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Tetracycline-Controlled Transactivators and Their Potential Use in Gene Therapy Applications

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Transcription Factors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 166))

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Abstract

The control of gene expression in higher eukaryotes has developed into an invaluable tool for both the design of gene therapy strategies and the study of gene function. Application of gene therapy to a number of diseases will require that therapeutic protein expression level is adjusted to prevent toxicity and to ensure biological efficacy. Amongst currently available chimeric regulatable systems, those derived from the tetracycline operon of Escherichia coli are by far the best documented and the most frequently used. This review will describe the various tetracycline systems. Advantages and drawbacks for in vitro studies and in vivo applications will be presented, as well as the development of viral vectors and gene therapy applications. Tetracycline regulatable expression systems progressively turned out to be effective tools for a broad range of investigations. These include studies of gene function in transgenic animals, analysis of complex and multi-staged biological processes including embryogenesis and cancer, and the generation of animal models of human disorders aimed at understanding the cause and progression of diseases. Strategies developed for these various purposes will be discussed and examples will be given, preferentially with respect to the central nervous system.

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References

  • Ackland-Berglund CE, Leib DA (1995). Efficacy of tetracycline-controlled gene express ion is influenced by cell type. BioTechniques 18:196–200

    PubMed  CAS  Google Scholar 

  • Agha-Mohammadi S, Alvarez-Vallina L, Ashworth LJ, Hawkins RE (1997) Delay in resumption of the activity of tetracycline-regulatable promoter following removal of tetracycline analogues. Gene Ther 4:993–997

    Article  Google Scholar 

  • Akagi K, Kanai M, Saya H, Kozu T, Berns A (2001) A novel tetracycline-dependent transactivator with E2F4 transcriptional activation domain. Nucl Acids Res 29:E23

    Article  PubMed  CAS  Google Scholar 

  • Baron U, Freundlieb S, Gossen M, Bujard H (1995) Co-regulation of two gene activities by tetracycline via bidirectional promoter. Nucl Acids Res 23:3605–3606

    Article  PubMed  CAS  Google Scholar 

  • Baron U, Schnappinger D, Helbl V, Gossen M, Hillen W, Bujard H (1999) Generation of conditional mutants in higher eukaryotes by switching between the expression of two genes. Proc Natl Acad Sci USA 96:1013–1018

    Article  PubMed  CAS  Google Scholar 

  • Blesh A, Conner J, Tuszynski M (2001) Modulation of neuronal survival and axonal growth in vivo by tetracycline-regulated neurotrophin expression. Gene Ther 8:954–960

    Article  Google Scholar 

  • Bohl D, Heard J (2000) Delivering erythropoietin through genetically engineered cells. J Am Soc Nephrol 11:S159–S162

    PubMed  CAS  Google Scholar 

  • Bohl D, Heard J (1997) Modulation of erythropoietin delivery from engineered muscles in mice. Human Gene Ther 8:195–204

    Article  CAS  Google Scholar 

  • Bohl D, Naffakh N, Heard JM (1997). Long term control of erythropoietin secretion levels by tetracycline in mice transplanted with engineered primary myoblasts. Nat Med 3:299–312

    Article  PubMed  CAS  Google Scholar 

  • Bohl D, Salvetti A, Moullier P, Heard JM (1998). Control of erythropoietin delivery by doxycycline in mice after intramuscular injection of adeno-associated vector. Blood 92:1512–1517

    PubMed  CAS  Google Scholar 

  • Bond C, Sprengel R, Bissonnette J, Kaufmann W, Probnow D, Neelands T, Storck T, Baetscher M, Jerenic J, Maylie J, Knaus H, Seeburg P, Adelman J (2000) Respiration and parturition affected by conditional overexpression of the Ca2+-activated K+ channel subunit, SK3. Science 289:1942–1946

    Article  PubMed  CAS  Google Scholar 

  • Chtarto A, Bender H, Hanemann C, Kemp T, Lehtonen E, Levivier M, Brotchi J, Velu T, Tenenbaum L (2003) Tetracycline-inducible transgene expression mediated by a single AAV vector. Gene Ther 10:84–94

