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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Background
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Evaluation of the tetracycline‐ and ecdysone‐inducible systems for expression of neurotransmitter receptors in mammalian cells
van Craenenbroeck, K., Vanhoenacker, P., Leysen, J., & Haegeman, G. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01719.x · Cited by 39
“For the construction of the luciferase (luc) expressing plasmid, pluc, the XhoI±BsrBI fragment of pUHC13-3 (Gossen et al., 1995) consisting of TRE±CMVmin±luc±polyA, was inserted into the HindIII±SalI site of p220.”
MethodInfluential
Baculovirus Insecticide Production in Insect Larvae.
van Beek, N. V., & Davis, D. C. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3043-2_20 · Cited by 39
Gene regulation technologies for gene and cell therapy
Butterfield, G. L., Reisman, S. J., Iglesias, N., & Gersbach, C. A. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.004 · Cited by 43
“92,93 This approach has resulted in FDA-approved treatments such as Amondys 45, Exondys 51, and Vyondys 53, which lead to the production of partially functional dystrophin protein by skipping mutated exons.”
Loss of biased signaling at a G protein-coupled receptor in overexpressed systems
Li, A., Liu, S., Huang, R., Ahn, S., & Lefkowitz, R. (2023) · PLoS ONE · doi:10.1371/journal.pone.0283477 · Cited by 38
“Such systems consist of two elements–a constitutively expressed reverse tetracycline-controlled transactivator (rtTA) and a gene of interest controlled by an rtTA-dependent tetracycline response element (TRE)–and thereby enable titration of gene expression by treatment with variable amounts of doxycycline (Fig 1A) [31…”
Background
Genetically Encoded Protein Thermometer Enables Precise Electrothermal Control of Transgene Expression
Stefanov, B., Teixeira, A. P., Mansouri, M., Bertschi, A., Krawczyk, K., Hamri, G. C., Xue, S., & Fussenegger, M. (2021) · Advanced Science · doi:10.1002/advs.202101813 · Cited by 43
A precisely adjustable, variation-suppressed eukaryotic transcriptional controller to enable genetic discovery
Azizoğlu, A., Brent, R., & Rudolf, F. (2019) · bioRxiv · doi:10.7554/elife.69549 · Cited by 38
Characterization of MYC-Induced Tumorigenesis by in Situ Lipid Profiling
Perry, R. H., Bellovin, D. I., Shroff, E. H., Ismail, A. I., Zabuawala, T., Felsher, D. W., & Zare, R. N. (2013) · Analytical Chemistry · doi:10.1021/ac400479j · Cited by 40
Involvement of Dynamin-Related Protein 1 in Free Fatty Acid-Induced INS-1-Derived Cell Apoptosis
Peng, L., Men, X., Zhang, W., Wang, H., Xu, S., Fang, Q., Liu, H., Yang, W., & Lou, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049258 · Cited by 31
“The plasmid for second stable transfection was constructed by subcloning cDNA encoding rat Drp-1 or its dominantnegative mutant Drp-1 K38A into the expression vector PUHD103 [36].”
Destabilizing Domains Mediate Reversible Transgene Expression in the Brain
Tai, K., Quintino, L., Isaksson, C., Gussing, F., & Lundberg, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046269 · Cited by 38
“Moreover, mutations on the transcription factors can be created to make the systems more sensitive to induction, thereby increasing their operational window [4,10].”
Transcription regulates telomere dynamics in human cancer cells
Arora, R., Brun, C. M., & Azzalin, C. M. (2012) · RNA · doi:10.1261/rna.029587.111 · Cited by 41
“To overcome this limitation we combined the telomere-seeding phenomenon with the inducible gene expression Tet-ON technology (Barnett et al. 1993; Gossen et al. 1995) and engineered a human cell line carrying ‘‘transcriptionally inducible telomeres’’ (tiTELs).”
