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The Tissue Inhibitors of Metalloproteinases (TIMPs)

Biology and Regulation
  • Dylan R. Edwards
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

The Tissue Inhibitors of Metalloproteinases (TIMPs) are a family of secreted proteins whose primary function is to limit the degradative actions of the matrix metalloproteinases (MMPs) during tissue remodeling (1). This ability to neutralize the collagenases, stromelysins, gelatinases, and membrane-type-MMPs that destroy basement membranes and tissue matrices is central to their potency as suppressors of tumor invasion, metastasis, and angiogenesis. It is also consistent with their involvement in the orchestrated remodeling that occurs during wound repair and embryogenesis. However, TIMPs may be multifunctional, since additional effects on cell growth and apoptosis have been reported, and in some cases these activities appear to be distinct from their MMP inhibitory capabilities.

Keywords

Fibroblast Growth Factor Receptor Tissue Inhibitor Retinal Pigment Epithelial Chicken Embryo Fibroblast Human Gingival Fibroblast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Nagase, H. and Woessner, J. F. Jr. (1999) Matrix metalloproteinases. J. Biol. Chem. 274, 21491–21494.PubMedCrossRefGoogle Scholar
  2. 2.
    Greene, J., Wang, M., Liu, Y. E., Raymond, L. A., Rosen, C., and Shi, Y. E. (1996) Molecular cloning and characterization of human Tissue Inhibitor of Metalloproteinases 4. J. Biol. Chem. 271, 30375–30380.PubMedCrossRefGoogle Scholar
  3. 3.
    Pohar, N., Godenschwege, T. A., and Buchner, E. (1999) Invertebrate tissue inhibitor of metalloproteinase: structure and nested gene organization within the synapsin locus is conserved from Drosophila to human. Genomics 57, 293–296.PubMedCrossRefGoogle Scholar
  4. 4.
    Weber, B. H., Vogt, G., Pruett, R. C., Stohr, H., and Felbor, U. (1994) Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nature Genetics 8, 352–356.PubMedCrossRefGoogle Scholar
  5. 5.
    Denhardt, D. T., Feng, B., Edwards, D. R., Cocuzzi, E. T., and Malyankar, U. M. (1993) Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmac. Ther. 59, 329–341.CrossRefGoogle Scholar
  6. 6.
    Edwards, D. R., Beaudry, P. P., Laing, T. D., Kowal, V., Leco, K. J., Leco, P. A., and Lim, M. S. (1996) The roles of tissue inhibitors of metalloproteinases in tissue remodeling and cell growth. Int. J. Obes. 20, S9 - S15.Google Scholar
  7. 7.
    Gomez, D. E., Alonso, D. F., Yoshiji, H., and Thorgeirsson, U. P. (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur. J. Cell Biol. 74, 111–122.PubMedGoogle Scholar
  8. 8.
    Strongin, A. Y., Marmer, B. L., Grant, G. A., and Goldberg, G. I. (1993) Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2. J. Biol. Chem. 268, 14033–14039.PubMedGoogle Scholar
  9. 9.
    Will, H., Atkinson, S. J., Butler, G., Smith, B., and Murphy, G. (1996) The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation- Regulation by TIMP-2 and TIMP-3. J. Biol. Chem. 271, 17119–17123.PubMedCrossRefGoogle Scholar
  10. 10.
    Apte, S. S., Murphy, G., and Olsen, B. R. (1995) The gene structure of Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) and its inhibitory activities define the distinct TIMP family. J. Biol. Chem. 270, 14313–14318.PubMedCrossRefGoogle Scholar
  11. 11.
    Black, R. A. and White, J. M. (1998) ADAMs: focus on the protease domain. Curr. P. Cell Biol. 10, 654–659.CrossRefGoogle Scholar
  12. 12.
    Blobel C. P. (1997) Metalloprotease-Disintegrins: Links to cell adhesion and cleavage of TNFa and Notch. Cell 90, 589–592.PubMedCrossRefGoogle Scholar
  13. 13.
