Skip to main content
SpringerLink
Log in

Utilization of transgenic mice in the study of matrix degrading proteinases and their inhibitors

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The extracellular matrix (ECM) acts as both a structural scaffold and an informational medium. Its dynamic status is determined by cells that secrete its constituent molecules and, in most cases, also secrete enzymes that catalyze degradation of these molecules. A stasis between ECM degrading enzymes and their inhibitors maintains the integrity of the matrix. While controlled ECM remodelling is fundamental to several normal processes, uncontrolled disruption underlies diverse pathological conditions. Transgenic mice with specific modulations or a total lack of expression of certain metalloproteinases, serine proteinases or their inhibitors have been generated to elucidate endogenous expression patterns, identify regulatory elements of these genes, and study the physiological consequences of their deregulated expression. With these models we enhance our understanding of the role of proteinases and their inhibitors in diverse normal processes and pathologies including mammary gland development, hemostasis, emphysema and cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rohrbach DH, Timpl R: Molecular and cellular aspects of basement membranes, San Diego: Academic Press, 1993

    Google Scholar 

  2. Mignatti P, Welgus HG, Rifkin DB: Role of degradative enzymes in wound healing. In: Clark RAF, Henson PM (eds) The Molecular and Cellular Biology of Wound Repair. Plenum Press, New York, 1988, pp 497–523

    Google Scholar 

  3. Thomson BM, Atkinson SJ, McGarrity AM, Hembry RM, Reynolds JJ, Meikle MC: Type I collagen degradation by mouse calvarial osteoblasts stimulated with 1,25-dihydrox-yvitamin D-3: evidence for a plasminogen-plasmin-metalloproteinase activation cascade. Biochim Biophys Acta 1014: 125–132, 1989

    Google Scholar 

  4. Sellers A, Woessner JF: The extraction of a neutral metalloproteinase from the involuting rat uterus, and its action on cartilage proteoglycans. Biochem J 189: 521–531, 1980

    Google Scholar 

  5. LeMaire WJ: Mechanism of mammalian ovulation. Steroids 54: 455–469, 1989

    Google Scholar 

  6. Lala PK, Graham CH: Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. Cancer Metastasis Rev 9: 369–379, 1990

    Google Scholar 

  7. Boyce BF: Normal bone remodelling and its disruption in metastatic bone disease. In: Rubens RD, Fogolman I (eds) Bone Metastases: Diagnosis and Treatment. Springer-Verlag, London, 1991, pp 11–30

    Google Scholar 

  8. Brenner CA, Adler RR, Rappolee DA, Pedersen RA, Werb Z: Genes for extracellular-matrix-degrading metalloproteinases and their inhibitor, TIMP, are expressed during early mammalian development. Genes Dev 3: 848–859, 1989

    Google Scholar 

  9. Cawston T, McLaughlan P, Coughlan R, Kyle V, Hazleman B: Synovial fluids from infected joints contain metalloproteinase-tissue inhibitor of metalloproteinase (TIMP) complexes. Biochim Biophys Acta 1033: 96–102, 1990

    Google Scholar 

  10. Gadek JE, Pacht ER: The protease-antiprotease balance within the human lung: implications for the pathogenesis of emphysema. Lung Suppl 168: 552–564, 1990

    Google Scholar 

  11. Liotta LA, Steeg PS, Stetler Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Google Scholar 

  12. Grillo HC, Gross J: Collagenolytic activity during mammalian wound repair. Dev Biol 15: 300–317, 1967

    Google Scholar 

  13. Welgus HG, Stricklin GP, Eisen AZ, Bauer EA, Cooney RV, Jeffrey JJ: A specific inhibitor of vertebrate collagenase produced by human skin fibroblasts. J Biol Chem 254: 1938–1943, 1979