Method
Increased Expression of the Pro-apoptotic Protein BIM, a Mechanism for cAMP/Protein Kinase A (PKA)-induced Apoptosis of Immature T Cells
Zambon, A. C., Wilderman, A. S., Ho, A., & Insel, P. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.268979 · Cited by 33
Tetracycline‐regulated bone morphogenetic protein 2 gene expression in lentivirally transduced primary rabbit chondrocytes for treatment of cartilage defects
Wübbenhorst, D., Dumler, K., Wagner, B., Wexel, G., Imhoff, A. B., Gänsbacher, B., Vogt, S., & Anton, M. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27461 · Cited by 32
Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis
Hintze, V., Steplewski, A., Ito, H., Jensen, D. A., Rodeck, U., & Fertala, A. (2008) · Human Mutation · doi:10.1002/humu.20736 · Cited by 35
“Such a baseline expression of recombinant proteins whose biosynthesis depends on a Tet-responsive promoter is expected and may be a result of residual amounts of tetracycline present in cell culture media or a marginal nonspecific activation of the Tet promoter [Gossen et al., 1995].”
Background
Transactivator and structurally optimized inducible lentiviral vectors.
Haack, K., Cockrell, A., Ma, H., Israeli, D., Ho, S., McCown, T., & Kafri, T. (2004) · Molecular Therapy · doi:10.1016/j.ymthe.2004.06.109 · Cited by 38
“Several regulatable gene expression systems have been described [2–7], among which the tetracycline-inducible systems (‘‘Tetoff’’ and ‘‘Tet-on’’) are the best characterized [8–10].”
Depletion of Collagen II-Reactive T Cells and Blocking of B Cell Activation Prevents Collagen II-Induced Arthritis in DBA/1j Mice
Zhang, H.-G., Yang, P., Xie, J.-F., Liu, Z., Liu, D., Xiu, L., Zhou, T., Wang, Y., Hsu, H.-C., & Mountz, J. (2002) · Journal of Immunology · doi:10.4049/jimmunol.168.8.4164 · Cited by 38
“E-mail address: Huang-Ge.Zhang@ccc.uab.edu 2 Abbreviations used in this paper: CII, collagen II; BlyS, B lymphocyte stimulator; rtTA, reverse tetracycline transactivator; FasL, Fas ligand; TRE, tetracycline response element; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; sTACI,…”
BackgroundInfluential
Oxygen tension and a pharmacological switch in the regulation of transgene expression for gene therapy
Payen, E., Bettan, M., Henri, A., Tomkiewitcz, E., Houque, A., Kuzniak, I., Zuber, J., Scherman, D., & Beuzard, Y. (2001) · The Journal of Gene Medicine · doi:10.1002/jgm.217 · Cited by 36
“Several other interesting areas are currently under study, as follows: (i) the combination of transactivator and reporter genes in the same vector, in order to facilitate gene transfer in vivo; (ii) the association of the hypoxia regulation system with the reverse tetracyclinedependent transactivator [44], instead of…”
Background
A novel 52 kDa protein induces apoptosis and concurrently activates c-Jun N-terminal kinase 1 (JNK1) in mouse C3H10T1/2 fibroblasts.
Sun, L.-J., Liu, Y., Frémont, M., Schwarz, S., Siegmann, M., Matthies, R., & Jost, J.-P. (1998) · Gene · doi:10.1016/s0378-1119(97)00626-4 · Cited by 38
Prometheus' myth revisited: transgenic mice as a powerful tool to study liver regeneration
Pistoi, S., & Morello, D. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.8.8666158 · Cited by 38
“A further refinement would be to obtain an inducible expression of the Crc, for instance, by putting it under the control of tetracycline (13) or interferon (14) responding sequences.”
Background
Serotonin Receptors: Genetic insights into serotonin function
Heath, M. J., & Hen, R. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00199-0 · Cited by 38
Light-regulated gene expression in Bacteria: Fundamentals, advances, and perspectives
Ohlendorf, R., & Möglich, A. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.1029403 · Cited by 37
“The homodimeric Tet repressor (TetR) supports many applications in both prokaryotic and eukaryotic hosts, prominently so within the Tet-ON and Tet-OFF systems (Gossen et al., 1995).”
