Cited by 2,488Bacterial Genetics and BiotechnologyGene Regulatory Network AnalysisCRISPR and Genetic Engineering

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Transcriptional Activation by Tetracyclines in Mammalian Cells

Gossen, Manfred, Freundlieb, Sabine, Bender, Gabriele, Müller, Gerhard, Hillen, Wolfgang, Bujard, Hermann·1995·Science

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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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Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
Gossen, M., & Bujard, H. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5547 · Cited by 4,943
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10.1016/0003-2697(87)90021-2 · DOI
10.1016/0003-2697(83)90418-9 · DOI
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Result
Streptogramin-based gene regulation systems for mammalian cells
Fussenegger, M., Morris, R. P., Fux, C., Rimann, M., von Stockar, B., Thompson, C. J., & Bailey, J. E. (2000) · Nature Biotechnology · doi:10.1038/81208 · Cited by 351
SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs
Sureau, A., Gattoni, R., Dooghe, Y., Ste'venin, J., & Soret, J. (2001) · EMBO Journal · doi:10.1093/emboj/20.7.1785 · Cited by 347
CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis.
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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).”
Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases
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Construction and Characterization of a Conditionally Active Version of the Serine/Threonine Kinase Akt
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Tet repressor-based system for regulated gene expression in eukaryotic cells: Principles and advances
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Self-citation
Lentiviral vectors: basic to translational
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Essential Role of Interferon Regulatory Factor 3 in Direct Activation of RANTES Chemokine Transcription
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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).”
Method
Biophysical and Structural Characterization of Polyethylenimine-Mediated siRNA Delivery in Vitro
Grayson, A. C. R., Doody, A. M., & Putnam, D. A. (2006) · Pharmaceutical Research · doi:10.1007/s11095-006-9009-2 · Cited by 324
“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 ).”
Method
The role of NF-κB in the regulation of cell stress responses
Wang, T., Zhang, X., & Li, J. J. (2002) · International Immunopharmacology · doi:10.1016/s1567-5769(02)00058-9 · Cited by 350
The controlling role of ATM in homologous recombinational repair of DNA damage
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“repressible (Gossen et al., 1995) RAD54 expression vector, a ScaI–MluI”
Method
Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression.
Chen, H., Thiagalingam, A., Chopra, H., Borges, M., Feder, J. N., Nelkin, B., Baylin, S., & Ball, D. W. (1997) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.94.10.5355 · Cited by 310
Inducible site-directed recombination in mouse embryonic stem cells.
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Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease
Wyttenbach, A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.17.1829 · Cited by 274
“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).”
Background
Mesenchymal 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
Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain
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“Furthermore, a reverse trans-activator (rtTA) system has also been developed, in which tetracycline turns on the gene expression (Gossen et al 1995).”
Background
Functional Fluorescent Ca2+ Indicator Proteins in Transgenic Mice under TET Control
Hasan, M. T., Friedrich, R. W., Euler, T., Larkum, M. E., 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 242
“5 lg of synthetic reverse tTA (rtTA-M2s) (Gossen et al. 1995; Urlinger et al. 2000) and 0.”
BackgroundMethodInfluentialSelf-citation
Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators.
Simmons, A., Aluvihare, V., & McMichael, A. (2001) · Immunity · doi:10.1016/s1074-7613(01)00158-3 · Cited by 299
An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice
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“1865" language="eng" relation="no"> Conditional gene expression systems, such as the tetracycline-dependent (Tet) syste”
Self-citation
Gene 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
“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 ].”
Background
SOCS-3 Is Tyrosine Phosphorylated in Response to Interleukin-2 and Suppresses STAT5 Phosphorylation and Lymphocyte Proliferation
Cohney, 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
“We established clones in which SOCS-3 expression is suppressed by the presence of tetracycline (8, 9, 23).”
An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo
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
“…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
“Thus, transcription of the E4 genes should be turned off in the presence of tetracycline (25).”
Background
Direct 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 120
Self-citation
Expression of Glucosylceramide Synthase, Converting Ceramide to Glucosylceramide, Confers Adriamycin Resistance in Human Breast Cancer Cells*
Liu, Y.-Y., Han, T.-R., Giuliano, A., & Cabot, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.2.1140 · Cited by 287
Mouse Cre-LoxP system: general principles to determine tissue-specific roles of target genes
Kim, H., Kim, M., Im, S., & Fang, S. (2018) · Laboratory Animal Research · doi:10.5625/lar.2018.34.4.147 · Cited by 414
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
“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.).”
Influential
Development 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 267
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
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 287
“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.”
Method
Reengineering 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
Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi
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
“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
“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).”
BackgroundMethod
An Endogenous Inhibitor of Human Immunodeficiency Virus in Human Lymphocytes Is Overcome by the Viral Vif Protein
Madani, N., & Kabat, D. (1998) · Journal of Virology · doi:10.1128/jvi.72.12.10251-10255.1998 · Cited by 275
“These cells were generated by transfecting HeLa-tTA (12) cells with pUHD10-3(gp160/rev) by the calcium phosphate transfection method (1).”
MethodInfluential
Cre-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
Retention of mutant α 1 -antitrypsin Z in endoplasmic reticulum is associated with an autophagic response
Teckman, J. H., & Perlmutter, D. H. (2000) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.2000.279.5.g961 · Cited by 275

Authors: Gossen, M., Freundlieb, S., Bender, G., Müller, G., Hillen, W., & Bujard, H.
Affiliations: Heidelberg University (DE)
ORCID: Gossen, Manfred
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1995-06-23
Volume: 268
Issue: 5218
Pages: 1766-1769
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.7792603
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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Transcriptional Activation by Tetracyclines in Mammalian Cells

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