    Google Scholar 

  14. Matrisian LM, Bowden GT, Krieg P, Furstenberger G, Briand JP, Leroy P, Breathnach R: The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors. Proc Natl Acad Sci USA 83: 9413–9417, 1986

    Google Scholar 

  15. Docherty AJ, Murphy G: The tissue metalloproteinase family and the inhibitor TIMP: a study using cDNAs and recombinant proteins. Ann Rheum Dis 49: 469–479, 1990

    Google Scholar 

  16. Edwards DR, Waterhouse P, Holman ML, Denhardt DT: A growth-responsive gene (16C8) in normal mouse fibroblasts homologous to a human collagenase inhibitor with erythroid-potentiating acivity: evidence for inducible and constitutive transcripts. Nucleic Acids Res 14: 8863–8878, 1986

    Google Scholar 

  17. Bosma PJ, van den Berg EA, Kooistra T, Siemieniak DR, Slightom JL: Human plasminogen activator inhibitor-1 gene. Promoter and structural gene nucleotide sequences. J Biol Chem 263: 9129–9141, 1988

    Google Scholar 

  18. Rickles RJ, Darrow AL, Strickland S: Molecular cloning of complementary DNA to mouse tissue plasminogen activator mRNA and its expression during F9 teratocarcinoma cell differentiation. J Biol Chem 263: 1563–1569, 1988

    Google Scholar 

  19. Sinha S, Watorek W, Karr S, Giles J, Bode W, Travis J: Primary structure of human neutrophil elastase. Proc Natl Acad Sci USA 84: 2228–2232, 1987

    Google Scholar 

  20. Khokha R, Waterhouse P, Yagel S, Lala PK, Overall CM, Norton G, Denhardt DT: Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 243: 947–950, 1989

    Google Scholar 

  21. Sordat B, Reiter L, Cajot JF: Modulation of the malignant phenotype with the urokinase-type plasminogen activator and the type I plasminogen activator inhibitor. Cell Differ Dev 32: 277–285, 1990

    Google Scholar 

  22. Khokha R: Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cellsin vivo by the overexpression of the tissue inhibitor of the metalloproteinase-1. J Natl Can Res 86: 299–304, 1994

    Google Scholar 

  23. DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52: 701–708, 1992

    Google Scholar 

  24. Albini A, Melchiori A, Santi L, Liotta LA, Brown PD, Stetler Stevenson WG: Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst 83: 775–779, 1991

    Google Scholar 

  25. Mignatti P, Rifkin DB: Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161–195, 1993

    Google Scholar 

  26. Birkedal Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal Hansen B, DeCarlo A, Engler JA: Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4: 197–250, 1993

    Google Scholar 

  27. Nagase H, Barrett AJ, Woessner JFJ: Nomenclature and glossary of the matrix metalloproteinases. Matrix Suppl 1: 421–424, 1992

    Google Scholar 

  28. Shapiro SD, Griffin GL, Gilbert DJ, Jenkins NA, Copeland NG, Welgus HG, Senior RM, Ley TJ: Molecular cloning, chromosomal localization, and bacterial expression of a murine macrophage metalloelastase. J Biol Chem 267: 4664–4671, 1992

    Google Scholar 

  29. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–65, 1994

    Google Scholar 

  30. Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC, Chambon P: A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348: 699–704, 1990

    Google Scholar 

  31. Woessner JFJ: Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5: 2145–2154, 1991

    Google Scholar 

  32. Kleiner DEJ, Stetler Stevenson WG: Structural biochemistry and activation of matrix metalloproteases. Curr Opin Cell Biol 5: 891–897, 1993

    Google Scholar 

  33. Matrisian LM: The matrix-degrading metalloproteinases. Bioessays 14: 455–463, 1992

    Google Scholar 

  34. He CS, Wilhelm SM, Pentland AP, Marmer BL, Grant GA, Eisen AZ, Goldberg GI: Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 86: 2632–2636, 1989