    Black, R. A., Rauch, C. T., Kozlosky, C. J., et al. (1997) A metalloproteinase disintegrin that releases tumor-necrosis factor-alpha from cells. Nature 385, 729–733.PubMedCrossRefGoogle Scholar
  14. 14.
    Qi, H., Rand, M. D., Wu, X., Sestan, N., Wang, W., Rakic, P., et al. (1999) Processing of the Notch ligand Delta by the metalloprotease kuzbanian. Science 283, 91–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Amour, A., Slocombe, P. M., Webster, A., Butler, M., Knight, C. G., Smith, B. J., et al. (1998) TNF-a converting enzyme (TACE) is inhibited by TIMP-3. FEBS Letts. 435, 39–44.CrossRefGoogle Scholar
  16. 16.
    Borland, G., Murphy, G., and Ager, A. (1999) Tissue inhibitor of metalloproteinase-3 inhibits shedding of L-selectin from leukocytes. J. Biol. Chem. 274, 2810–2815.PubMedCrossRefGoogle Scholar
  17. 17.
    Hargreaves, P. G., Wang, F., Antcliff, J., Murphy, G., Lawry, J., Russell, G. G., et al. (1998) Human myeloma cells shed the interleukin-6 receptor: inhibition by tissue inhibitor of metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor. Br. J. Haematol. 101, 694–702.PubMedCrossRefGoogle Scholar
  18. 18.
    Peschon, J. J., Slack, J. L., Reddy, P., et al. (1998) An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284.PubMedCrossRefGoogle Scholar
  19. 19.
    Lombard, M. A., Wallace, T. L., Kubicek, M. F., Petzold, G. L., Mitchell, M. A., Hendges, S. K., et al. (1998) Synthetic matrix metalloproteinase inhibitors and tissue inhibitor of metalloproteinase -2 (TIMP-2), but not TIMP-1, inhibit shedding of tumor necrosis factor-a receptors in a human colon adenocarcinoma (Co1o205) cell line. Cancer Res. 58, 4001–4007.PubMedGoogle Scholar
  20. 20.
    Codony-Servat, J., Albanell, J., Lopez-Talavera, J. C., Arribas, J., and Baselga, J. (1999) Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the Tissue Inhibitor of Metalloproteinases-1 in breast cancer cells. Cancer Res. 59, 1196–1201.PubMedGoogle Scholar
  21. 21.
    Murphy, G., Houbrechts, A., Cockett, M. I., Williamson, R. A., O’Shea M., and Docherty, A. J. P. (1991) The N-terminal domain of tissue inhibitor of metalloproteinase retains metalloproteinase inhibitory activity. Biochemistry 30, 8097–8102.PubMedCrossRefGoogle Scholar
  22. 22.
    Williamson, R. A., Martorell, G., Carr, M. D., Murphy, G., Docherty, A. J. P., Freedman, R. B., et al. (1994) Solution structure of the active domain of tissue inhibitor of metalloproteinases-2: A new member of the OB fold protein family. Biochemistry 33, 11745–11759.PubMedCrossRefGoogle Scholar
  23. 23.
    Gomis-Ruth, F-X., Maskos, K., Betz, M., Bergner, A., Huber, R., Suzuki, K., et al. (1997) Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 389, 77–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Fernandez-Catalan, C., Bode, W., Huber, R., Turk, D., Calvete, J. J., Lichte, A., et al. (1998) Crystal structure of the complex formed by the membrane type-l-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. EMBO J. 17, 5238–5248.PubMedCrossRefGoogle Scholar
  25. 25.
    Wingfield, P. T., Sax, J. K., Stahl, S. J., Kaufman, J., Palmer, I., Chung, V., et al. (1999) Biophysical and functional characterization of full length recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherischia coli. J. Biol. Chem. 274, 21362–21368.Google Scholar
  26. 26.
