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Transcriptional Activation by Tetracyclines in Mammalian Cells
Abstract
A transcriptional transactivator was developed that fuses the VP16 activation domain with a mutant Tet repressor from Escherichia coli. This transactivator requires certain tetracycline (Tc) derivatives for specific DNA binding. Thus, addition of doxycycline to HeLa cells that constitutively synthesized the transactivator and that contained an appropriate, stably integrated reporter unit rapidly induced gene expression more than a thousandfold. The specificity of the Tet repressor-operator-effector interaction and the pharmacological characteristics of Tc's make this regulatory system well suited for the control of gene activities in vivo, such as in transgenic animals and possibly in gene therapy.
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“In 1995, Gossen et al. developed the Tet-On system (Fig. 1C), a regulatory system that allows activation of gene expression by the addition - instead of removal - of dox [12].”
From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [12]
In the citing paper
“This reverse-TetR (rTetR) differed at four amino acid positions from the original protein (Fig. 2).”
From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [12]
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Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
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Research works printed but not linked: 13
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A new non‐catalytic role for ubiquitin ligase RNF8 in unfolding higher‐order chromatin structure
Luijsterburg, M. S., Ács, K., Ackermann, L., Wiegant, W. W., Bekker‐Jensen, S., Larsen, D. H., Khanna, K. K., van Attikum, H., Mailand, N., & Dantuma, N. P. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.104 · Cited by 117
“For this purpose, we fused RNF8 to the reverse tetracycline repressor protein (rTetR; Gossen et al , 1995) and expressed the GFP-rTetR-RNF8 fusion in human U2OS 2-6-3 cells, which harbour B 200 copies of a TetO-containing cassette integrated in the genome (Janicki et al , 2004).”
Rodríguez-García, A., Combes, P., Pérez-Redondo, R., Smith, M. C. A., & Smith, M. C. M. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni086 · Cited by 123
“The tetracycline (Tc)-inducible repressor (tetR)-operator (tetO) interaction from the Escherichia coli transposon Tn10 has been successfully adapted for use as a tool for regulating gene expression in many organisms (7,8).”
Masui, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni043 · Cited by 107
“The Tet-off system is based on a Tc-regulatabletransactivator(tTA),whichinducestranscription in the absence of Tc or its analog doxycycline (Dox) through binding to the hCMV*-1 promoter.”
BackgroundChemogenetic Tools for Causal Cellular and Neuronal Biology
Atasoy, D., & Sternson, S. M. (2017) · Physiological Reviews · doi:10.1152/physrev.00009.2017 · Cited by 137
“Traditionally small molecule control of protein abundance has been mediated by small molecule-dependent transcriptional systems such as the doxycycline controlled tetracycline transactivator (76).”
BackgroundSperm Alert: Semen Quality Decline Linked to Ozone Pollution
Tillett, T. (2006) · Environmental Health Perspectives · doi:10.1289/ehp.114-a177 · Cited by 122
“For controlling transgenic Tet-responder genes, we used activator mice which express tTA [1,9] and rtTA-M2 [2,28] from the promoter for aCaMKII [9], which is active mainly in principle forebrain neurons.”
Salvi, R., Castillo, E., Voirol, M., Glauser, M., Rey, J.-P., Gaillard, R. C., Vollenweider, P., & Pralong, F. P. (2005) · Endocrinology · doi:10.1210/en.2005-0728 · Cited by 125
Massie, B., Couture, F., Lamoureux, L., Mosser, D. D., Guilbault, C., Jolicoeur, P., Bélanger, F., & Langelier, Y. (1998) · Journal of Virology · doi:10.1128/jvi.72.3.2289-2296.1998 · Cited by 118
“A modified tTA (rtTA) which interacts with tetO only when certain tetracycline analogs are present has also been developed (13).”
BackgroundMethodInfluentialHubbard, G. K., Mutton, L. N., Khalili, M., McMullin, R. P., Hicks, J. L., Bianchi-Frias, D., Horn, L. A., Kulaç, İ., Moubarek, M. S., Nelson, P. S., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3280 · Cited by 135
“The ß-globin intron/poly(A) signal present in the pUGH17-1 vector (32) was PCR amplified and inserted downstream of the MYC open reading to generate pHoxb13-MYC-BG poly(A).”