    Google Scholar 

  35. Sorsa T, Ingman T, Suomalainen K, Haapasalo M, Konttinen YT, Lindy O, Saari H, Uitto VJ: Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophil and fibroblast-type interstitial collagenases. Infect Immun 60: 4491–4495, 1992

    Google Scholar 

  36. Nagase H, Cawston TE, De Silva M, Barrett AJ: Identification of plasma kallikrein as an activator of latent collagenase in rheumatoid synovial fluid. Biochim Biophys Acta 702: 133–142, 1982

    Google Scholar 

  37. Stricklin GP, Bauer EA, Jeffrey JJ, Eisen AZ: Human skin collagenase: isolation of precursor and active forms from both fibroblasts and organ cultures. Biochemistry 16: 1607–1615, 1977

    Google Scholar 

  38. Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H: Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry 29: 10261–10270, 1990

    Google Scholar 

  39. Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR: 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, 1994

    Google Scholar 

  40. Waterhouse P, Denhardt DT, Khokha R: Temporal expression of tissue inhibitors of metalloproteinases in mouse reproductive tissues during gestation. Mol Reprod Dev 35: 219–226, 1993

    Google Scholar 

  41. Denhardt DT, Feng B, Edwards DR, Cocuzzi ET, Malyancar UM: Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmacol Ther 59: 329–341, 1993

    Google Scholar 

  42. Murphy G, Houbrechts A, Cockett MI, Williamson RA, O'Shea M, Docherty AJ: The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity [published erratum appears in Biochemistry 1991 Oct 22;30(42):10362]. Biochemistry 30: 8097–8102, 1991

    Google Scholar 

  43. Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA, Goldberg GI: SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages [published erratum appears in J Biol Chem 1990 Dec 25;265(36):22570]. J Biol Chem 264: 17213–17221, 1989

    Google Scholar 

  44. Goldberg GI, Marmer BL, Grant GA, Eisen AZ, Wilhelm S, He CS: Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. Proc Natl Acad Sci USA 86: 8207–8211, 1989

    Google Scholar 

  45. Kleiner DEJ, Tuuttila A, Tryggvason K, Stetler Stevenson WG: Stability analysis of latent and active 72-kDa type IV collagenase: the role of tissue inhibitor of metalloproteinases-2 (TIMP-2). Biochemistry 32: 1583–1592, 1993

    Google Scholar 

  46. Staskus PW, Masiarz FR, Pallanck LJ, Hawkes SP: The 21-kDa protein is a transformation-sensitive metalloproteinase inhibitor of chicken fibroblasts. J Biol Chem 266: 449–454, 1991

    Google Scholar 

  47. Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett 298: 29–32, 1992

    Google Scholar 

  48. Murphy AN, Unsworth EJ, Stetler Stevenson WG: Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Physiol 157: 351–358, 1993

    Google Scholar 

  49. Koop S, Khokha R, Schmidt EE, MacDonald IC, Morris VL, Chambers AF, Groom AC: Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. Cancer Res 54: 4791–4797, 1994

    Google Scholar 

  50. Rifkin DB: Plasminogen activator expression and matrix degradation. Matrix Suppl 1: 20–22, 1992

    Google Scholar 

  51. Collen D, Lijnen HR: Fibrinolysis and the control of hemostasis. In: Stamatoyannoupoulos G, Nienhuis AW, Leder P, Majerus PW (eds) The Molecular Basis of Blood Diseases. W.B. Saunders Co, Philadelphia, 1987, pp 662–688

    Google Scholar 

  52. Werb Z, Mainardi C, Vater CA, Harris ED: Endogenous activation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator. N Eng J Med 296: 1017–1023, 1977

    Google Scholar 

  53. Werb Z, Banda MJ, Jones PA: Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins and collagen by proteinases isolated from macrophages. J Exp Med 152: 1340–1357, 1980