Background
An Engineered Optogenetic Switch for Spatiotemporal Control of Gene Expression, Cell Differentiation, and Tissue Morphogenesis
Polstein, L. R., Juhas, M., Hanna, G., Bursac, N., & Gersbach, C. (2017) · ACS Synthetic Biology · doi:10.1021/acssynbio.7b00147 · Cited by 37
Genetically Engineered Mouse Models for Drug Development and Preclinical Trials
Lee, H. (2014) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2014.074 · Cited by 37
“It was fi rst developed for in vivo use in 1995 (Gossen et al., 1995), and this system has been used in many fi elds to analyze the outcomes of gene expression after the onset of disease in mice.”
Method
Tetracycline-dependent expression of the human erythropoietin gene in transgenic chickens
Koo, B., Kwon, M., Lee, H., Kim, M., Kim, D., Roh, J., Park, Y.-Y., Cui, X.-S., Kim, N.-H., Byun, S., et al. (2010) · Transgenic research · doi:10.1007/s11248-009-9327-3 · Cited by 37
R992C (p.R1192C)Substitution in Collagen II Alters the Structure of Mutant Molecules and Induces the Unfolded Protein Response
Chung, H., Jensen, D. A., Gawron, K., Steplewski, A., & Fertala, A. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.05.004 · Cited by 37
A genetic time‐delay circuitry in mammalian cells
Weber, W., Kramer, B. P., & Fussenegger, M. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21463 · Cited by 37
“We compared expression kinetics of the tetracyclineresponsive time-delay circuitry to the conventional tetracycline-inducible TET-ON system (Gossen et al., 1995) following inducer administration.”
Conditional gene expression in the mouse using a Sleeping Beauty gene-trap transposon
Geurts, A. M., Wilber, A., Carlson, C. M., Lobitz, P. D., Clark, K., Hackett, P. B., McIvor, R., & Largaespada, D. (2006) · BMC Biotechnology · doi:10.1186/1472-6750-6-30 · Cited by 37
“The activity of tTA is regulable by administering the drug tetracycline or its analog doxycycline [15].”
Background
RNAi Based Approaches to the Treatment of Malignant Glioma
Mathupala, S., Guthikonda, M., & Sloan, A. (2006) · Technology in Cancer Research and Treatment · doi:10.1177/153303460600500313 · Cited by 37
Versatile macrolide‐responsive mammalian expression vectors for multiregulated multigene metabolic engineering
Weber, W., Marty, R. R., Keller, B., Rimann, M., Kramer, B. P., & Fussenegger, M. (2002) · Biotechnology and Bioengineering · doi:10.1002/bit.10461 · Cited by 37
“Both systems have been found to be functionally compatible with each other as well as with the well-established Tet systems (Fussenegger et al., 2000; Gossen and Bujard, 1992; Gossen et al., 1995).”
Background
Inducible expression of the gap junction protein connexin43 decreases the neoplastic potential of HT‐1080 human fibrosarcoma cells in vitro and in vivo
King, T. J., Fukushima, L. H., Yasui, Y., Lampe, P. D., & Bertram, J. S. (2002) · Molecular Carcinogenesis · doi:10.1002/mc.10071 · Cited by 38
“Our development of HT-1080 human fibrosarcoma cell lines containing an inducible Cx43 gene allows for the evaluation of effects of Cx43 induction both in vitro and in vivo [12,13].”
Background
Tightly Regulated Long-Term Erythropoietin Expression In Vivo Using Tet-Inducible Recombinant Adeno-Associated Viral Vectors
Rendahl, K. G., Quiroz, D., Ladner, M. B., Coyne, M. Y., Seltzer, J., Manning, W. C., & Escobedo, J. A. (2002) · Human Gene Therapy · doi:10.1089/10430340252769842 · Cited by 36
“The first in vivo studies incorporating the original tet-off (Gossen and Bujard, 1992) and tet-on (Gossen et al ., 1995) systems into recombinant adeno-associated viral (rAAV) vectors showed robust induction of transgene expression in muscle, and a lack of significant humoral or T cell response to…”
The Cellular Protein PRA1 Modulates the Anti-apoptotic Activity of Epstein-Barr Virus BHRF1, a Homologue of Bcl-2, through Direct Interaction*
Li, L.-Y., Shih, H.-M., Liu, M.-Y., & Chen, J.-Y. Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103821200 · Cited by 37
The Cell Cycle Inhibitor p16INK4A Sensitizes Lymphoblastic Leukemia Cells to Apoptosis by Physiologic Glucocorticoid Levels*
Ausserlechner, M., Obexer, P., Wiegers, G. J., Hartmann, B., Geley, S., & Kofler, R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008188200 · Cited by 37
Upregulation of Tyrosine Kinase TKT by the Epstein-Barr Virus Transactivator Zta
Lu, J., Chen, S.-Y., Chua, H.-H., Liu, Y.-S., Huang, Y.-T., Chang, Y., Chen, J.-Y. Y., Sheen, T., & Tsai, C.-H. (2000) · Journal of Virology · doi:10.1128/jvi.74.16.7391-7399.2000 · Cited by 37
“3 tet-on system (kindly provided by H. Bujard, University of Heidelberg, Heidelberg, Germany) (16).”
