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Ligand-inducible and liver-specific target gene expression in transgenic mice

Abstract

Transgenic mice have been used as models for tissue-specific gene regulation and to examine the molecular and cellular effects of altered expression of specific genes in disease processes such as tumorigenesis. Because of the deleterious effects of constitutive expression of transgenes, which frequently result in prenatal or postnatal death, only a limited number of disease models have been established in transgenic mice. We report an inducible binary transactivation system that permits the control of transgene expression in a tissue-specific and inducible fashion in mice. In this system, transcription of the target transgene is kept silent until turned on by the administration of an exogenous compound. We also demonstrate that expression level of the target gene can be induced three to four orders of magnitude and can be controlled by the administrated compound in a dose-dependent manner.

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References

  1. Bienz, M. and Pelham, H.R. 1986. Heat shock regulatory elements function as an inducible enhancer in the Xenopushsp70 gene and when linked to a heterolo-gous promoter. Cell 45: 753–760.

    Article  CAS  Google Scholar 

  2. Bairn, S.B., Labow, M.A., Levine, A.J. and Shenk, T. 1991. A chimeric mammalian transactivator based on the lac represser that is regulated by temperature and isopropyl β-D-thiogalactoside. Proc. Natl. Acad. Sci. USA 88: 5072–5076.

    Article  Google Scholar 

  3. Mayo, K.E., Warren, R. and Palmiter, R.D. 1982. The mouse metallothionein-l gene is transcriptionally regulated by cadmium following transfection into human or mouse cells. Cell 29: 99–108.

    Article  CAS  Google Scholar 

  4. Wang, Y., O'Malley, B.W., Jr Tsai, S.Y. and O'Malley, B.W. 1994. A regulatory system for use in gene transfer. Proc. Natl. Acad. Sci. USA 91: 8180–8184.

    Article  CAS  Google Scholar 

  5. Gossen, M., Freundlied, S., Bender, G., Muller, G., Hillen, W. and Bujard, H. 1995. Transcriptional activation by tetracyclines in mammalian cells. Science 268: 1766–1769.

    Article  CAS  Google Scholar 

  6. No, D., Yao, T.-R. and Evans, R.M. 1996. Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc. Natl. Acad. Sci. USA 93: 3346–3351.

    Article  CAS  Google Scholar 

  7. Spencer, D.M., Wandless, T.J., Schreiber, S.L. and Crabtree, G.R. 1993. Controlling signal transduction with synthetic ligands. Science 262: 1019–1024.

    Article  CAS  Google Scholar 

  8. Yan, C., Costa, R.H., Darnell, J.E., Jr Chen, J. and Van Dyke, T.A. 1990. Distinct positive and negative elements control the limited hepatocyte and choroid plexus expression of transthyretin in transgenic mice. EMBO J. 9: 869–878.

    Article  CAS  Google Scholar 

  9. Wu, H., Wade, M., Krall, L., Grisham, J., Xiong, Y. and Van Dyke, T.A. 1996. Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. Genes & Development 10: 245–260.

    CAS  Google Scholar 

  10. Chung, J.H., Whiteley, M. and Felsenfeld, G. 1993. A 5′ element of the chicken β-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell 74: 505–514.

    Article  CAS  Google Scholar 

  11. Cai, H. and Levine, M. 1995. Modulation of enhancer-promoter interactions by insulators in the Drosophilaembryo. Nature 376: 533–536.

    Article  CAS  Google Scholar 

  12. Brand, A.H. and Perrimon, N. 1993. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415.

    CAS  Google Scholar 

  13. Ornitz, D.M., Moreadith, R.W. and Leder, R. 1991. Binary system for regulating transgene expression in mice: Targeting int-2 gene expression with yeast GAL4/UAS control elements. Proc. Natl. Acad. Sci. USA 88: 698–702.

    Article  CAS  Google Scholar 

  14. Murad, F. and Haynes, R., 1985. pp. 1366–1371, in Goodman and Oilman's The Pharmacological Basis of Therapeutics, ed 7. MacMillan, New York.

    Google Scholar 

  15. Heikinheimo, O. and Kekkonen, R. 1993. Dose-response relationships of RU 486. Ann. Med. 25: 71–76.

    Article  CAS  Google Scholar 

  16. Shi, Y.E., Ye, Z.H., He, C.H., Zhang, G.Q., Xu, J.Q., Van Look, P.F. et al. 1993. Pharmacokinetic study of RU 486 and its metabolites after oral administration of single doses to pregnant and non-pregnant women. Contraception 48: 133–149.

    Article  CAS  Google Scholar 

  17. Kawai, S., Nieman, L.K., Brandon, D.D., Udelsman, R., Loriaus, D.L. and Ghrousos, G.R. 1987. Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man. J. Pharmacol. Exp. Therapeutics 241: 401–406.

    CAS  Google Scholar 

  18. Palmiter, P.D., Norstedt, G., Gelinas, R.E., Hammer, R.E. and Brinster, R.L. 1983. Metallothionein-human GH fusion genes stimulated growth of mice. Science 222: 809–814.

    Article  CAS  Google Scholar 

  19. Spitz, I.M. and Bardin, C.W. 1993. Mifepristone (RU 486)—a modulator of prog-estin and glucocorticoid action. N. Engl. J. Med. 329: 404–412.

    Article  CAS  Google Scholar 

  20. Grunberg, S.M., Weiss, M.H., Spitz, I.M., Ahmadi, J., Sadum, A., Russell, C.A. et al. 1991. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J. Neursurg. 74: 861–866.

    Article  CAS  Google Scholar 

  21. Borgden, R.N., Goa, K.L. and Faulds, D., 1993. ne, a review of its phar-macodynamic and pharmacokinetic properties, and therapeutic potential. Drugs B>45:384–409.

    Article  CAS  Google Scholar 

  22. Felsenfeld, G., Boyes, J., Chung, J., Clark, D. and Studitsky, V. 1996. Chromatin structure and gene expression. Proc. Natl. Acad. Sci. USA 93: 9384–9388.

    Article  CAS  Google Scholar 

  23. Zhao Keji Hart, C.M. and Laemmli, U.K. 1995. Visualization of chromosomal domains with boundary element-associated factor BEAF-32. Cell 81: 879–889.

    Article  Google Scholar 

  24. Reneker, L.W., Silversides, D.W., Patel, K. and Overbeek, P.A. 1995. TGFα can act as a chemoattractant to perioptic mesenchymal cells in developing mouse eyes. Development 121: 1669–1680.

    CAS  PubMed  Google Scholar 

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Wang, Y., DeMayo, F., Tsai, S. et al. Ligand-inducible and liver-specific target gene expression in transgenic mice. Nat Biotechnol 15, 239–243 (1997). https://doi.org/10.1038/nbt0397-239

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