    Google Scholar 

  54. Bieth JG: Elastases: Catalytic and biological properties. In: Mecham RP (ed) Regulation of Matrix Accumulation. Academic Press, New York, 1986, pp 217–320

    Google Scholar 

  55. Roberts RC: Protease inhibitors of human plasma. Alpha-2-macroglobulin. J Med 16: 129–224, 1985

    Google Scholar 

  56. Hekman CM, Loskutoff DJ: Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J Biol Chem 260: 11581–11587, 1985

    Google Scholar 

  57. Kruithof EK, Vassalli JD, Schleuning WD, Mattaliano RJ, Bachmann F: Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem 261: 11207–11213, 1986

    Google Scholar 

  58. Baker JB, Low DA, Simmer RL, Cunningham DD: Protease-nexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Cell 21: 37–45, 1980

    Google Scholar 

  59. Heeb MJ, Espana F, Geiger M, Collen D, Stump DC, Griffin JH: Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3. J Biol Chem 262: 15813–15816, 1987

    Google Scholar 

  60. Eaton DL, Scott RW, Baker JB: Purification of human fibroblast urokinase proenzyme and analysis of its regulation by proteases and protease nexin. J Biol Chem 259: 6241–6247, 1984

    Google Scholar 

  61. Crystal RG: The alpha 1-antitrypsin gene and its deficiency states. Trends Genet 5: 411–417, 1989

    Google Scholar 

  62. Carlson JA, Rogers BB, Sifers RN, Hawkins HK, Finegold MJ, Woo SL: Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. J Clin Invest 82: 26–36, 1988

    Google Scholar 

  63. Crystal RG: Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy. J Clin Invest 85: 1343–1352, 1990

    Google Scholar 

  64. Adams JC, Watt FM: Regulation of development and differentiation by the extracellular matrix. Development 117: 1183–1198, 1993

    Google Scholar 

  65. Hay ED: Extracellular matrix alters epithelial differentiation. Curr Opin Cell Biol 5: 1029–1035, 1993

    Google Scholar 

  66. Juliano RL, Haskill S: Signal transduction from the extracellular matrix. J Cell Biol 120: 577–585, 1993

    Google Scholar 

  67. Lin CQ, Bissell MJ: Multi-faceted regulation of cell differentiation by extracellular matrix. FASEB J 7: 737–743, 1993

    Google Scholar 

  68. Sympson CJ, Talhouk RS, Alexander CM, Chin JR, Clift SM, Bissell MJ, Werb Z: Targeted expression of strome-lysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J Cell Biol 125: 681–693, 1994

    Google Scholar 

  69. Chin JR, Murphy G, Werb Z: Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates. J Biol Chem 260: 12367–12376, 1985

    Google Scholar 

  70. Talhouk RS, Bissell MJ, Werb Z: Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J Cell Biol 118: 1271–1282, 1992

    Google Scholar 

  71. Schmidhauser C, Casperson GF, Myers CA, Sanzo KT, Bolten S, Bissell MJ: A novel transcriptional enhancer is involved in the prolactin- and extracellular matrix-dependent regulation of beta-casein gene expression. Mol Biol Cell 3: 699–709, 1992

    Google Scholar 

  72. Uitto J, Perejda AJ: Connective tissue disease: molecular pathology of the extracellular matrix. Vol. 12, New York: Marcel Dekker, Inc., 1987

    Google Scholar 

  73. Christner P, Fein A, Goldberg S, Lippmann M, Abrams W, Weinbaum G: Collagenase in the lower respiratory tract of patients with adult respiratory distress syndrome. Am Rev Resp Dis 131: 690–695, 1994

    Google Scholar 

  74. D'Armiento J, Dalal SS, Okada Y, Berg RA, Chada K: Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 71: 955–961, 1992

    Google Scholar 

  75. Johanson WG, Pierce AK: Effects of elastase, collagenase, and papain on structure and function of rat lungsin vitro. J Clin Invest 51: 288–293, 1972