    Article  PubMed  CAS  Google Scholar 

  • Corti O, Sabate O, Horellou P, Colin P, Dumas S, Buchet D, Buc-Caron M-H, Mallet J (1999a) A single adenovirus vector mediates doxycycline-controlled expression of tyrosine hydroxylase in brain grafts of human neural progenitors. Nat Biotechnol 17:349–354

    Article  PubMed  CAS  Google Scholar 

  • Corti O, Sanchez-Capelo A, Colin P, Hanoun N, Hamon M, Mallet J (1999b) Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson’s disease. Proc Natl Acad Sci USA 96:12120–12125

    Article  PubMed  CAS  Google Scholar 

  • Degenkolb J, Takahashi M, Ellestad GA, Hillen W (1991) Structural requirements of tetracycline-tetrepressor interaction: determination of equilibrium binding constants for tetracycline analogs with the tetrepressor. Antimicrob Agents Chemother 35: 1591–1595

    Article  PubMed  CAS  Google Scholar 

  • Deuschle U, Meyer WK-H, Thiesen HJ (1995) Tetracycline-reversible silencing of eukaryotic promoters. Mol Cell Biol 15:1907–1914

    PubMed  CAS  Google Scholar 

  • Emerman M, Temin HM (1984) Genes with promoters in retrovirus vectors can be independently suppressed by an epigenetic mechanism. Cell 39:459–467

    Article  CAS  Google Scholar 

  • Favre D, Blouin V, Provost N, Spisek R, Porrot F, Bohl D, Marme F, Cherel Y, Salvetti A, Hurtrel B, Heard J, Riviere Y, Moullier P (2002) Lack of immune response against the tetracycline-dependent transactivator correlates with long-term doxycycline-regulated transgene expression in nonhuman primates after intramuscular injection of recombinant adeno-associated virus. J Virol 76:11605–11611

    Article  PubMed  CAS  Google Scholar 

  • Felsher D, Bishop J (1999) Reversible tumorigenesis by Myc in hematopoietic lineages. Mol Cell 4:199–207

    Article  PubMed  CAS  Google Scholar 

  • Fisher LJ, Iinnah HA, Kale LC, Higgins GA, Gage FH (1991) Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-dopa. Neuron 6:371–380

    Article  PubMed  CAS  Google Scholar 

  • Fishman GI, Kaplan ML, Buttrick PM (1994) Tetracycline-regulated cardiac gene expression in vivo. J Clin Invest 93:1864–1868

    Article  PubMed  CAS  Google Scholar 

  • Fitzsimons H, McKenzie J, During M (2001) Insulators coupled to a minimal bidirectional tet cassette for tight regulation of rAAV-mediated gene transfer in the mammalian brain. Gene Ther 8:1675–1681

    Article  PubMed  CAS  Google Scholar 

  • Folliot S, Briot D, Conrath H, Provost N, Cherel Y, Moullier P, Rolling F (2003) Sustained tetracycline-regulated transgene expression in vivo in rat retinal ganglion cells using a single type 2 adeno-associated vector. J Gene Med 5:493–501

    Article  PubMed  CAS  Google Scholar 

  • Freunlieb S, Chirra-Muller C, Bujard H (1999) A tetracycline controlled activation/repression system with increased potential for gene transfer into mammalian cells. J Gene Med 1:4–12

    Article  Google Scholar 

  • Furth PA, St. Onge L, Böger H, Gruss P, Gossens M, Kistner A, Bujard H, Hennighausen L (1994) Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci USA 91:9302–9306

    Article  PubMed  CAS  Google Scholar 

  • Ghavami A, Stark K, Jareb M, Ramboz S, Segu L, Hen R (1999) Differential addressing of 5-HT1A and 5-HT1B receptors in epithelial cells and neurons. J Cell Sci 112:967–976

    PubMed  CAS  Google Scholar 

  • Gossen M, Bujard H (1993) Anhydrotetracyclin, a novel effector for tetracycline controlled gene expression in eukaryotic cells. Nucl Acids Res 21:4411–4412

    Article  PubMed  CAS  Google Scholar 

  • Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551

    Article  PubMed  CAS  Google Scholar 

  • Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769

    Article  PubMed  CAS  Google Scholar 

  • Haberman RP, McCown TJ, Samulski RJ (1998) Inducible long-term gene expression in brain with adeno-associated virus gene transfer. Gene Ther 5:1604–1611