MethodUse of bone morphogenetic protein—9 gene therapy to induce spinal arthrodesis in the rodent
Helm, G. A., Alden, T. D., Beres, E. J., Hudson, S. B., Das, S., Engh, J. A., Pittman, D. D., Kerns, K. M., & Kallmes, D. F. (2000) · Journal of Neurosurgery Spine · doi:10.3171/spi.2000.92.2.0191 · Cited by 117
Conditional brain-specific knockdown of MAPK using Cre/loxP regulated RNA interference
Hitz, C., Wurst, W., & Kühn, R. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm475 · Cited by 120
“pCMV-hLuc was generated by ligation of the CMV promoter (770 bp XhoI/EcoRI fragment) from pUHD17-1 (14) into the XhoI/HindIII sites of pGL3 basic (Promega) that contains a codon optimized F-Luciferase gene.”
MethodConditional control of mammalian gene expression by tetracycline-dependent hammerhead ribozymes.
Beilstein, K., Wittmann, A., Grez, M., & Suess, B. (2015) · ACS Synthetic Biology · doi:10.1021/sb500270h · Cited by 119
The food additive vanillic acid controls transgene expression in mammalian cells and mice
Gitzinger, M., Kemmer, C., Fluri, D. A., El‐Baba, M. D., Weber, W., & Fussenegger, M. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1251 · Cited by 118
Tetracycline-regulated gene expression in the brain
Mansuy, I. M., & Bujard, H. (2000) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00127-6 · Cited by 115
Self-citationCowman, A., Baldi, D. L., Healer, J., Mills, K. E., O'Donnell, R., Reed, M., Triglia, T., Wickham, M. E., & Crabb, B. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01703-8 · Cited by 119
Baron, U., Schnappinger, D., Helbl, V., Gossen, M., Hillen, W., & Bujard, H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.3.1013 · Cited by 110
Self-citationRossi, F. M. V., Guicherit, O. M., Spicher, A., Kringstein, A. M., Fátyol, K., Blakely, B. T., & Blau, H. M. (1998) · Nature Genetics · doi:10.1038/3871 · Cited by 121
“The transactivator (rtTA) is a fusion protein of viral VP16 and a mutant bacterial tet repressor, designated 'reverse tetR”
BackgroundFlorio, M., Hernandez, M., Yang, H. J., Shu, H. G., Cleveland, J. L., & Israel, M. A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.9.5435 · Cited by 108
“filled-in fragment of Id2 cDNA was inserted into the pUHD10-3 vector (26) at EcoRI blunt-ended sites to prepare a tetracycline-regulatable transactivator”
MethodO’Neal, W. K., Zhou, H., Morral, N., Aguilar-Córdova, E., Pestaner, J. P., Langston, C., Mull, B. B., Wang, Y., Beaudet, A. L., & Lee, B. (1998) · Human Gene Therapy · doi:10.1089/hum.1998.9.11-1587 · Cited by 121
“These cells are derived from 293 cells and contain multiple copies of a tetracycline-repressed expression cassette (Gossen and Bujard, 1992; Gossen et al, 1995) regulating a functional E2a gene.”
Baburina, I., & Jackowski, S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.4.2169 · Cited by 119
S1P1 inhibits sprouting angiogenesis during vascular development
Shoham, A. B., Malkinson, G., Krief, S., Shwartz, Y., Ely, Y., Ferrara, N., Yaniv, K., & Zelzer, E. (2012) · Development · doi:10.1242/dev.078550 · Cited by 118
“Inducible Vegfa overexpression in the limb mesenchyme was carried out by the reverse tetracycline transactivator (rtTA)/tetracycline-responsive element (tetO)-driven transgene system (Belteki et al., 2005; Gossen et al., 1995), with Prx1-Cre mouse (Logan et al., 2002) as an inducer.”
BackgroundMethodInfluentialCammas, F. M., Herzog, M., Lerouge, T., Chambon, P., & Losson, R. (2004) · Genes & Development · doi:10.1101/gad.302904 · Cited by 107
“…doxycycline (Dox)-inducible expression of TIF1 : (1) an expression cassette encoding the reverse tetracycline-controlled transactivator (rtTA; Gossen et al. 1995); (2) a construct containing the mouse Flag-tagged TIF1 or TIF1 HP1box cDNAs (f.TIF1 and f.TIF1 HP1box, respectively) under the…”
BackgroundSchultze, N., Burki, Y., Lang, Y., Certa, U., & Bluethmann, H. (1996) · Nature Biotechnology · doi:10.1038/nbt0496-499 · Cited by 111
Homeodomain protein IDX-1: a master regulator of pancreas development and insulin gene expression.