    Huang, W., Meng, Q., Suzuki, K., Nagase, H., and Brew, K. (1997) Mutational study of the amino-terminal domain of human tissue inhibitor of metalloproteinase 1 (TIMP-1) locates an inhibitory region for matrix metalloproteinases. J. Biol. Chem. 272, 22086–22091.PubMedCrossRefGoogle Scholar
  27. 27.
    Meng, Q., Malinovskii, V., Huang, W., Chung, L., Nagase, H., Bode, W., et al. (1999) Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1’ residue of substrate. J. Biol. Chem. 274, 10184–10189.PubMedCrossRefGoogle Scholar
  28. 28.
    Butler, G. S., Hutton, M., Wattam, B. A., Williamson, R. A., Knäuper, V., Willenbrock, F., et al. (1999) The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. J. Biol. Chem. 274, 20391–20396.PubMedCrossRefGoogle Scholar
  29. 29.
    Nemunaitis, J., Poole, C., Primrose, J., Rosemurgy, A., Malfetano, J., Brown, P., et al. (1998) Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin. Cancer Res. 4, 1101–1109.PubMedGoogle Scholar
  30. 30.
    Murphy, G. and Knäuper, V. (1997) Relating matrix metalloproteinase structure to function: Why the “hemopexin” domain? Matrix Biol. 15, 511–518.PubMedCrossRefGoogle Scholar
  31. 31.
    Overall, C. M., King, A. E., Sam, D. K., Ong, A. D., Lau, T. T., Wallon, U. M., et al. (1999) Identification of the tissue inhibitor of metalloproteinases-2 (TIMP-2) binding site on the hemopexin carboxyl domain of human gelatinase A by site-directed mutagenesis. The hierarchical role in binding TIMP-2 of the unique cationic clusters of hemopexin modules II and IV. J. Biol. Chem 274, 4421–4429.PubMedCrossRefGoogle Scholar
  32. 32.
    Butler, G. S., Butler, M. J., Atkinson, S. A., Will, H., Tamura, T., Schade van Westrum, S., et al. (1998). The TIMP2 membrane type 1 metalloproteinase “receptor” regulates the concentration and efficient activation of progelatinase A. J. Biol. Chem. 273, 873–880.CrossRefGoogle Scholar
  33. 33.
    O’Connell, J. P., Willenbrock, F., Docherty, A. J. P., Eaton, D., and Murphy, G. (1994) Analysis of the role of the COOH-terminal domain in the activation, proteolytic activity and tissue inhibitor of metalloproteinase interactions of gelatinase B. J. Biol. Chem. 269, 14967–14973.PubMedGoogle Scholar
  34. 34.
    Bigg, H. F., Shi, Y. E., Liu, Y. E., Steffenson, B., and Overall, C. M. (1997) Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. J. Biol. Chem. 272, 15496–15500.PubMedCrossRefGoogle Scholar
  35. 35.
    Butler, G. S., Apte, S. S., Willenbrock, F., and Murphy, G. (1999) Human tissue inhibitor of metalloproteinases 3 interacts with both N- and C-terminal domains of gelatinases A and B. J. Biol. Chem. 274, 10846–10851.PubMedCrossRefGoogle Scholar
  36. 36.
    Itoh, Y. and Nagase, H. (1995) Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase. J. Biol. Chem. 270, 16518–16521.PubMedCrossRefGoogle Scholar
  37. 37.
    Apte, S. S., Fukai, N., Beier, D. R., and Olsen, B. R. (1997) The matrix metalloproteinase14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis. J. Biol. Chem. 272, 25511–25517.PubMedCrossRefGoogle Scholar
  38. 38.
    Gasson, J. C., Golde, D. W., Kaufman, S. E., Westbrook, C. A., Hewick, R. M., Kaufman, R. J., et al. (1985) Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 315, 768–771.PubMedCrossRefGoogle Scholar
  39. 39.
