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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The Tet-On system allows activation of gene expression by the addition of dox.
“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]
The reverse-TetR (rTetR) differed at four amino acid positions from the original TetR, and fusion of the VP16 activation domain resulted in rtTA that binds Ptet and activates transcription exclusively in the presence of dox.
“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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“Doxycycline (tet, Sigma) was used at the concentration of 10 ng/ml (Gossen et al., 1995). γ-irradiation was performed using 137Cs (0.02 Gy/s, Gammacell 40, Atomic Energy of Canada Limited Industrial Products, Ontario).”
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“rtTA consists of a DNA binding domain, the reverse TetR (TetR) and an activator domain, VP16ad (VP16) (Gossen et al., 1995).”
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“To overcome these problems, I generated clones of RT4-D6P2T cells that can be induced to express merlin at various levels (Gossen et al., 1995).”
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“The second step was to cotransfect a resulting clonal cell line with the pTet-On regulator plasmid and with GLT-1 cDNA inserted in the pTet response element plasmid (Resnitzky et al., 1994; Gossen et al., 1995) and select the clonal cell line with the largest increase of D-aspartate uptake induced by doxycycline (whic…”
BackgroundMethodSpatiotemporal control of gene expression by a light-switchable transgene system
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“For example, the tetracycline-inducible gene expression system developed for mammalian cells (“tet-on”) (18) has recently been adapted to transgenic Drosophila (7).”
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“In Tet-On systems, doxycycline binds the tetracycline transactivator protein and thereby allows binding to a tetracycline response element and transcriptional activation to occur (Gossen et al., 1995).”
BackgroundProtein phosphatase 1 is a molecular constraint on learning and memory
Genoux, D., Haditsch, U., Knobloch, M., Michalon, A., Storm, D., & Mansuy, I. M. (2002) · Nature · doi:10.1038/nature00928 · Cited by 472 · see citing works
“13 ), were generated using the reversible tetracycline-controlled transactivator (rtTA) system under the control of the Ca 2p /calmodulin-dependent protein kinase α (CaMKIIα) promote”
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Tet-On Systems For Doxycycline-inducible Gene Expression
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“Subsequent fusion of the VP16 activation domain resulted in a reverse-tTA (rtTA) that binds Ptet and activates transcription exclusively in the presence of dox [12].”
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“The tetracycline-inducible cell line ONK2 was generated by transfecting HTB96 cells with pUHG17-1 (Gossen et al., 1995) (a gift from H. Bujard, Zentrum für Molekulare Biologie, Heidelberg, Germany) and pEFblas-tetKRAB.”
BackgroundMethodConditional control of gene expression in the mouse
Lewandoski, M. (2001) · Nature reviews genetics · doi:10.1038/35093537 · Cited by 442 · see citing works
“1a ), whereas in a modified version, the 'reverse tTA' (rtTA) binds DNA only when the inducer is present ('tet-on'”
Chromosomal clustering of muscle-expressed genes in Caenorhabditis elegans
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“gif" NDATA ITEM> ]> We mated transgenic mouse lines expressing the reverse tetracycline-dependent transcriptional activator (rtTA) under the control of the mouse mammary tumor virus long terminal repeat (MMTV-LTR; mouse line named Tg(rtTA)1lach called here MTB), to a second transgenic line containing exons 2 and 3 of…”
BackgroundRegulation of bacterial drug export systems
Grkovic, S., Brown, M. H., & Skurray, R. A. (2002) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.66.4.671-701.2002 · Cited by 423 · see citing works
“In addition to identifying amino acids involved in the induction process, random mutagenesis has even produced a TetR mutant that exhibits increased, not decreased, affinity for the tet operator upon inducer binding, which, in combination with the relative nontoxicity of tetracycline to eukaryotic cells, has facilitat…”
BackgroundBelteki, G., Haigh, J., Kabacs, N., Haigh, K., Sison, K., Costantini, F., Whitsett, J., Quaggin, S., & Nagy, A. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni051 · Cited by 423 · see citing works
“allow for reversible temporal regulation of transgene expression (6,7).”
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“In order to test this possibility, we used a Tet-inducible expression system [18,19] to control expression of HPV16-E6/ E7 in iPS-derived hematopoietic progenitor cells and investigated whether such expression inhibited establishment of immortalized erythroid progenitor cell lines.”
MethodA versatile tool for conditional gene expression and knockdown
Szulc, J., Wiznerowicz, M., Sauvain, M., Trono, D., & Aebischer, P. (2006) · Nature Methods · doi:10.1038/nmeth846 · Cited by 394 · see citing works
“The systems developed so far rely on the transactivation of artificial promoters by chimeric transcription factor”
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“PKR genes were cut from pET11a vectors using NdeI and blunted using Klenow and dNTPs After heat inactivation, the constructs were cut with BamHI and placed into SacII- (blunted) and BamHI-digested pUHD10-3 [pTRE; Clontech, CA (Gossen et al., 1995)].”