Stoffers, D., Thomas, M. K., & Habener, J. (1997) · Trends in endocrinology and metabolism · doi:10.1016/s1043-2760(97)00008-8 · Cited by 117
Virus-based gene therapy strategies for bone regeneration
Phillips‐Cremins, J. E., Gersbach, C. A., & García, A. J. (2006) · Biomaterials · doi:10.1016/j.biomaterials.2006.07.032 · Cited by 111
Tetracycline-inducible transgene expression mediated by a single AAV vector
Chtarto, A., Bender, H., Hanemann, C. O., Kemp, T., Lehtonen, E., Levivier, M., Brotchi, J., Velu, T. J., & Tenenbaum, L. (2003) · Gene Therapy · doi:10.1038/sj.gt.3301838 · Cited by 108
Brain-Specific Rescue of Clock Reveals System-Driven Transcriptional Rhythms in Peripheral Tissue
Hughes, M. E., Hong, H., Chong, J. L., Indacochea, A. A., Lee, S. S., Han, M., Takahashi, J. S., & Hogenesch, J. B. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002835 · Cited by 115
Régulier, E., de Almeida, L. P., Sommer, B., Aebischer, P., & Déglon, N. (2002) · Human Gene Therapy · doi:10.1089/10430340260355383 · Cited by 113
“…(tTA) and reverse tTA (rtTA), thus providing an opportunity to develop animal models of human neuropatholo-gies and to study developmental processes and high-order brain functions (Gossen and Bujard, 1992; Furth et al ., 1994; Gossen et al ., 1995; Kistner et al ., 1996; Yamamoto et al ., 2000).”
InfluentialMcCubbrey, A. L., Allison, K. C., Lee-Sherick, A. B., Jakubzick, C. V., & Janssen, W. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01618 · Cited by 114
“The two most common include estrogen receptorCre (ERCre) (6) and tetracycline-On-Cre (tet-On-Cre) (7, 8).”
BackgroundLatta-Mahieu, M., Rolland, M., Caillet, C., Wang, M., Kennel, P., Mahfouz, I., Loquet, I., Dedieu, J.-F., Mahfoudi, A., Trannoy, E., et al. (2002) · Human Gene Therapy · doi:10.1089/10430340260201707 · Cited by 114
“…of tetR-derived transcription factors have been extensively documented (Baron et al ., 1997; Deuschle et al ., 1995; Gossen and Bujard, 1992; Gossen et al ., 1995; Urlinger et al ., 2000), and they are good candidates for a clinical application because the adverse effects of tetracyclines…”
Gitzinger, M., Kemmer, C., El‐Baba, M. D., Weber, W., & Fussenegger, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901501106 · Cited by 113
“In recent years, a panoply of such heterologous transcription control modalities have been developed, which are responsive to various inducer molecules such as antibiotics (13, 14, 17), steroid hormones and their analogs (18, 19), quorum-sensing molecules (20, 21), immunosuppressive and antidiabetic drugs (22, 23), bi…”
BackgroundEshkar-Oren, I., Viukov, S. V., Salameh, S., Krief, S., Oh, C., Akiyama, H., Gerber, H., Ferrara, N., & Zelzer, E. (2009) · Development · doi:10.1242/dev.034199 · Cited by 114
Endosome to Golgi Transport of Ricin Is Independent of Clathrin and of the Rab9- and Rab11-GTPases
Iversen, T., Skretting, G., Llorente, A., Nicoziani, P., van Deurs, B., & Sandvig, K. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.7.2099 · Cited by 90
“…of sub- Iversen et al. Molecular Biology of the Cell 2100 confluent HeLa-TetOn cells expressing the transactivator-tetracycline chimera (Gossen et al., 1995), with 12 g Rab9S21N-pTetSplice (containing the mutant Rab9S21N cDNA) and 2 g of plasmid pPur, according to the manufacturer's…”
MethodRecent advances in inducible gene expression systems
Rossi, F. M. V., & Blau, H. M. (1998) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(98)80028-1 · Cited by 113
Harnessing HIV for therapy, basic research and biotechnology
Wiznerowicz, M., & Trono, D. (2004) · Trends in biotechnology · doi:10.1016/j.tibtech.2004.11.001 · Cited by 112
“In aged monkeys, expression of GDNF augmented dopamine function, whereas in those treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a drug used to model the effects of Parkinson’s disease) it completely reversed functional defects and prevented neurostriatal degeneration [ 7 ].”
BackgroundGenetic optimization of recombinant glycoprotein production by mammalian cells.
Fussenegger, M., Bailey, J. E., Hauser, H., & Mueller, P. P. (1999) · Trends in Biotechnology · doi:10.1016/s0167-7799(98)01248-7 · Cited by 113
How to Choose the Right Inducible Gene Expression System for Mammalian Studies?