    Article  PubMed  CAS  Google Scholar 

  • Harding TC, Geddes BJ, Murphy D, Knight D, Uney JB (1998) Switching transgene expression in the brain using adenoviral tetracycline-regulatable system. Nat Biotechnol 16:553–555

    Article  PubMed  CAS  Google Scholar 

  • Hasan M, Schonig K, Berger S, Graewe W, Bujard H (2001) Long-term, noninvasive imaging of regulated gene expression in living mice. Genesis 29:116–122

    Article  PubMed  CAS  Google Scholar 

  • Hofman A, Nolan G, Blau HB (1996) Rapid retroviral delivery of tetracycline-inducible genes in a single autoregulatory cassette. Proc Natl Acad Sci USA 93:5185–5190

    Article  Google Scholar 

  • Hoshimaru M, Ray J, Sah DWY, Gage FH (1996) Differentiation of the immortalized adult neuronal progenitor cell line HC2S2 into neurons by regulatable suppression of the v-myc oncogene. Proc Natl Acad Sci USA 93:1518–1523

    Article  PubMed  CAS  Google Scholar 

  • Hu SX, Ji W, Zhou Y, Logothetis C, Xu H-J (1997) Development of an adenovirus vector with tetracycline-regulatable human tumor necrosis factor alpha gene expression. Cancer Res 57:3339–3343

    PubMed  CAS  Google Scholar 

  • Huettner C, Zhang P, van Etten R, Tenen D (2000) Reversibility of acute B cell leukemia induced by BCR-ABL1. Nat Genet 24:57–60

    Article  PubMed  CAS  Google Scholar 

  • Hug H, Costas M, Staeheli P, Aebi M, Weissmann C (1988) Organization of the murine Mx gene and characterization of its interferon-and virus-inducible promoter. Mol Cell Biol 8:3065–3079

    PubMed  CAS  Google Scholar 

  • Hwang JJ, Scuric Z, Anderson WF (1996) Novel retroviral vector transferring a suicide gene and a selectable marker gene with enhanced gene expression by using a tetracycline-responsive expression system. J Virol 70:8138–8141

    PubMed  CAS  Google Scholar 

  • Iida A, Chen ST, Friedmann T, Yee JK (1996) Inducible gene expression by retrovirus-mediated transfer of a modified tetracycline-regulated system. J Virol 70:6054–6059

    PubMed  CAS  Google Scholar 

  • Ingles CJ, Shales M, Cress WD, Triezenberg SJ, Greenblatt J (1991) Reduced binding of TFIID to transcriptionally compromised mutants of VP16. Nature 351:588–590

    Article  PubMed  CAS  Google Scholar 

  • Israel D, Kaufman RJ (I989) Highly inducible expression from vectors containing multiple GRE’s in CHO cells overexpressing the glucocorticoid receptor. Nucl Acids Res 17:4589–4604

    Article  Google Scholar 

  • Kafri T, van Praag H, Gage F, Verma I (2000) Lentiviral vectors: regulated gene expression. Mol Ther 1:516–521

    Article  PubMed  CAS  Google Scholar 

  • Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H, Bujard H (I996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 93:10933–10938

    Article  Google Scholar 

  • Ko MSH, Takahashi N, Sugiyama N, Takano T (I989) An auto-inducible vector conferring high glucocorticoid inducibility upon stable transformant cells. Gene 84:383–389

    Article  Google Scholar 

  • Kojima H, Abiru Y, Sakajiri K, Watabe K, Ihishi N, Takamori M, Hatanaka H, Yagi K (1997) Adenovirus-mediated transduction with human glial cell line-derived neurotrophic factor gene prevents 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced dopamine depletion in striatum of mouse brain. Biochem Biophys Res Commun 238:569–573

    Article  PubMed  CAS  Google Scholar 

  • Krestel H, Mayford M, Seeburg P, Sprengel R (2001) A GFP-equipped bidirectional expression module well suited for monitoring tetracycline-regulated gene expression in mouse. Nucl Acids Res 29:e39