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“The tetracycline-regulated Tet-On system was used to generate an LRRK2-expressing stable cell line (49).”
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“, the bacterial based tetracycline (tet)-inducible system offers many advantage”
BackgroundGene delivery by lentivirus vectors
Cockrell, A. S., & Kafri, T. (2007) · Molecular Biotechnology · doi:10.1007/s12033-007-0010-8 · Cited by 358 · see citing works
Gene Therapy: Promises and Problems
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ResultStreptogramin-based gene regulation systems for mammalian cells
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“CD24 expression was introduced into the MTLyCD24mut cell line under the control of a tetracycline-inducible promoter using the pTRE vector system (33).”
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“To begin to identify other cytokine-chemokine genes that may be regulated by the IRF-3 transcription factor, human embryonic kidney (293) cells inducibly expressing IRF-3 and IRF-3(5D) were created by using the reverse tTA activator (rtTA) (10, 25), which permits Dox-inducible expression of IRF-3 and IRF-3(5D).”
MethodBiophysical and Structural Characterization of Polyethylenimine-Mediated siRNA Delivery in Vitro
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“The HR5-CL11 cell line, a HeLa cell line derivative that stably expresses luciferase via a tetracycline-controlled transcriptional transactivator, was used as a model system ( 37 ).”
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“repressible (Gossen et al., 1995) RAD54 expression vector, a ScaI–MluI”
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“In order to model the biology of polyglutamine diseases in tissue culture, we have generated inducible lines in PC12 (rat phaeochromocytoma) cells, which express a GFP-tagged exon 1 fragment of the HD gene with 23, 43, 53 or 74 glutamine repeats, driven by a doxycycline (dox)-dependent Tet-On promoter (12).”
BackgroundMesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses
Komarova, S., Kawakami, Y., Stoff-Khalili, M. A., Curiel, D. T., & Pereboeva, L. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0334 · Cited by 302 · see citing works
Chen, C., & Tonegawa, S. (1997) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.20.1.157 · Cited by 300 · see citing works
“Furthermore, a reverse trans-activator (rtTA) system has also been developed, in which tetracycline turns on the gene expression (Gossen et al 1995).”
BackgroundFunctional Fluorescent Ca2+ Indicator Proteins in Transgenic Mice under TET Control
Hasan, M. T., Friedrich, R., Euler, T., Larkum, M., Giese, G., Both, M., Duebel, J., Waters, J., Bujard, H., Griesbeck, O., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020163 · Cited by 299 · see citing works
“5 lg of synthetic reverse tTA (rtTA-M2s) (Gossen et al. 1995; Urlinger et al. 2000) and 0.”
BackgroundMethodInfluentialSelf-citationSimmons, A., Aluvihare, V., & McMichael, A. (2001) · Immunity · doi:10.1016/s1074-7613(01)00158-3 · Cited by 299 · see citing works
Traykova-Brauch, M., Schönig, K., Greiner, O., Miloud, T., Jauch, A., Bode, M., Felsher, D., Glick, A., Kwiatkowski, D., Bujard, H., et al. (2008) · Nature Medicine · doi:10.1038/nm.1865 · Cited by 297 · see citing works
“1865" language="eng" relation="no"> Conditional gene expression systems, such as the tetracycline-dependent (Tet) syste”
Self-citationGene expression systems in Drosophila: a synthesis of time and space.
McGuire, S., Roman, G., & Davis, R. L. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.06.012 · Cited by 294 · see citing works
“A second Tet-regulated system (Figure 2b) has been developed in which the presence of doxycycline positively regulates the activity of the tetracycline transactivator (Tet-On) [ 24 ].”
BackgroundCohney, S., Sanden, D., Cacalano, N., Yoshimura, A., Mui, A., Migone, T., & Johnston, J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.7.4980 · Cited by 293 · see citing works
“We established clones in which SOCS-3 expression is suppressed by the presence of tetracycline (8, 9, 23).”
Midgley, C., Desterro, J. M. P., Saville, M. K., Howard, S. F., Sparks, A., Hay, R. T., & Lane, D. P. (2000) · Oncogene · doi:10.1038/sj.onc.1203593 · Cited by 250 · see citing works
“…expression vector pCAMTet (constructed by inserting fragments carrying the CMV promoter and rtTA gene (tetRrVP16 fusion) from pUHD172-1neo (Gossen et al., 1995) and the PhCMV*-1 regulatory promoter from pUHG 10-3 (Gossen and Bujard, 1992) into pcDNA3) to create pCAMTet GFP-Peptide3.…”
In Vitro and In Vivo Biology of Recombinant Adenovirus Vectors with E1, E1/E2A, or E1/E4 Deleted
Lusky, M., Christ, M., Rittner, K., Dieterlé, A., Dreyer, D., Mourot, B., Schultz, H., Stoeckel, F., Pavirani, A., & Mehtali, M. (1998) · Journal of Virology · doi:10.1128/jvi.72.3.2022-2032.1998 · Cited by 289 · see citing works
“Thus, transcription of the E4 genes should be turned off in the presence of tetracycline (25).”