Kallunki, T., Barišić, M., Jäättelä, M., & Liu, B. (2019) · Cells · doi:10.3390/cells8080796 · Cited by 140
“Thus, a mutant tTA with four amino acid substitutions, termed rtTA, was developed by random mutagenesis of tTA [24,25].”
MethodFernandez, J., Yaman, I., Merrick, W., Koromilas, A., Wek, R., Sood, R., Hensold, J., & Hatzoglou, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109199200 · Cited by 112
Corti, O., Sabaté, O., Horellou, P., Colin, P., Dumas, S., Buchet, D., Buc‐Caron, M., & Mallet, J. J. (1999) · Nature Biotechnology · doi:10.1038/7901 · Cited by 102
“Among these, the system exploiting the Escherichia coli Tn10 tetracycline opero”
MethodSers, C., Emmenegger, U., Husmann, K., Bucher, K., Andres, A.-C., & Schäfer, R. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.136.4.935 · Cited by 107
“This plasmid expresses the modified tetracycline repressor which was turned into an activator ( Gossen et al., 1995 ).”
BackgroundGenes and physiology: molecular physiology in genetically engineered animals.
Chien, K. R. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118512 · Cited by 105
Tissue-engineered cartilage with inducible and tunable immunomodulatory properties
Glass, K. A., Link, J. M., Brunger, J. M., Moutos, F. T., Gersbach, C., & Guilak, F. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.03.073 · Cited by 111
“tetracycline-controlled transcriptional activator [30,31,38].”
Oram, S. W., Liu, X. X., Lee, T., Chan, W., & Lau, Y. C. (2006) · BMC Cancer · doi:10.1186/1471-2407-6-154 · Cited by 130
“To test the hypothesis that TSPY is involved in cell cycle regulation and its aberrant expression could contribute to the overall tumorigenesis, we have examined the effects of ectopic expression of TSPY in cell proliferation and tumorigenesis in athymic nude mice, using the tetracycline (Tet-off) regulation system in…”
MethodPeptide blockade of HIFα degradation modulates cellular metabolism and angiogenesis
Willam, C., Masson, N., Tian, Y., Mahmood, S., Wilson, M. I., Bicknell, R., Eckardt, K., Maxwell, P. H., Ratcliffe, P. J., & Pugh, C. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162119399 · Cited by 104
Baetu, T. M., Kwon, H., Sharma, S., Grandvaux, N., & Hiscott, J. B. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.6.3164 · Cited by 113
“For this purpose, Jurkat T cells selected for the expression of the rtTA (46) were stably transfected with a CMVt-Neo construct expressing the 2N 4 I B mutant in which both Ser(32) and Ser(36) were mutated to alanines.”
MethodStieger, K., Le Meur, G., Lasne, F., Weber, M., Deschamps, J.-Y., Nivard, D., Mendes-Madeira, A., Provost, N., Martin, L., Moullier, P., et al. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2005.12.001 · Cited by 110
FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis
Ishii, H., Vecchione, A., Murakumo, Y., Baldassarre, G., Numata, S., Trapasso, F., Alder, H., Baffa, R., & Croce, C. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.181222898 · Cited by 110
Li, D. W.-C., Liu, J.-P., Schmid, P. C., Schlosser, R., Feng, H., Liu, W.-B., Yan, Q., Gong, L., Sun, S.-M., Deng, M., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209334 · Cited by 98
“Overexpression of PP-1cas through tet-on expression system The Tet-on expression system was established with a kit from BD Biosciences Clontech, Inc. as described previously (Gossen et al., 1995).”
MethodPluta, K. D., Luce, M. J., Bao, L., Agha‐Mohammadi, S., & Reiser, J. (2005) · The Journal of Gene Medicine · doi:10.1002/jgm.712 · Cited by 103
“Using a tet-inducible lentivirus vector bearing a lacZ reporter gene, NL-TRE/CMV-lacZ U3, the activities of three different transactivators were tested in HOS cells including the prototypical rtTA [6], and the enhanced rtTA2S-S2 and rtTA2S-M2 transactivators [14], and rTE4d38 [34].”
BackgroundMethodInfluentialRETRACTED: Gene therapy and wound healing
Eming, S. A., Krieg, T. M., & Davidson, J. M. (2007) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2006.09.011 · Cited by 100
“Further, multiple regulatory systems have been developed, including the tetracycline inducible system (94,95), the ecdysone (an insect steroid) inducible system (96), the RU486/anti-progestin mifepristone inducible system (97,98), and the rapamycin inducible system (99).”
