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Gene Review

Timp1  -  tissue inhibitor of metalloproteinase 1

Mus musculus

Synonyms: Clgi, Collagenase inhibitor 16C8 fibroblast, EPA, Erythroid-potentiating activity, Metalloproteinase inhibitor 1, ...
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Disease relevance of Timp1

  • Here we show that Timp1 gene transfer delivered by an adeno-associated virus (AAV) vector inhibits tumor growth in a murine xenotransplant model [1].
  • A human Kaposi's sarcoma cell line, forming highly vascularized tumors in vivo and having a high natural permissivity to AAV gene transfer, was transduced to express the Timp1 cDNA [1].
  • Here, we examined the expression of matrix metalloproteases (MMP) -2, -3, -9, -12, and -13 and their inhibitors, tissue inhibitor of metalloproteases (TIMP) -1, -2, and -3, in the livers of infected mice and correlated their expression profiles with fibrosis and type 2 cytokine production [2].
  • Interestingly, enzymatic activities of MMP-12 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions, demonstrating that MMP/TIMP balance is shifted toward increased matrix degradation in obesity [3].
  • These data, in addition to our knockout studies, demonstrate that TIMP-1/TIMP-2 play no essential role in fibrogenesis in schistosomiasis [2].

Psychiatry related information on Timp1

  • In the TPA-induced ear inflammation model, the three compounds showed a moderate reduction of edema, and 1 produced a significant increase in the reaction time against thermal painful stimuli in the tail immersion test [4].
  • Because arachidonic acid-derived eicosanoids are potent modulators of hyperproliferation and inflammation during skin tumor promotion with the phorbol ester, 12-0-tetradecanoylphorbol-13-acetate (TPA) (17, 18), it was hypothesized that dietary modification of epidermal fatty acids might modulate TPA-induced biochemical events in mouse skin [5].

High impact information on Timp1

  • These changes are blocked by coexpression of a TIMP1 transgene [6].
  • Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction [7].
  • Although the mechanisms governing the production of TIMP are unknown, immunologically identical forms of this glycoprotein have been detected in a wide variety of human body fluids and cell and tissue culture media [8].
  • These results indicate that TIMP suppresses oncogenicity, at least in immortal murine 3T3 cells [9].
  • Mouse 3T3 cell lines capable of constitutively synthesizing an RNA complementary to the messenger RNA encoding TIMP, tissue inhibitor of metalloproteinases, were constructed by transfection with appropriate plasmid constructs [9].

Chemical compound and disease context of Timp1


Biological context of Timp1

  • Histological analyses showed that the AAV-Timp1-transduced tumors had limited development of vascular structures and extensive areas of cell death, suggesting that Timp1 overexpression had an antiangiogenic effect [1].
  • These results indicate that transfer and overexpression of the Timp1 gene is a promising therapeutic strategy to target tumor-associated angiogenesis in cancer gene therapy [1].
  • In the present study, we examined the role of TIMP-1 in de novo hepatocyte cell division during liver regeneration [15].
  • Conversely, TIMP-1 gain of function delayed cell cycle progression [15].
  • We have previously demonstrated that TIMP-1 inhibits preneoplastic hepatocyte proliferation by attenuating growth factor bioavailability [15].

Anatomical context of Timp1

  • To further support this conclusion, we demonstrated that AAV-Timp1 transduction significantly reduced endothelial cell migration and the invasion of a Matrigel barrier and strongly inhibited angiogenesis in the chick chorioallantoic membrane assay [1].
  • Induction of TIMP-1 occurred during the peak of hepatocyte DNA synthesis [15].
  • In situ localization experiments revealed a dichotomy between MMP expression that was restricted to leukocytes and possibly microglia within inflammatory lesions and TIMP-1 expression that was observed in activated astrocytes circumscribing the lesions [16].
  • Concomitant with the formation of an extensive hyperproliferative epithelium, TIMP-1 transcripts accumulated at the mesenchymal/epidermal border of the granulation tissue [17].
  • METHODS: Ribonuclease protection assays were used to detect and quantitate TIMP mRNA expression in uninfected (wounded and unwounded) and in wounded corneas inoculated with P. aeruginosa [18].