    Google Scholar 

  76. Flenniken AM, Williams BR: Developmental expression of the endogenous TIMP gene and a TIMP-lacZ fusion gene in transgenic mice. Genes Dev 4: 1094–1106, 1990

    Google Scholar 

  77. Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK: Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 6: 1899–1904, 1987

    Google Scholar 

  78. Matrisian LM, Hogan BL: Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development. Curr Top Dev Biol 24: 219–259, 1990

    Google Scholar 

  79. Kawabe TT, Rea TJ, Flenniken AM, Williams BR, Groppi VE, Buhl AE: Localization of TIMP in cycling mouse hair. Development 111: 877–879, 1991

    Google Scholar 

  80. Couchman JR, Gibson WT: Expression of basement membrane components through morphological changes in the hair growth cycle. Dev Biol 108: 290–298, 1985

    Google Scholar 

  81. Couchman JR, King JL, McCarthy KJ: Distribution of two basement membrane proteoglycans through hair follicle development and the hair growth cycle in the rat. J Invest Dermatol 94: 65–70, 1990

    Google Scholar 

  82. Pittelkow MR: Regulation of the hair cycle and growth factors. J Ultrastruct Res 29: 210–217, 1969

    Google Scholar 

  83. Alexander CM, Werb Z: Targeted disruption of the tissue inhibitor of metalloproteinases gene increases the invasive behavior of primitive mesenchymal cells derived from embryonic stem cellsin vitro. J Cell Biol 118: 727–739, 1992

    Google Scholar 

  84. Soloway PD, Jaenisch R: Timp-1 genotype of tumors but not host influences metastasis. Mouse Molecular Genetics 268, 1994 (Abstract)

  85. Khokha R, Zimmer MJ, Graham CH, Lala PK, Waterhouse P: Suppression of invasion by inducible expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in B16-F10 melanoma cells. J Natl Cancer Inst 84: 1017–1022, 1992

    Google Scholar 

  86. Martin DC, Rüther U, Khokha R: Altered development of hepatocellular carcinoma in TIMP-1 transgenic mice. Clin Exp Met 12: 12–13, 1994 (Abstract)

    Google Scholar 

  87. Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo KT, Yeo TK, Dvorak AM, van de Water L, Sioussat TM, Senger DR: Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann N Y Acad Sci 667: 101–111, 1992

    Google Scholar 

  88. Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC: Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368: 419–424, 1994

    Google Scholar 

  89. Stoppelli MP, Corti A, Soeffientini A, Casani G, Blasi F, Assoian RK: Differentiation-enhanced binding of the amino-terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci USA 82: 4939–4943, 1985

    Google Scholar 

  90. Heckel JL, Sandgren EP, Degen JL, Palmiter RD, Brinster RL: Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell 62: 447–456, 1990

    Google Scholar 

  91. Carmeliet P, Kieckens L, Schoonjans L, Ream B, van Nuffelen A, Prendergast G, Cole M, Bronson R, Collen D, Mulligan RC: Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 92: 2746–2755, 1993a

    Google Scholar 

  92. Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord JJ, De Mol M, Mulligan RC, Collen D: Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 92: 2756–2760, 1993b

    Google Scholar 

  93. Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR: Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 346: 74–76, 1990

    Google Scholar 

  94. Tripodi M, Abbott C, Vivian N, Cortese R, Lovell Badge R: Disruption of the LF-A1 and LF-B1 binding sites in the human alpha-1-antitrypsin gene has a differential effect during development in transgenic mice. EMBO J 10: 3177–3182, 1991

    Google Scholar 

  95. Hurt MM, Pandey NB, Marzluff WF: A region in the coding sequence is required for high-level expression of murine histone H3 gene. Proc Natl Acad Sci USA 86: 4450–4454, 1989