BackgroundRetractedLiu, S., Sandner, B., Schackel, T., Nicholson, L., Chtarto, A., Tenenbaum, L., Puttagunta, R., Müller, R., Weidner, N., & Blesch, A. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.07.024 · Cited by 131
“To further improve this vector, the original tet-responsive transactivator (rtTA) sequence [35] was replaced by rtTAV16, a mutated rtTA with improved doxycyclinesensitivity [36].”
BackgroundDoxycycline restrains glia and confers neuroprotection in a 6‐OHDA Parkinson model
Lazzarini, M., Martin, S., Mitkovski, M., Raisman‐Vozari, R., Stühmer, W., & Bel, E. D. (2013) · Glia · doi:10.1002/glia.22496 · Cited by 119
“Furthermore, doxycycline is one of the tetracyclines most commonly used in conditional transgene expression systems in lab animals, being added either to the drinking water or chow (Furth et al., 1994; Gossen et al., 1995; Lee et al., 2009; Mansuy et al., 1998; Redfern et al., 1999; for review see Berkhout et al., 200…”
BackgroundAstrocytic cAMP modulates memory via synaptic plasticity
Zhou, Z., Okamoto, K., Onodera, J., Hiragi, T., Andoh, M., Ikawa, M., Tanaka, K. F., Ikegaya, Y., & Koyama, R. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016584118 · Cited by 120
“Finally, we confirmed that GFP expression was abolished in the Mlc1-bPAC mice by administrating doxycycline, which is known to turn off tTA-tetO binding (20) ( SI Appendix , Fig.”
Inoue, N., & Russell, D. (1998) · Journal of Virology · doi:10.1128/jvi.72.9.7024-7031.1998 · Cited by 107
“derivatives of pUHD10-3 (15) (a gift of H.”
BackgroundMethodInfluentialReichheld, S. E., Yu, Z., & Davidson, A. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0911566106 · Cited by 106
Liu, Z., Xu, X., Hsu, H., Tousson, A., Yang, P., Wu, Q., Liu, C., Yu, S., Zhang, H., & Mountz, J. D. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319209 · Cited by 97
Wang, H.-Y., & Wollheim, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201635200 · Cited by 106
King, T. J., Fukushima, L. H., Hieber, A. D., Shimabukuro, K. A., Sakr, W., & Bertram, J. S. (2000) · Carcinogenesis · doi:10.1093/carcin/21.6.1097 · Cited by 105
“The HeLa-On line is the result of stable transfection of the human cervical carcinoma HeLa cell line with a construct containing both a gene encoding rtTA, constructed from the reverse mutant tetracycline receptor fused to the herpes simplex virus VP-16 transcription transactivator domain ( 36 ), as well as a gene enc…”
BackgroundMethodInfluentialKoponen, J., Kankkonen, H. M., Kannasto, J., Wirth, T., Hillen, W., Bujard, H., & Ylä‐Herttuala, S. (2003) · Gene Therapy · doi:10.1038/sj.gt.3301889 · Cited by 96
Self-citationThe Temporal Importance of TNFα Expression in the Development of Diabetes
Green, E. A., & Flavell, R. A. (2000) · Immunity · doi:10.1016/s1074-7613(00)80198-3 · Cited by 98
Feuillard, J., Schuhmacher, M., Kohanna, S., Asso‐Bonnet, M., Ledeur, F., Joubert‐Caron, R., Bissières, P., Polack, A., Bornkamm, G. W., & Raphaël, M. (2000) · Blood · doi:10.1182/blood.v95.6.2068.2068 · Cited by 95
Transient Growth Factor Delivery Sustains Regenerated Axons after Spinal Cord Injury
Blesch, A., & Tuszynski, M. H. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1903-07.2007 · Cited by 109
“To address this hypothesis, we used tetracycline-regulatable systems (Gossen and Bujard, 1992; Gossen et al., 1993, 1995) to control the duration of BDNF gene Received April 26, 2007; revised Aug. 9, 2007; accepted Aug. 16, 2007.”
MethodOcular neovascularization: a valuable model system
Campochiaro, P. A., & Hackett, S. F. (2003) · Oncogene · doi:10.1038/sj.onc.1206773 · Cited by 100
“This hypothesis was tested by using the rhodopsin promoter in combination with the reverse tetracycline-inducible promoter system (Gossen et al., 1995); double transgenic mice with doxycycline-inducible expression of VEGF in photoreceptors were generated (Ohno-Matsui et al., 2002).”