Associations of Timp1 with chemical compounds


Physical interactions of Timp1

  • Transfection of a series of Timp-1 promoter constructs identified three regions through which TSA superinduces PMA-induced Timp-1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v-ets) oncogene homologue (Ets) or Sp1 binding motif [24].
  • In addition, resveratrol prevented TPA-induced DNA binding of activator protein-1 (AP-1) [25].
  • In another study, topical application of TPA induced DNA binding of cyclic AMP response element binding (CREB) protein in mouse skin in vivo, which was abrogated by pretreatment with either CB or DC [26].
  • Strikingly, Jnk1(-/-) mouse skin was more sensitive to TPA-induced AP-1 DNA binding activity and phosphorylation of extracellular signal-regulated kinases and Akt, which are two important survival signaling components [27].
  • Based on above findings, CB and BB are likely to inhibit TPA-induced COX-2 expression through suppression of DNA binding of NF-kappaB, which may contribute to the chemopreventive or chemoprotective activity of these African plants [28].

Regulatory relationships of Timp1

  • Because of these findings, we infected IL-10/IFN-gamma-deficient mice that develop an exaggerated fibrotic response to determine whether changes in type 2 cytokine dominance influence the pattern of MMP and TIMP expression [2].
  • Here, we (i) investigate the mechanism(s) by which TGF-beta1 induces expression of the Timp-1 gene and (ii) compare this with TGF-beta1 repression of phorbol ester-induced MMP-1 expression [29].
  • CONCLUSION: We provide evidence that the alteration of the MMP/TIMP balance in astrocytes influences their reactivity to pro-inflammatory stimuli and that Fas activation modulates the expression of members of the MMP/TIMP axis [30].
  • It is concluded from this study that TIMP-1 plays a pivotal role in regulating uterine stromelysins both at the level of protease activity and the level of transcript expression [31].
  • This suggests that blocking TPA-induced AP-1- or NF kappa B-regulated gene expression by TAM67 inhibits TPA-induced progression [32].

Other interactions of Timp1

  • In contrast, in u-PA(-/-) mice or in WT mice after PAI-1- and TIMP-1-gene transfer, cardiomyocyte hypertrophy was moderate and only minimally associated with cardiac fibrosis and LV dilatation, resulting in better preservation of pump function [33].
  • Lethal infection induced increased levels of MMP-3 and MMP-12 mRNAs as well as that of tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) compared to sublethal infection [34].
  • There were no significant changes in TIMP-3 message levels in retinal tissues, and TIMP-1 message and protein were undetectable [35].
  • We have isolated cDNA clones corresponding to a new member of the murine tissue inhibitor of metalloproteinase (TIMP) family, designated Timp-4 [22].
  • The gene expression and protein distribution of matrix metalloproteinase (MMP) -2, -9, membrane type-1 MMP (MT1-MMP), as well as of TIMP-1, -2, and -3 were analyzed during mouse molar development [36].

Analytical, diagnostic and therapeutic context of Timp1

  • The expression of all classes of MMPs and TIMP-1 and TIMP-2 by MOB in culture was demonstrated by reverse transcriptase-polymerase chain reaction [37].
  • In addition, retinal tissue removed from control (without NV) and experimental animals (with NV) was analyzed for the expression of TIMP-1, TIMP-2, and TIMP-3 mRNA and protein using RT-PCR and Western blot analysis [35].
  • We have used real-time quantitative reverse transcriptase PCR (TaqMan) to quantify the expression of the four tissue inhibitor of metalloproteinases (Timp) genes in mouse tissues during development and in the adult [38].
  • Via Northern and in situ hybridization, we have analyzed the spatio-temporal expression patterns of members of the MMP family (stromelysin-3, gelatinases A and B), as well as their inhibitors TIMP-1, -2 and -3 in late murine placenta (days 10.5 to 18.5 of gestation) [39].
  • Detailed restriction mapping shows that Timp is transcribed in the same direction as Araf but in the opposite direction to the Syn-1 gene [40].