BackgroundDirect Immunologic activities of CpG DNA and implications for gene therapy
Krieg, A. Μ. (1999) · The Journal of Gene Medicine · doi:10.1002/(sici)1521-2254(199901/02)1:1 · Cited by 116 · see citing works
Self-citationLiu, Y.-Y., Han, T.-R., Giuliano, A., & Cabot, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.2.1140 · Cited by 287 · see citing works
Mouse Cre-LoxP system: general principles to determine tissue-specific roles of target genes
Kim, H., Kim, M., Im, S.-K., & Fang, S. (2018) · Laboratory Animal Research · doi:10.5625/lar.2018.34.4.147 · Cited by 283 · see citing works
Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin
Wong, A., & Gumbiner, B. (2003) · Journal of Cell Biology · doi:10.1083/jcb.200212033 · Cited by 280 · see citing works
“Stable transfections were performed first to establish clonal lines constitutively expressing rtTA encoded by the pTet-ON regulator plasmid, which contains a neomycin resistance gene, allowing cells to be selected in G418 (Gossen et al., 1995) (CLONTECH Laboratories, Inc.).”
InfluentialDevelopment of a hypoxia-responsive vector for tumor-specific gene therapy
Shibata, T., Giaccia, A. J., & Brown, J. M. (2000) · Gene Therapy · doi:10.1038/sj.gt.3301124 · Cited by 266 · see citing works
Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes
Kobayashi, N., Fujiwara, T., Westerman, K. A., Inoue, Y., Sakaguchi, M., Noguchi, H., Miyazaki, M., Cai, J., Tanaka, N., Fox, I. J., et al. (2000) · Science · doi:10.1126/science.287.5456.1258 · Cited by 331 · see citing works
Functional Connectome of the Striatal Medium Spiny Neuron
Chuhma, N., Tanaka, K. F., Hen, R., & Rayport, S. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3833-10.2011 · Cited by 273 · see citing works
“We used the tetracycline transactivator (tTA)–tetracycline operator (tetO) promoter strategy (Gossen et al., 1995) to drive cell type-specific expression of ChR2 in MSNs of the striatum.”
MethodReengineering Inducible Cardiac-Specific Transgenesis With an Attenuated Myosin Heavy Chain Promoter
Sanbe, A., Gulick, J. M., Hanks, M. C., Liang, Q., Osińska, H. E., & Robbins, J. M. (2003) · Circulation Research · doi:10.1161/01.res.0000065442.64694.9f · Cited by 249 · see citing works
Zuber, J., McJunkin, K., Fellmann, C., Dow, L. E., Taylor, M. J., Hannon, G., & Lowe, S. (2010) · Nature Biotechnology · doi:10.1038/nbt.1720 · Cited by 277 · see citing works
“A particularly useful approach to evaluate such genes is Tet-On RNAi, which uses a two-component conditional expression system that requires a reverse tetracycline transactivator (rtTA) and a tetracycline-responsive element (TRE) promoter driving shRNA expressio”
A Packaging Cell Line for Lentivirus Vectors
Kafri, T., van Praag, H., Ouyang, L., Gage, F. H., & Verma, I. (1999) · Journal of Virology · doi:10.1128/jvi.73.1.576-584.1999 · Cited by 276 · see citing works
“Here we describe the generation of an inducible lentivirus vector packaging cell line that was constructed in 293 cells and that constitutively expresses a tetracycline-regulated transactivator (tTA) (8, 9).”
BackgroundMethodMadani, N., & Kabat, D. (1998) · Journal of Virology · doi:10.1128/jvi.72.12.10251-10255.1998 · Cited by 275 · see citing works
“These cells were generated by transfecting HeLa-tTA (12) cells with pUHD10-3(gp160/rev) by the calcium phosphate transfection method (1).”
MethodInfluentialCre-mediated somatic site-specific recombination in mice.
Akagi, K., Sandig, V., Vooijs, M., van der Valk, M. V., Giovannini, M., Strauss, M., & Berns, A. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.9.1766 · Cited by 275 · see citing works
Teckman, J., & Perlmutter, D. (2000) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.2000.279.5.g961 · Cited by 274 · see citing works
- 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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