    Google Scholar 

  96. Miskin R, Axelrod JH, Griep AE, Lee E, Belin D, Vassalli JD, Westphal H: Human and murine urokinase cDNAs linked to the murine alpha A-crystallin promoter exhibit lens and non-lens expression in transgenic mice. Eur J Biochem 190: 31–38, 1990

    Google Scholar 

  97. Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D: Tissue-plasminogen activator is induced as an immediateearly gene during seizure, kindling and long-term potentiation. Nature 361: 453–457, 1993

    Google Scholar 

  98. Meiri N, Masos T, Rosenblum K, Miskin R, Dudai Y: Overexpression of urokinase-type plasminogen activator in transgenic mice is correlated with impaired learning. Proc Natl Acad Sci USA 91: 3196–3200, 1994

    Google Scholar 

  99. Kelsey GD, Povey S, Bygrave AE, Lovell Badge RH: Species-and tissue-specific expression of human alpha 1-antitrypsin in transgenic mice. Genes Dev 1: 161–171, 1987

    Google Scholar 

  100. Rüther U, Tripodi M, Cortese R, Wagner EF: The human alpha-1 antitrypsin gene is efficiently expressed from two tissue-specific promoters in transgenic mice. Nucleic Acids Res 15: 7519–7529, 1987

    Google Scholar 

  101. Sifers RN, Carlson JA, Clift SM, DeMayo FJ, Bullock DW, Woo SL: Tissue specific expression of the human alpha-1 antitrypsin gene in transgenic mice. Nucleic Acids Res 15: 1459–1475, 1987

    Google Scholar 

  102. Dycaico MJ, Grant SG, Felts K, Nichols WS, Geller SA, Hager JH, Pollard AJ, Kohler SW, Short HP, Jirik FRet al.: Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model. Science 242: 1409–1412, 1988

    Google Scholar 

  103. Carlson JA, Rogers BB, Sifers RN, Finegold MJ, Clift SM, DeMayo FJ, Bullock DW, Woo SL: Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest 83: 1183–1190, 1989

    Google Scholar 

  104. Geller SA, Nichols WS, Dycaico MJ, Felts KA, Sorge JA: Histopathology of alpha 1-antitrypsin liver disease in a transgenic mouse model. Hepatology 12: 40–47, 1990

    Google Scholar 

  105. Sifers RN, Finegold MJ, Woo SL: Alpha-1-antitrypsin deficiency: accumulation or degradation of mutant variants within the hepatic endoplasmic reticulum. Am J Respir Cell Mol Biol 1: 341–345, 1989

    Google Scholar 

  106. Quon D, Wang Y, Catalano R, Scardina JM, Murakami K, Cordell B: Formation of beta-amyloid protein deposits in brains of transgenic mice. Nature 352: 239–241, 1991

    Google Scholar 

  107. Nayernia K, Burkhardt E, Beimesche S, Keime S, Engel W: Germ cell-specific expression of a proacrosin-CAT fusion gene in transgenic mouse testis. Mol Reprod Dev 31: 241–248, 1992

    Google Scholar 

  108. MacDonald RJ: Expression of the pancreatic elastase I gene in transgenic mice. Hepatology 7: 42S-51S, 1987

    Google Scholar 

  109. Platt KA, Min HY, Ross SR, Spiegelman BM: Obesitylinked regulation of the adipsin gene promoter in transgenic mice. Proc Natl Acad Sci USA 86: 7490–7494, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Oncology and Biochemistry, University of Western Ontario, London Regional Cancer Centre, N6A 4L6, London, Ontario, Canada

    Rama Khokha, David C. Martin & Jimmie E. Fata

Authors
  1. Rama Khokha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David C. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jimmie E. Fata
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khokha, R., Martin, D.C. & Fata, J.E. Utilization of transgenic mice in the study of matrix degrading proteinases and their inhibitors. Cancer Metast Rev 14, 97–111 (1995). https://doi.org/10.1007/BF00665794

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00665794

Key words

Search

Navigation