    Article  PubMed  CAS  Google Scholar 

  • Lamartina S, Roscilli G, Rinaudo C, Sporeno E, Silvi L, Hillen W, Bujard H, Cortese R, Ciliberto G, Toniatti C (2002) Stringent control of gene expression in vivo by using novel doxycycline-dependent trans-activators. Hum Gene Ther 13:199–210

    Article  PubMed  CAS  Google Scholar 

  • Lamartina S, Silvi L, Roscilli G, Casimiro D, Simon A, Davies M, Shiver J, Rinaudo C, Zampaglione I, Fattori E, Colloca S, Gonzalez Paz O, Laufer R, Bujard H, Cortese R, Ciliberto G, Toniatti, C. (2003) Construction of an rtTA2S-M2/tTSkid-based transcription regulatory switch that displays no basal activity, good inducibility, and high responsiveness to doxycycline in mice and non-human primates. Mol Ther 7:271–280

    Article  PubMed  CAS  Google Scholar 

  • Latta-Mahieu M, Rolland M, Caillet C, Wang M, Kennel P, Mahfouz I, Loquet I, Dedieu J, Mahfoudi A, Trannoy E, Thuiller V (2002) Gene transfer of a chimeric trans-activator is immunogenic and results in short-lived transgene expression. Hum Gene Ther 13:1611–1620

    Article  PubMed  CAS  Google Scholar 

  • Lee P, Morley G, Huang Q, Fischer A, Seiler S, Horner J, Factor S, Baidya D, Jalife J, Fishman G. (I998) Conditional lineage ablation to model human diseases. Proc Natl Acad Sci USA 95:11371–11376

    Article  Google Scholar 

  • Lin Y-S, Ha I, Maldonado E, Reinberg D, Green MR (I991) Binding of general transcription factors TFIIB to an acidic activating region. Nature 353:569–571

    Article  Google Scholar 

  • Mader S, White JS (1993) A steroid-inducible promoter for the controlled overexpression of cloned genes in eukaryotic cells. Proc Natl Acad Sci USA 90:5603–5607

    Article  PubMed  CAS  Google Scholar 

  • Malleret G, Haditsch U, Genoux D, Jones M, Bliss T, Vanhoose A, Weitlauf C, Kandel E, Winder D, Mansuy I (2001) Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104:675–686

    PubMed  CAS  Google Scholar 

  • Mansuy I, Bujard H (2000) Tetracycline-regulated gene expression in the brain. Curr Opin Neurobiol 10:593–596

    Article  PubMed  CAS  Google Scholar 

  • Mansuy I, Mayford M, Jacob B, Kandel E, Bach M (1998) Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92:39–49

    Article  PubMed  CAS  Google Scholar 

  • Marsden CD, Parkes, JD (I976) “On-off” effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet 1:292–296

    Google Scholar 

  • Massie B, Couture F, Lamoureux L, Mosser DD, Guibault C, Jolicoeur P, Belanger F, Langelier Y (I998) Inducible overexpression of a toxic protein by an adenovirus vector with a tetracycline-regulatable expression cassette. J Virol 72:2289–2296

    Google Scholar 

  • Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER (1996) Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678–1683

    Article  PubMed  CAS  Google Scholar 

  • Mayo KE, Warren R, Palmiter RD (1982) The mouse metallothionein-I gene is transcriptionally regulated by cadmium following transfaction into human or mouse cells. Cell 29:99–108

    Article  PubMed  CAS  Google Scholar 

  • Mizuguchi H, Hayakawa T (2002) The tet-off system is more effective than the tet-on system for regulating transgene expression in a single adenovirus vector. J Gene Med 4:240–247

    Article  PubMed  Google Scholar 

  • Molin M, Shoshan M-C, Ohman-Forslund K, Linder S, Akusjarvi G (1998) Two novel adenovirus vector systems permitting regulated protein expression in gene transfer experiments. J Virol 72:8358–8361

    PubMed  CAS  Google Scholar 

  • Neering SJ, Hardy SF, Minamoto D, Spratt SK, Jordan CT (1996) Transduction of primitive human hematopoietic cells with recombinant adenovirus vectors. Blood 88:1147–1155

    PubMed  CAS  Google Scholar 

  • Obeso JA, Grandas F, Herrero MT, Horowski R (1994) The role of pulsatile versus continuous dopamine receptor stimulation for functional recovery in Parkinson’s disease. Eur J Neurosci 6:889–897