  1. AAV-mediated gene transfer of tissue inhibitor of metalloproteinases-1 inhibits vascular tumor growth and angiogenesis in vivo. Zacchigna, S., Zentilin, L., Morini, M., Dell'Eva, R., Noonan, D.M., Albini, A., Giacca, M. Cancer Gene Ther. (2004) [Pubmed]
  2. Regulation of hepatic fibrosis and extracellular matrix genes by the th response: new insight into the role of tissue inhibitors of matrix metalloproteinases. Vaillant, B., Chiaramonte, M.G., Cheever, A.W., Soloway, P.D., Wynn, T.A. J. Immunol. (2001) [Pubmed]
  3. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. Chavey, C., Mari, B., Monthouel, M.N., Bonnafous, S., Anglard, P., Van Obberghen, E., Tartare-Deckert, S. J. Biol. Chem. (2003) [Pubmed]
  4. Analgesic, anti-inflammatory, antipyretic and haematological effects of aethiopinone, an o-naphthoquinone diterpenoid from Salvia aethiopis roots and two hemisynthetic derivatives. Hernández-Pérez, M., Rabanal, R.M., de la Torre, M.C., Rodríguez, B. Planta Med. (1995) [Pubmed]
  5. Modulation of phorbol ester-elicited events in mouse epidermis by dietary n-3 and n-6 fatty acids. Belury, M.A., Leyton, J., Patrick, K.E., Cumberland, A.G., Locniskar, M., Fischer, S.M. Prostaglandins Leukot. Essent. Fatty Acids (1991) [Pubmed]
  6. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Sternlicht, M.D., Lochter, A., Sympson, C.J., Huey, B., Rougier, J.P., Gray, J.W., Pinkel, D., Bissell, M.J., Werb, Z. Cell (1999) [Pubmed]
  7. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Heymans, S., Luttun, A., Nuyens, D., Theilmeier, G., Creemers, E., Moons, L., Dyspersin, G.D., Cleutjens, J.P., Shipley, M., Angellilo, A., Levi, M., Nübe, O., Baker, A., Keshet, E., Lupu, F., Herbert, J.M., Smits, J.F., Shapiro, S.D., Baes, M., Borgers, M., Collen, D., Daemen, M.J., Carmeliet, P. Nat. Med. (1999) [Pubmed]
  8. Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Docherty, A.J., Lyons, A., Smith, B.J., Wright, E.M., Stephens, P.E., Harris, T.J., Murphy, G., Reynolds, J.J. Nature (1985) [Pubmed]
  9. Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Khokha, R., Waterhouse, P., Yagel, S., Lala, P.K., Overall, C.M., Norton, G., Denhardt, D.T. Science (1989) [Pubmed]
  10. TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. Kim, H., Oda, T., López-Guisa, J., Wing, D., Edwards, D.R., Soloway, P.D., Eddy, A.A. J. Am. Soc. Nephrol. (2001) [Pubmed]
  11. Pattern of messenger ribonucleic acid expression of tissue inhibitors of metalloproteinases (TIMPs) during testicular maturation in male mice lacking a functional TIMP-1 gene. Nothnick, W.B., Soloway, P.D., Curry, T.E. Biol. Reprod. (1998) [Pubmed]
  12. Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice. Kim, K.H., Burkhart, K., Chen, P., Frevert, C.W., Randolph-Habecker, J., Hackman, R.C., Soloway, P.D., Madtes, D.K. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  13. Steroidal regulation of uterine edema and tissue inhibitors of metalloproteinase (TIMP)-3 messenger RNA expression is altered in TIMP-1-deficient mice. Nothnick, W.B., Zhang, X., Zhou, H.E. Biol. Reprod. (2004) [Pubmed]
  14. Carvedilol improves left ventricular function in murine coxsackievirus-induced acute myocarditis association with reduced myocardial interleukin-1beta and MMP-8 expression and a modulated immune response. Pauschinger, M., Rutschow, S., Chandrasekharan, K., Westermann, D., Weitz, A., Peter Schwimmbeck, L., Zeichhardt, H., Poller, W., Noutsias, M., Li, J., Schultheiss, H.P., Tschope, C. Eur. J. Heart Fail. (2005) [Pubmed]
  15. Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. Mohammed, F.F., Pennington, C.J., Kassiri, Z., Rubin, J.S., Soloway, P.D., Ruther, U., Edwards, D.R., Khokha, R. Hepatology (2005) [Pubmed]
  16. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states. Pagenstecher, A., Stalder, A.K., Kincaid, C.L., Shapiro, S.D., Campbell, I.L. Am. J. Pathol. (1998) [Pubmed]
  17. Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Madlener, M., Parks, W.C., Werner, S. Exp. Cell Res. (1998) [Pubmed]
  18. Early TIMP gene expression after corneal infection with Pseudomonas aeruginosa. Kernacki, K.A., Goebel, D.J., Poosch, M.S., Hazlett, L.D. Invest. Ophthalmol. Vis. Sci. (1998) [Pubmed]
  19. Stromelysin-1 regulates adipogenesis during mammary gland involution. Alexander, C.M., Selvarajan, S., Mudgett, J., Werb, Z. J. Cell Biol. (2001) [Pubmed]
