, R., MacKean, G.L., Arthur, C., Sueda, T., Land, S., Kuivaniemi, H. J. Vasc. Surg. (2005) [Pubmed]
  27. Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. Leung, W.K., To, K.F., Chu, E.S., Chan, M.W., Bai, A.H., Ng, E.K., Chan, F.K., Sung, J.J. Br. J. Cancer (2005) [Pubmed]
  28. Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. Groft, L.L., Muzik, H., Rewcastle, N.B., Johnston, R.N., Knäuper, V., Lafleur, M.A., Forsyth, P.A., Edwards, D.R. Br. J. Cancer (2001) [Pubmed]
  29. mRNA levels of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9 and of their inhibitors TIMP-2 and TIMP-3 in normal thyrocytes and thyroid carcinoma cell lines. Hofmann, A., Laue, S., Rost, A.K., Scherbaum, W.A., Aust, G. Thyroid (1998) [Pubmed]
  30. Dibutyryl cyclic AMP-induced enhancement of tissue inhibitor of metalloproteinases-3 expression and its possible relation to the invasive activity of the human hepatoma cell line PLC/PRF/5. Okamoto, Y., Nakano, H. Anticancer Res. (1999) [Pubmed]
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