MethodStimulation of 3T3-L1 Adipogenesis by Signal Transducer and Activator of Transcription 5
Nanbu-Wakao, R., Morikawa, Y., Matsumura, I., Masuho, Y., Muramatsu, M., Senba, E., & Wakao, H. (2002) · Molecular Endocrinology · doi:10.1210/mend.16.7.0862 · Cited by 96
“In this report, we have constructed conditional expression systems in which the expression of either a wild-type (wt) or a dominant negative (dn) form of Stat5A was regulated under the doxycycline (Dox)- controlled promoter in 3T3-L1 cells (36).”
MethodWang, H.-Y., Gauthier, B. R., Hagenfeldt-Johansson, K., Iezzi, M., & Wollheim, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111037200 · Cited by 104
Yayoshi-Yamamoto, S., Taniuchi, I., & Watanabe, T. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.18.6872-6881.2000 · Cited by 104
“In order to study the functional properties of FRL in macrophages, a doxycycline-regulated inducible vector system (15) was used for expression of the full-length frl cDNA and three types of truncated frl cDNAs (FH3-FRL, FH11FH3-FRL, and FH2FRL) in P388D1 cells (Fig.”
MethodReversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3
Boy, J., Schmidt, T., Wolburg, H., Mack, A. F., Nuber, S., Böttcher, M., Schmitt, I., Holzmann, C., Zimmermann, F., Servadio, A., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp381 · Cited by 113
“SCA3 responder mice were generated using a XhoI/BstEII fragment of the pUHD 10-3 expression vector (43), which contains full-length ataxin-3 cDNA (ataxin-3c isoform) (19) with 77 CAG repeats downstream of the tTA-responsive promoter (containing a TRE).”
MethodHigh Expression of Aurora-B/Aurora and Ipl1-Like Midbody-Associated Protein (AIM-1) in Astrocytomas
Araki, K., Nozaki, K., Ueba, T., Tatsuka, M., & Hashimoto, N. (2004) · Journal of Neuro-Oncology · doi:10.1023/b:neon.0000021784.33421.05 · Cited by 95
“These plasmids were co-transfected with 1/20 amount of tetracycline reverse transactivator (rtTA) with a selection marker neomycin [29] into the human glioma cell line U251MG, using Lipofectamine PlusTM Reagent (Gibco BRL/Invitrogen, CA, USA) according to the manufacture’s recommendations.”
MethodTransgenic methods for increasing Drosophila life span
Tower, J. (2000) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(00)00152-4 · Cited by 105
Maechler, P., Wang, H.-Y., & Wollheim, C. (1998) · FEBS Letters · doi:10.1016/s0014-5793(97)01618-9 · Cited by 103
Peters, B. S., Grisk, O., Becher, B., Wanka, H., Kuttler, B., Lüdemann, J., Lorenz, G., Rettig, R., Mullins, J., & Peters, J. (2008) · Journal of Hypertension · doi:10.1097/hjh.0b013e3282f0ab66 · Cited by 102
Parr‐Brownlie, L. C., Bosch‐Bouju, C., Schoderboeck, L., Sizemore, R. J., Abraham, W. C., & Hughes, S. M. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00014 · Cited by 121
“The Tet-On system was derived by mutation of the tTA leading to the opposite phenotype, where administration of tetracycline induces gene expression (Gossen et al., 1995).”
BackgroundNF-κB Down-regulates Expression of the B-lymphoma Marker CD10 through a miR-155/PU.1 Pathway
Thompson, R. C., Herscovitch, M., Zhao, I., Ford, T. J., & Gilmore, T. D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.177063 · Cited by 91
The Transcription Factor SREBP-1c Is Instrumental in the Development of औ-Cell Dysfunction
Wang, H., Maechler, P., Antinozzi, P. A., Herrero, L., Hagenfeldt-Johansson, K. A., Björklund, A., & Wollheim, C. B. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212488200 · Cited by 92
Corbel, S. Y., & Rossi, F. M. V. (2002) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(02)00361-0 · Cited by 89
Oshima, Y., Oshima, S., Nambu, H., Kachi, S., Hackett, S., Melia, M., Kaleko, M., Connelly, S., Esumi, N., Zack, D. J., et al. (2004) · Journal of Cellular Physiology · doi:10.1002/jcp.20110 · Cited by 100
“MATERIALS AND METHODS Generation of VMD2 promoter/reverse tetracycline transactivator (VMD2/rtTA) transgenic mice A plasmid pUHD172-1neo, which contains the gene encoding rtTA (Gossen et al., 1995), was kindly provided by Dr. Manfred Gossen (University of Heidelberg, Germany).”