    Article  PubMed  CAS  Google Scholar 

  • Okoye G, Zimmer J, Sung J, Gehlbach P, Deering T, Nambu H, Hackett S, Melia M, Esumi N, Zack D, Campochiaro P (2003) Increased expression of brain-derived neurotrophic factor preserves retinal funtion and slows cell death from rhodopsin mutation or oxidative damage. J Neurosci 23:4164–4172

    PubMed  CAS  Google Scholar 

  • Paulus W, Baur I, Boyce FM, Breakefield XO, Reeves SA (1996) Self-contained, tetracycline-regulated retroviral system for gene delivery to mammalian cells. J Virol 70:6267

    Google Scholar 

  • Payen E, Bettan M, Henri A, Tomkiewitcz E, Houque A, Kuzniak I, Zuber J, Scherman D, Beuzard Y (2001) Oxygen tension and a pharmacological switch in the regulation of transgene expression for gene therapy. J Gene Med 3:498–504

    Article  PubMed  CAS  Google Scholar 

  • Perez N, Plence P, Millet V, Greuet D, Minot C, Noel D, Danos O, Jorgensen C, Apparailly F (2002) Tetracycline transcriptional silencer tightly controls transgene expression after in vivo intramuscular electro-transfer: application to interleukin 10 therapy in experimental arthritis. Hum Gene Ther 13:2161–2172

    Article  PubMed  CAS  Google Scholar 

  • Petersen A, Mani K, Brundin P (1999) Recent advances on the pathogenesis of Huntington’s disease. Exp Neurol 157:1–18

    Article  PubMed  CAS  Google Scholar 

  • Picard D, Salser SJ, Yamamoto KR (1988) A movable and regulable inactivation function within the steroid binding domain of the glucocorticoid Receptor. Cell 54:1073–1080

    Article  PubMed  CAS  Google Scholar 

  • Reiser J, Lai Z, Zhang X, Brady R (2000) Development of multigene and regulated lentivirus vectors. J Virol 74:10589–10599

    Article  PubMed  CAS  Google Scholar 

  • Rendhal KG, Leff SE, Otten GR, Spratt SK, Bohl D, Van Roey M, Donahue BA, Cohen LK, Mandel RJ, Danos O, Snyder RO (1998) Regulation of gene expression in vivo following transduction by two separate rAAV vectors. Nat Biotechnol 16:757–761

    Article  Google Scholar 

  • Rinsch C, Régulier E, Déglon N, Daile B, Beuzard Y, Aebischer P (1997) A gene therapy approach to regulated delivery of erythropoietin as a function of oxygen tension. Hum Gene Ther 8:1881–1889

    Article  PubMed  CAS  Google Scholar 

  • Rivera VM, Clackson T, Natesan S, Pollock R, Amara JF, Keenan T, Magari SR, Phillips T, Courage NL, Cerasoli F, Dennis AH, Gilman M (1996) A humanized system for pharmacologic control of gene expression. Nat Med 2:1028–1032

    Article  PubMed  CAS  Google Scholar 

  • Salucci V, Scarito A, Aurisicchio L, Lamartina S, Nicolaus G, Giampaoli S, Gonzalez-Paz O, Toniatti C, Bujard H, Hillen W, Ciliberto G, Palombo F (2002) Tight control of gene expression by a helper-dependent adenovirus vector carrying the rtTA2S-M2 tetracycline transactivator and repressor system. Gene Ther 9:1415–1421

    Article  PubMed  CAS  Google Scholar 

  • Samakoglu S, Bohl D, Heard JM (2002) Mechanisms leading to sustained reversion of β-thalassemia in mice by doxycycline-controlled Epo delivery from muscles. Mol Ther 6:793–803

    Article  PubMed  CAS  Google Scholar 

  • Schultze N, Burki Y, Lang Y, Certa U, Bluethmann H (1996) Efficient control of gene expression by single step integration of the tetracycline system in transgenic mice. Nat Biotech 14:499–505

    Article  CAS  Google Scholar 

  • Schweinfest CW, Jorcyk CL, Fujiwara S, Papas TS (1988) A heat-shock inductible eukaryotic expression vector. Gene 71:207–210