    Hayakawa, T., Yamashita, K., Tanzawa, K., Uchijima, E., and Iwata, K. (1992) Growth promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. FEBS Letts. 298, 29–32.CrossRefGoogle Scholar
  40. 40.
    Hayakawa, T., Yamashita, K., Ohuchi, E., and Shinagawa, A. (1994) Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J. Cell Sci. 107, 2373–2379.PubMedGoogle Scholar
  41. 41.
    Corcoran, M. L. and Stetler-Stevenson, W. G. (1995) Tissue inhibitor of metalloproteinases-2 (TIMP-2) stimulates fibroblast proliferation via a cyclic adenosine 3’,5’-monophosphate (cAMP)-dependent mechanism. J. Biol. Chem. 270, 13453–13459.PubMedCrossRefGoogle Scholar
  42. 42.
    Nemeth, J. A., Rafe, A., Steiner, M., and Goolsby, C. L. (1996) TIMP-2 growth-stimulatory activity: a concentration-and cell type-specific response in the presence of insulin. Exp. Cell Res. 224, 110–115.PubMedCrossRefGoogle Scholar
  43. 43.
    Chesler, L., Golde, D. W., Bersch, N., and Johnson, M. D. (1995) Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1. Blood 86, 4506–4515.PubMedGoogle Scholar
  44. 44.
    Yamashita, K., Suzuki, M., Iwata, H., Koike, T., Hamaguchi, M., Shinagawa, A., et al. (1996) Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). FEBS Letts. 396, 103–107.CrossRefGoogle Scholar
  45. 45.
    Kossakowska, A. E., Urbanski, S., and Edwards, D. R. (1991) Tissue inhibitor of metalloproteinases (TIMP) RNA is expressed at elevated levels in malignant non-Hodgkin’s lymphomas. Blood 77, 2475–2481.PubMedGoogle Scholar
  46. 46.
    Stetler-Stevenson, M., Mansoor, A., Lim, M. S., Fukushima, P., Kerhl, J., Marti, G., et al. (1997) Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) in reactive and neoplastic lymph nodes. Blood 89, 1708–1715.PubMedGoogle Scholar
  47. 47.
    Zeng, Z. S., Cohen, A. M., Zhang, Z. F., Stetler-Stevenson, W., and Guillem, J. G. (1995) Elevated tissue inhibitor of metalloproteinase 1 RNA in colorectal cancer stroma correlates with lymph node and distant metastases. Clin. Cancer Res. 1, 899–906.PubMedGoogle Scholar
  48. 48.
    Grignon, D. J., Sakr, W., Toth, M., Ravery, V., Angulo, J., Shamsa, F., et al. (1996) High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res. 56, 1654–1659.PubMedGoogle Scholar
  49. 49.
    Holten-Andersen, M. N., Murphy, G., Nielsen, H. J., Pedersen, A. N., Christensen, I. J., Hoyer-Hansen, G., et al. (1999) Quantitation of TIMP-1 in plasma of healthy blood donors and patients with advanced cancer. Br. J. Cancer 80, 495–503.PubMedCrossRefGoogle Scholar
  50. 50.
    Ritter, L. M., Garfield, S. H., and Thorgeirsson, U. P. (1999) Tissue inhibitor of metalloproteinases-, (TIMP-1) binds to the cell surface and translocates to the nucleus of human MCF-7 breast carcinoma cells. Biochim. Biophys. Res. Comm. 257, 494–499.CrossRefGoogle Scholar
  51. 51.
    Zhao, W. Q., Li, H., Yamashita, K., Guo, X. K., Hoshino, T., Yoshida, S., et al. (1998) Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts. J. Cell Sci. 111, 1147–1153.PubMedGoogle Scholar
  52. 52.
    Fowlkes, J. L., Enghild, J. J., Suzuki, K., and Nagase, H. (1994) Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures. J. Biol. Chem. 269, 25742–25746.PubMedGoogle Scholar
  53. 53.