MethodGraded transcriptional response to different concentrations of a single transactivator
Kringstein, A. M., Rossi, F. M. V., Hofmann, A., & Blau, H. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.23.13670 · Cited by 94
Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis
Brancaccio, M., Pivetta, C., Granzotto, M., Filippis, C., & Mallamaci, A. (2010) · Stem Cells · doi:10.1002/stem.443 · Cited by 105
Böttcher, E., Freuer, C., Steinmetzer, T., Klenk, H., & Garten, W. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.03.029 · Cited by 99
Trost, T. M., Lausch, E., Fees, S. A., Schmitt, S., Enklaar, T., Reutzel, D., Brixel, L., Schmidtke, P., Maringer, M., Schiffer, I., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.840.65.3 · Cited by 99
“We intended to investigate the immediate effects of ERBB2 signaling using the tetracycline-based expression system (28).”
MethodTetracycline-inducible systems for Drosophila
Stebbins, M., Urlinger, S., Byrne, G., Bello, B., Hillen, W., & Yin, J. C. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.121186498 · Cited by 99
Self-citationRescue of the early vascular defects in Tek/Tie2 null mice reveals an essential survival function
Jones, N., Voskas, D., Master, Z., Sarao, R., Jones, J. V., & Dumont, D. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve093 · Cited by 90
“To investigate the role of Tek in the mature vasculature, we have utilized a binary transgenic approach based on the bacterial tetracycline repressor (Gossen et al., 1995; Kistner et al., 1996) to specifically regulate the temporal expression of Tek during mouse embryonic development.”
MethodPlant cell cultures as heterologous bio-factories for secondary metabolite production
Wu, T., Kerbler, S. M., Fernie, A. R., & Zhang, Y. (2021) · Plant Communications · doi:10.1016/j.xplc.2021.100235 · Cited by 130
Synthetic control systems for high performance gene expression in mammalian cells
Lillacci, G., Benenson, Y., & Khammash, M. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky795 · Cited by 94
“A typical configuration consists of a ligand-responsive transactivator or repressor that acts on a downstream gene of interest (3,4).”
BackgroundRecombinant AAV-mediated gene transfer to the retina: gene therapy perspectives
Rolling, F. (2004) · Gene Therapy · doi:10.1038/sj.gt.3302366 · Cited by 93
Conditional Targeting of the DNA Repair Enzyme hOGG1 into Mitochondria
Rachek, L. I., Grishko, V. I., Musiyenko, S. I., Kelley, M. R., LeDoux, S. P., & Wilson, G. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208770200 · Cited by 95
Codon optimization markedly improves doxycycline regulated gene expression in the mouse heart
Valencik, M. L., & McDonald, J. A. (2001) · Transgenic Research · doi:10.1023/a:1016601928465 · Cited by 89
“While pursuing this approach, we discovered that the rtTA coding sequence originally described by Gossen and Bujard (Gossen et al., 1995) exhibits a severe prokaryotic codon usage bias.”
MethodMETZGER, D., Scheer, E., Soldatov, A., & Tora, L. (1999) · The EMBO Journal · doi:10.1093/emboj/18.17.4823 · Cited by 100
“(Gossen et al., 1995) is under the control of the PGK promoter, was constructed by inserting the 1044-bp EcoRI–BamHI fragment isolated”
BackgroundMethodInfluentialQiu, G., Ahmed, M. M., Sells, S., Mohiuddin, M., Weinstein, M., & Rangnekar, V. (1999) · Oncogene · doi:10.1038/sj.onc.1202344 · Cited by 97
“DCTH (Sells et al., 1997) was inserted into vector pUHD10-3 which contains the tetracycline-regulated promoter-operator system (Gossen et al., 1995), to obtain constructs tetO-Par-4 or tetODCTH, respectively.”
MethodAging mechanisms in fruit flies
Tower, J. (1996) · BioEssays · doi:10.1002/bies.950181006 · Cited by 97
Shi, Y., Lin, S., Wong, I. P. L., Baldock, P. A. J., Aljanova, A., Enriquez, R. F., Castillo, L. E., Mitchell, N. F., Ye, J., Zhang, L., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011361 · Cited by 101
“). The tetR gene product on its own is inactive, and it is only after the addition of doxycycline (Dox) that it gains activity as a transcription factor by binding and activating the TRE promoter region and transcribing the adjoining gene, in this case Cre”
BackgroundActivity reversal of Tet repressor caused by single amino acid exchanges
Scholz, O., Henssler, E.-M., Bail, J., Schubert, P., Bogdanska-Urbaniak, J., Sopp, S., Reich, M., Wisshak, S., Köstner, M., Bertram, R., et al. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04159.x · Cited by 96
“coli (Gossen et al., 1995).”