    Article  PubMed  CAS  Google Scholar 

  • Searl PF, Stuart GW, Palmiter RD (1985) Building a metal-responsive promoter with synthetic regulatory elements. Mol Cell Biol 5:1480–1489

    Google Scholar 

  • Serguera C, Bohl D, Rolland E, Prevost P, Heard JM (1999) Control of erythropoietin secretion by doxycycline or mifepristone in mice bearing polymer encapsulated engineered cells. Hum Gene Ther 10:375–383

    Article  PubMed  CAS  Google Scholar 

  • Shin M, Levorse J, Ingram R, Tilgham S (1999) The temporal requirement for endothelin receptor-B signalling during neural crest development. Nature 402:496–501

    Article  PubMed  CAS  Google Scholar 

  • Smith-Arica J, Morelli A, Larregina A, Smith J, Lowenstein P, Castro M (2000) Cell-type specific and regulatable trans genesis in the adult brain: adenovirus-encoded combined transcroptional targeting and inducible transgene expression. Mol Ther 2

    Google Scholar 

  • Squire S, Raymackers J, Vandebrouck C, Potter A, Tinsley J, Fisher R, Gillis J, Davies K (2002) Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system. Hum Mol Genet 11:3333–3344

    Article  PubMed  CAS  Google Scholar 

  • Staeheli P, Danielson P, Haller O, Sutcliffe JG (1986) Transciptional activation of the mouse Mx gene by type 1 interferon. Mol Cell Biol 6:4770–4774

    PubMed  CAS  Google Scholar 

  • Tremblay P, Meiner Z, Galou M, Heinrich C, Petromilli C, Lisse T, Cayetano J, Torchia M, Mobley W, Bujard H, DeArmont S, Prusiner S (1998) Doxycycline control of prion protein transgene expression modulates prion disease in mice. Proc Natl Acad Sci USA 95:12580–12585

    Article  PubMed  CAS  Google Scholar 

  • Ueberham E, Low R, Ueberman U, Schönig K, Bujard H, Gebhardt R (2003) Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology 37:1067–1078

    Article  PubMed  CAS  Google Scholar 

  • Urlinger S, Baron U, Thellman M, Hasan M, Bujard H, Hillen W (2000) Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci USA 97:7963–7968

    Article  PubMed  CAS  Google Scholar 

  • Verma IM, Somia N (1997) Gene therapy promises, problems and prospects. Nature 389:239–242

    Article  PubMed  CAS  Google Scholar 

  • Vigna E, Cavalieri S, Ailles L, Geuna M, Loew R, Bujard H, Naldini L (2002) Robust and efficient regulation of transgene expression in vivo by improved tetracycline-dependent lentiviral vectors. Mol Ther 5:252–261

    Article  PubMed  CAS  Google Scholar 

  • Webster NJG, Green S, Jin JR, Chambon P (1988) The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell 54:199–207

    Article  PubMed  CAS  Google Scholar 

  • Wilsey J, Zolotukhin S, Prima V, Shek E, Matheny M, Scarpace P (2002) Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses. Gene Ther 9:1492–1499

    Article  PubMed  CAS  Google Scholar 

  • Wurm FM, Gwinn KA, Kingston RE (1986) Inducible overexpression of a mouse c-myc protein in mammalian cells. Proc Natl Acad Sci USA 83:5414–5418

    Article  PubMed  CAS  Google Scholar 

  • Xu Z, Mizuguchi H, Mayumi T, Hayakawa T (2003) Regulated gene expression from adenovirus vectors: a systematic comparison of various inducible systems. Gene 309: 145–151

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto A, Lucas J, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101:57–66

    Article  PubMed  CAS  Google Scholar 

  • Yoshida Y, Hamada H (1997) Adenovirus-mediated inducible gene expression through tetracycline-controllable transactivator with nuclear localization signal. Biochem Biophys Res Commun 230:426–430

    Article  PubMed  CAS  Google Scholar 

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Bohl, D., Heard, JM. (2004). Tetracycline-Controlled Transactivators and Their Potential Use in Gene Therapy Applications. In: Gossen, M., Kaufmann, J., Triezenberg, S.J. (eds) Transcription Factors. Handbook of Experimental Pharmacology, vol 166. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18932-6_17

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