  20. Pentosan polysulfate decreases proliferation and net extracellular matrix production in mouse mesangial cells. Elliot, S.J., Striker, L.J., Stetler-Stevenson, W.G., Jacot, T.A., Striker, G.E. J. Am. Soc. Nephrol. (1999) [Pubmed]
  21. Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells. Crocker, S.J., Milner, R., Pham-Mitchell, N., Campbell, I.L. J. Neurochem. (2006) [Pubmed]
  22. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. Leco, K.J., Apte, S.S., Taniguchi, G.T., Hawkes, S.P., Khokha, R., Schultz, G.A., Edwards, D.R. FEBS Lett. (1997) [Pubmed]
  23. Temporal and spatial expression of tissue inhibitors of metalloproteinases during the natural ovulatory cycle of the mouse. Inderdeo, D.S., Edwards, D.R., Han, V.K., Khokha, R. Biol. Reprod. (1996) [Pubmed]
  24. Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-beta1 induced murine tissue inhibitor of metalloproteinases-1 gene expression. Young, D.A., Billingham, O., Sampieri, C.L., Edwards, D.R., Clark, I.M. FEBS J. (2005) [Pubmed]
  25. Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets. Kundu, J.K., Chun, K.S., Kim, S.O., Surh, Y.J. Biofactors (2004) [Pubmed]
  26. Inhibitory effects of the extracts of Sutherlandia frutescens (L.) R. Br. and Harpagophytum procumbens DC. on phorbol ester-induced COX-2 expression in mouse skin: AP-1 and CREB as potential upstream targets. Kundu, J.K., Mossanda, K.S., Na, H.K., Surh, Y.J. Cancer Lett. (2005) [Pubmed]
  27. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. She, Q.B., Chen, N., Bode, A.M., Flavell, R.A., Dong, Z. Cancer Res. (2002) [Pubmed]
  28. Inhibition of phorbol ester-induced COX-2 expression by some edible African plants. Na, H.K., Mossanda, K.S., Lee, J.Y., Surh, Y.J. Biofactors (2004) [Pubmed]
  29. The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-beta 1. Hall, M.C., Young, D.A., Waters, J.G., Rowan, A.D., Chantry, A., Edwards, D.R., Clark, I.M. J. Biol. Chem. (2003) [Pubmed]
  30. Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study. Ogier, C., Creidy, R., Boucraut, J., Soloway, P.D., Khrestchatisky, M., Rivera, S. BMC neuroscience [electronic resource]. (2005) [Pubmed]
  31. Disruption of the tissue inhibitor of metalloproteinase-1 gene in reproductive-age female mice is associated with estrous cycle stage-specific increases in stromelysin messenger RNA expression and activity. Nothnick, W.B. Biol. Reprod. (2001) [Pubmed]
  32. A dominant negative mutant of jun blocking 12-O-tetradecanoylphorbol-13-acetate-induced invasion in mouse keratinocytes. Dong, Z., Crawford, H.C., Lavrovsky, V., Taub, D., Watts, R., Matrisian, L.M., Colburn, N.H. Mol. Carcinog. (1997) [Pubmed]
  33. Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Heymans, S., Lupu, F., Terclavers, S., Vanwetswinkel, B., Herbert, J.M., Baker, A., Collen, D., Carmeliet, P., Moons, L. Am. J. Pathol. (2005) [Pubmed]
  34. Matrix metalloproteinase expression correlates with virulence following neurotropic mouse hepatitis virus infection. Zhou, J., Stohlman, S.A., Atkinson, R., Hinton, D.R., Marten, N.W. J. Virol. (2002) [Pubmed]
  35. The balance between proteinases and inhibitors in a murine model of proliferative retinopathy. Majka, S., McGuire, P., Colombo, S., Das, A. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  36. Temporospatial gene expression and protein localization of matrix metalloproteinases and their inhibitors during mouse molar tooth development. Yoshiba, N., Yoshiba, K., Stoetzel, C., Perrin-Schmitt, F., Cam, Y., Ruch, J.V., Lesot, H. Dev. Dyn. (2003) [Pubmed]
  37. Stromelysin (MMP-3) synthesis is up-regulated in estrogen-deficient mouse osteoblasts in vivo and in vitro. Breckon, J.J., Papaioannou, S., Kon, L.W., Tumber, A., Hembry, R.M., Murphy, G., Reynolds, J.J., Meikle, M.C. J. Bone Miner. Res. (1999) [Pubmed]
  38. Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene. Young, D.A., Phillips, B.W., Lundy, C., Nuttall, R.K., Hogan, A., Schultz, G.A., Leco, K.J., Clark, I.M., Edwards, D.R. Biochem. J. (2002) [Pubmed]
  39. Expression of matrix metalloproteinases during murine chorioallantoic placenta maturation. Teesalu, T., Masson, R., Basset, P., Blasi, F., Talarico, D. Dev. Dyn. (1999) [Pubmed]
  40. Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes. Derry, J.M., Barnard, P.J. Genomics (1992) [Pubmed]
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