Strategies of Conditional Gene Expression in Myocardium
Heine, H. L., Leong, H. S., Rossi, F. M. V., McManus, B. M., & Podor, T. J. (2005) · Methods in molecular medicine · doi:10.1007/978-1-59259-879-3_8 · Cited by 40
Conditional knockout mice.
Kühn, R., & Schwenk, F. (2003) · Methods in molecular biology · doi:10.1385/1-59259-340-2:159 · Cited by 37
Modelling acute myeloid leukemia (AML): What’s new? A transition from the classical to the modern
Dozzo, A., Galvin, A., Shin, J., Scalia, S., O’Driscoll, C. M., & Ryan, K. B. (2022) · Drug Delivery and Translational Research · doi:10.1007/s13346-022-01189-4 · Cited by 40
“While in the Tet-on system, the rtTA requires the presence of tetracycline or its derivatives for specific Tet-O binding and gene expression [230].”
Background
Expression vector cassette engineering for recombinant therapeutic production in mammalian cell systems
Wang, T., & Guo, X. H. (2020) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-020-10640-w · Cited by 42
Tissue Distribution of Doxycycline in Animal Models of Tuberculosis
Gengenbacher, M., Zimmerman, M., Sarathy, J., Kaya, F., Wang, H., Mina, M., Carter, C., Hossen, M. A., Su, H.-W., Trujillo, C., et al. (2020) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02479-19 · Cited by 36
A possible aid in targeted insertion of large DNA elements by CRISPR/Cas in mouse zygotes
Nakao, H., Harada, T., Nakao, K., Kiyonari, H., Inoue, K., Furuta, Y., & Aiba, A. (2015) · genesis · doi:10.1002/dvg.22914 · Cited by 36
“…cargo (designated as EGFP-TRE-Cas9) containing an EGFPpolyA cassette, an hCas9 cDNA and a bidirectional promoter TRE3G which is responsive to rtTA regulatory proteins in the Tet-On system (Gossen et al., 1995) flanked by 8.1 kb 50 and 3.6 kb 30 homology arms relative to the sgRNA target site (Fig.”
BackgroundInfluential
Selecting the optimal Tet‐On system for doxycycline‐inducible gene expression in transiently transfected and stably transduced mammalian cells
Das, A. T., Zhou, X., Metz, S. W., Vink, M. A., & Berkhout, B. (2016) · Biotechnology Journal · doi:10.1002/biot.201500236 · Cited by 36
“Because long-term exposure to effectors is often undesirable, the Tet-On system is preferred in applications in which gene expression should be switched off for extended periods or when rapid gene induction is required [6, 7].”
Background
Generation of transgenic dogs that conditionally express green fluorescent protein
Kim, M., Oh, H., Park, J., Kim, G. A., Hong, S., Jang, G., Kwon, M., Koo, B., Kim, T., Kang, S., et al. (2011) · Genesis · doi:10.1002/dvg.20737 · Cited by 36
Use of a New-Generation Reverse Tetracycline Transactivator System for Quantitative Control of Conditional Gene Expression in the Murine Lung
Duerr, J., Gruner, M., Schubert, S. C., Haberkorn, U., Bujard, H., & Mall, M. A. (2010) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2009-0115oc · Cited by 28
Self-citation

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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