    Manes, S., Llorente, M., Lacalle, R. A., Gómez-Moutón, C., Kremer, L., Mira, E., et al. (1999) The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J. Biol. Chem. 274, 6935–6945.PubMedCrossRefGoogle Scholar
  54. 54.
    Levi, E., Fridman, R., Miao, H-Q., Ma, Y-S., Yayon, A., and Voldoaysky, I. (1996) Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc. Natl. Acad. Sci. USA 93, 7069–7074.PubMedCrossRefGoogle Scholar
  55. 55.
    Orlando, S., Sironi, M., Bianchi, G., Drummond, A. H., Boraschi, D., Yabes, D., et al. (1997) Role of Metalloproteases in the Release of the IL-1 type II Decoy Receptor. J. Biol. Chem. 272, 31764–31769.PubMedCrossRefGoogle Scholar
  56. 56.
    Boujrad, N., Ogwuegbu, S. O., Gamier, M., Lee, C-H., Martin, B. M., and Papadopoulos, V. (1995) Identification of a stimulator of steroid hormone synthesis isolated from testis. Science 268, 1609–1612.PubMedCrossRefGoogle Scholar
  57. 57.
    Nothnick, W. B., Soloway, P., and Curry, T. E. Jr. (1997) Assessment of the role of tissue inhibitor of metalloproteinases-1 (TIMP-1) during the periovulatory period in female mice lacking a functional TIMP-1 gene. Biol. Reprod. 56, 1181–1188.PubMedCrossRefGoogle Scholar
  58. 58.
    Guedez, L., Courtemanch, L., and Stetler-Stevenson, M. (1998) Tissue Inhibitor of Metalloproteinase (TIMP-1) induces differentiation and an antiapoptotic phenotype in germinal center B cells. Blood 92, 1342–1349.PubMedGoogle Scholar
  59. 59.
    Guedez, L., Stetler-Stevenson, W. G., Wolff, L., Wang, J., Fukushima, P., Mansoor, A., et al. (1998) In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-l. J. Clin. Invest. 102, 2002–2010.PubMedCrossRefGoogle Scholar
  60. 60.
    Valente, P., Fassina, G., Melchiori, A., Masiello, L., Cilli, M., Vacca, A., et al. (1998) TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. Int. J. Cancer 75, 246–253.PubMedCrossRefGoogle Scholar
  61. 61.
    Baker, A. H., Zaltsman A. B., George, S. J., and Newby, A. C. (1998) Divergent effects of tissue inhibitors of metalloproteinase-1, -2 and -3 overexpression on rat vascular smooth muscle cell invasion, proliferation and death in vitro. J. Clin. Invest. 101, 1478–1487.PubMedCrossRefGoogle Scholar
  62. 62.
    Ahonen, M., Baker, A. H., and Kahari, V. M. (1998) Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res. 58, 2310–2315.PubMedGoogle Scholar
  63. 63.
    Baker, A. H., George, S. J., Zaltsman, A. B., Murphy, G., and Newby, A. C. (1999) Inhibition f invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br. J. Cancer 79, 1347–1355.PubMedCrossRefGoogle Scholar
  64. 64.
    Smith, M. R., Kung, H-F., Dumm, S. K., Colbum, N. H., and Sun, Y. (1997) TIMP-3 induces cell death by stabilizing TNF-a receptors on the surface of human colon carcinoma cells. Cytokine 9, 770–780.PubMedCrossRefGoogle Scholar
  65. 65.
    Blenis, J. and Hawkes, S. P. (1983) Transformation-sensitive protein associated with the cell substratum of chicken embryo fibroblasts. Proc. Natl. Acad. Sci. USA 80, 770–774.PubMedCrossRefGoogle Scholar
  66. 66.
    Yang, T-T. and Hawkes, S. P. (1992) Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. Proc. Natl. Acad. Sci. USA 89, 10,676–10, 680.Google Scholar
  67. 67.
    Alexander, C. M., Hansell, E. J., Behrendtsen, O., Flannery, M. L., Kishnani, N. S., Hawkes, S. P., et al. (1996) Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development 122, 1723–1736.PubMedGoogle Scholar
  68. 68.