MethodInfluentialSelf-citationWnt-4 regulation by the Wilms' tumour suppressor gene, WT1
Sim, E. U., Smith, A. G., Szilagi, E., Rae, F., Ioannou, P. A., Lindsay, M. H., & Little, M. H. (2002) · Oncogene · doi:10.1038/sj.onc.1205373 · Cited by 90
“Englert et al. (1997) investigated the e ect of WT1 by creating Saos2 and U2OS osteosarcoma cell lines inducibly expressing WT1 isoforms in response to tetracycline (Gossen et al., 1995).”
BackgroundStringent Control of Gene Expression In Vivo by Using Novel Doxycycline-Dependent Trans -Activators
Lamartina, S., Roscilli, G., Rinaudo, C. D., Sporeno, E., Silvi, L., Hillen, W., Bujard, H., Cortese, R., Ciliberto, G., & Toniatti, C. (2002) · Human Gene Therapy · doi:10.1089/10430340252769734 · Cited by 92
“An alternative version of this system is based on a mutated form of tTA called reverse tTA (rtTA), which binds to tetO only in the presence of the ligand (Gossen et al ., 1995).”
Self-citationConfronting complexity: strategies for understanding the microcircuitry of the retina.
Masland, R., & Raviola, E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.249 · Cited by 96
Heinz, N., Schambach, A., Galla, M., Maetzig, T., Baum, C., Loew, R., & Schiedlmeier, B. (2010) · Human Gene Therapy · doi:10.1089/hum.2010.099 · Cited by 93
“The original transactivator binds only in the absence of tetracycline (TetOff), whereas modifications have led to the reverse function (Gossen et al., 1995), i.”
ACE2: A novel therapeutic target for cardiovascular diseases
Sarkissian, S. D., Huentelman, M. J., Stewart, J. M., Katovich, M. J., & Raizada, M. K. (2005) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2005.05.011 · Cited by 94
Autoantibodies to NMDA receptor in patients with chronic forms of epilepsia partialis continua
Takahashi, Y., Mori, H., Mishina, M., Watanabe, M., Fujiwara, T., Shimomura, J., Aiba, H., Miyajima, T., Saito, Y., Nezu, A., et al. (2003) · Neurology · doi:10.1212/01.wnl.0000086819.53078.70 · Cited by 95
SAFB2, a New Scaffold Attachment Factor Homolog and Estrogen Receptor Corepressor
Townson, S. M., Dobrzycka, K. M., Lee, A. V., Air, M., Deng, W., Kang, K., Jiang, S., Kioka, N., Michaelis, K., & Oesterreich, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212988200 · Cited by 90
Agha‐Mohammadi, S., O'Malley, M., Etemad, A., Wang, Z., Xiao, X., & Lotze, M. T. (2004) · The Journal of Gene Medicine · doi:10.1002/jgm.566 · Cited by 110
“An up-regulatory version (Tet-On) utilizes a reverse tTA to induce transactivation in the presence of doxycycline (Dox) [6].”
BackgroundGranuphilin Modulates the Exocytosis of Secretory Granules through Interaction with Syntaxin 1a
Torii, S., Zhao, S., Yi, Z., Takeuchi, T., & Izumi, T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5518-5526.2002 · Cited by 94
“cDNA encoding a constitutive active form, Rab27a Q78L, under the tetO-CMV promoter (7) was introduced into INS-1 cells.”
Method
Metadata
- Authors
- Gossen, M., Freundlieb, S., Bender, G., Müller, G., Hillen, W., & Bujard, H.
- Affiliations
- Heidelberg University (DE)
- ORCID
- Gossen, Manfred
- Venue
- Science
- Published
- 1995-06-23
- Volume
- 268
- Issue
- 5218
- Pages
- 1766-1769
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2005275397
- Cited by
- 2,488
- References
- 0
- Citations by year
- 2026: 31 · 2025: 43 · 2024: 45 · 2023: 49 · 2022: 55 · 2021: 60 · 2020: 68 · 2019: 52 · 2018: 55 · 2017: 47 · 2016: 52 · 2015: 62 · 2014: 53 · 2013: 67 · 2012: 64
- FWCI
- 48.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- tetracycline, transcriptional activation, Tet repressor, VP16 activation domain, doxycycline, gene expression regulation, transcriptional activator, transgenic animals, gene therapy
- MeSH terms
- Amino Acid Sequence, Doxycycline, HeLa Cells, Humans, Molecular Sequence Data, Operator Regions, Genetic, Recombinant Fusion Proteins, Repressor Proteins, Transfection, Viral Proteins, Transcriptional Activation, Trans-Activators, Genes, Reporter, Simplexvirus
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