    Anand-Apte, B., Pepper, M. S., Voest, E., Montesano, R., Olsen, B., Murphy, G., et al. (1997) Inhibition of angiogenesis by tissue inhibitor of metalloproteinas-3. Invest. Opthalmol. 38, 817–823.Google Scholar
  69. 69.
    Langton, K. P., Barker, M. D., and McKie, N. (1998). Localization of the functional domains of human tissue inhibitor of metalloproteinase-3 and the effects of a Sorsby’s fundus dystrophy mutation. J. Biol. Chem. 273, 16778–16781.PubMedCrossRefGoogle Scholar
  70. 70.
    Polkinghorne, P. J., Capon, M. R. C., Berninger, T., Lyness, A. L., Sehmi, K., and Bird, A. C. (1989) Sorsby’s fundus dystrophy: a clinical study. Opthalmology 96, 1763–1768.Google Scholar
  71. 71.
    Capon, M. R. C., Marshall, J., Krafft, J. I., Alexander, R. A., Hiscott, P. S., and Bird, A. C. (1989) Sorsby’s fundus dystrophy: a light and electron microscopy study. Opthalmology 96, 1769–1777.Google Scholar
  72. 72.
    Fariss, R. N., Apte, S. S., Olsen, B. R., Iwata, K., and Milam, A. H. (1997) Tissue inhibitor of metalloproteinases-3 is a component of Bruch’s membrane of the eye. Am. J. Pathol. 150, 323–328.PubMedGoogle Scholar
  73. 73.
    Chambers, A. F. and Matrisian, L. M. (1997) Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer. Inst. 89, 1260–1270.PubMedCrossRefGoogle Scholar
  74. 74.
    Koop, S., Schmidt, E. E., MacDonald, I. C., Morris, V. L., Khokha, R., Grattan, M., et al. (1996) Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well. Proc. Natl. Acad. Sci. USA 93, 11080–11084.PubMedCrossRefGoogle Scholar
  75. 75.
    Koop, S., Khokha, R., Schmidt, E. E., MacDonald, I. C., Morris, V. L., Chambers, A. E, et al. (1994) Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravastion but reduces tumor growth. Cancer Res. 54, 4791–4797.PubMedGoogle Scholar
  76. 76.
    Lochter, A., Galosy, S., Muschler, J., Freedman, N., Werb, Z., and Bissell, M. J. (1997) Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J. Cell Biol. 139, 1861–1872.PubMedCrossRefGoogle Scholar
  77. 77.
    Martin, D. C., Rüther, U., Sanchez-Sweatman, O. H., Orr, E W., and Khokha, R. (1996) Inhibition of SV40 T antigen-induced hepatocellular carcinoma in TIMP-1 transgenic mice. Oncogene 13, 569–576.PubMedGoogle Scholar
  78. 78.
    Martin, D.C., Fowlkes, J.L., Babic, B., and Khokha, R. (1999) Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. J. Cell Biol. 146, 881–892.PubMedCrossRefGoogle Scholar
  79. 79.
    Ong, J., Opresko, L. K., Dempsey, P. J., Lauffenburger, D. A., Coffey, R. J., and Wiley, H. S. (1999) Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor. Proc. Natl. Acad. Sci. USA 96, 6235–6240.CrossRefGoogle Scholar
  80. 80.
    Zetter, B. R. (1998) Angiogenesis and tumor metastasis. Ann. Rev. Med. 49, 407–424.PubMedCrossRefGoogle Scholar
  81. 81.
    Hiraoka, N., Allen, E., Apel, I. J., Gyetko, M. R., and Weiss, S. J. (1998) Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 95, 365–377.PubMedCrossRefGoogle Scholar
  82. 82.
    Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., et al. (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422.PubMedCrossRefGoogle Scholar
  83. 83.
    Itoh, T., Tanioka, M., Yoshida, H., Yoshioka, T., Nishimoto, H., and Itohara, S. (1998) Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58, 1048–1051.PubMedGoogle Scholar
  84. 84.
    Soloway, R. D., Alexander, C. M., Werb. Z., and Jaenisch, R. (1996) Targeted mutagenesis of Timp-1 reveals that lung tumor invasion is influenced by Timp-1 genotype of the tumor but not by that of the host. Oncogene 13, 2307–2314.PubMedGoogle Scholar
  85. 85.
    Yoshiji, H., Harris, S. R., Raso, E., Gomez, D. E., Lindsay, C. K., Shibuya, M., et al. (1998) Mammary carcinoma cells over-expressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression. Int. J. Cancer 75, 81–87.PubMedCrossRefGoogle Scholar
  86. 86.
    Yoshijy, H., Buck, T. B., Harris, S. R., Ritter, L. M., Lindsay, C. K., and Thorgeirsson, U. R. (1998) Stimulatory effect of endogenous tissue inhibitor of metalloproteinases-1 (TIMP-1) overexpression on type IV collagen and laminin gene expression in rat mammary carcinoma cells. Biochem. Biophys. Res. Comm. 247, 605–609.CrossRefGoogle Scholar
  87. 87.
    Heppner Goss, K. J., Brown, P. D., and Matrisian, L. M. (1998) Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis. Int. J. Cancer 78, 629–635.CrossRefGoogle Scholar
  88. 88.
    Leco, K. J., Khokha, R., Pavloff, N., Hawkes, S. R, and Edwards, D. R. (1994) Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J. Biol. Chem. 269, 9352–9360.PubMedGoogle Scholar
  89. 89.
    Leco, K. J., Apte, S. S., Taniguchi, G. T., Hawkes, S. R, Choke, R., Schultz, G. A., et al. (1997) Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Letts. 401, 213–217.CrossRefGoogle Scholar
  90. 90.
    Bugno, M., Graeve, L., Gatsios, R, Koj, A., Heinrich, R. C., Travis, J., et al. (1995) Identification of the interleukin-6/oncostatin M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter. Nuc. Acids Res. 23, 5041–5047.CrossRefGoogle Scholar
  91. 91.
    Logan, S. K., Garabedian, M. J., Campbell, C. E., and Werb, Z. (1996) Synergistic transcriptional activation of the tissue inhibitor of metalloproteinases-1 promoter via functional interaction of AP-1 and Ets-1 transcription factors. J. Biol. Chem. 271, 774–782.PubMedCrossRefGoogle Scholar
  92. 92.
    Clark, I. M., Rowan, A. D., Edwards, D. R., Bech-Hansen, T., Mann, D. A., Bahr, M. J., et al. (1997) Transcriptional activity of the human tissue inhibitor of metalloproteinases 1(TIMP-1) gene in fibroblasts involves elements in the promoter, exon 1 and intron 1. Biochem. J. 324, 611–617.Google Scholar
  93. 93.
    Botelho, F. M., Edwards, D. R., and Richards, C. D. (1998) Oncostatin M stimulates c-fos to bind a transcriptionally responsive AP-1 element within the tissue inhibitor of metalloproteinase-1 promoter. J. Biol. Chem. 273, 5211–5218.PubMedCrossRefGoogle Scholar
  94. 94.
    Kim, H., Pennie, W. D., Sun, Y., and Colbum, N. H. (1997) Differential functional significance of AP-1 binding sites in the promoter of the gene encoding mouse tissue inhibitor of metalloproteinases-3. Biochem. J. 324, 547–553.PubMedGoogle Scholar
  95. 95.
    Phillips, B. W., Sharma, R., Leco, R. A., and Edwards, D. R. (1999) A Sequence-selective Single-strand DNA-binding Protein Regulates Basal Transcription of the Murine Tissue Inhibitor of Metalloproteinases-1 (Timp-1) Gene. J. Biol. Chem. 274, 22197–22207.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Dylan R. Edwards

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