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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TOK-1, a Novel p21Cip1-binding Protein That Cooperatively Enhances p21-dependent Inhibitory Activity toward CDK2 Kinase
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c-E10 Is a Caspase-recruiting Domain-containing Protein That Interacts with Components of Death Receptors Signaling Pathway and Activates Nuclear Factor-κB
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INDUCIBLE GENE EXPRESSION IN THE NERVOUS SYSTEM OF TRANSGENIC MICE
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Functional Access to Neuron Subclasses in Rodent and Primate Forebrain
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“This scheme is different from the better known Tet ON/OFF systems (Gossen and Bujard, 1992; Gossen et al., 1995), where the repressor acts as a transcription factor, in that here the repressor can block read-through from any TATA box-containing promoter, preserving cell type-specific expression for…”
Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis
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“We used the Tet-On gene expression system which enables us to regulate gene expression in a precise, reversible, and quantitative manner (17, 18).”
Method
Manufacture of Third-Generation Lentivirus for Preclinical Use, with Process Development Considerations for Translation to Good Manufacturing Practice
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Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP
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“Mutations in four amino acids of the tet repressor-binding domain of tTA generate a reverse tetracycline transactivator (rtTA) which works in the opposite manner to activate transcription in the presence of tetracycline or doxycycline (also called Tet-on system; Gossen et al. 1995).”
Background
Long‐term, noninvasive imaging of regulated gene expression in living mice
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“To exploit this technology for the above objective, we have combined the tetracycline controlled regulatory (Tet) system (Gossen and Bujard, 1992; Gossen et al., 1995) with the in vivo luciferase monitoring principle.”
MethodSelf-citation
Hevin is down-regulated in many cancers and is a negative regulator of cell growth and proliferation
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BackgroundMethod
Inducible upregulation of oestrogen receptor-beta1 affects oestrogen and tamoxifen responsiveness in MCF7 human breast cancer cells.
Murphy, L., Peng, B., Lewis, A., Davie, J., Leygue, E., Kemp, A., Ung, K., Vendetti, M., & Shiu, R. (2005) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.01688 · Cited by 79
“This cDNA was then subcloned downstream of the tetracycline-inducible promoter in the pTRE2 hyg plasmid (Gossen et al. 1995) (Clontech Laboratories Inc., Palo Alto, CA, USA).”
Method
Design of temperature-sensitive mutants solely from amino acid sequence.
Chakshusmathi, G., Mondal, K., Lakshmi, G. S., Singh, G., Roy, A., Ch, R. B., Madhusudhanan, S., & Varadarajan, R. (2004) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0402222101 · Cited by 79
Conditional expression of RET/PTC induces a weak oncogenic drive in thyroid PCCL3 cells and inhibits thyrotropin action at multiple levels.
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Prospects for Using Genetic Transformation for Improved SIT and New Biocontrol Methods
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“The tetracycline-resistance operon from the E. coli Tn10 transposon has been developed into positive and negative gene expression regulatory systems, resulting in either the promotion or inhibition of gene expression in the presence of tetracycline (or derivatives such as doxycycline) (Gossen & Bujard, 1992; Gossen et…”
Background
Regulatable systems: applications in gene therapy and replicating viruses
Agha‐Mohammadi, S., & Lotze, M. T. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10027 · Cited by 79
“The Tet-on system shows rapid kinetics of upregulation and thus overcomes the delay in TrRS activity after removal of tetracycline (17).”
Background
CHEMICAL CONTROL OF GENE EXPRESSION.
Gatz, C. (1997) · Annual Review of Plant Physiology and Plant Molecular Biology · doi:10.1146/annurev.arplant.48.1.89 · Cited by 79
Knocking out multigene redundancies via cycles of sexual assortment and fluorescence selection
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“, collectively allowing selection for MAT a /α diploid cells carrying both GMToolkit constructs; and (iii) the Tet activator rtTA”
Method
Comparison of single regulated lentiviral vectors with rtTA expression driven by an autoregulatory loop or a constitutive promoter
Markusic, D. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni062 · Cited by 78
“Induction with the Tet-Off system depends on the pharmacological elimination of doxycycline and tends to be slower as compared with the Tet-On system (9,12,13).”
BackgroundMethod
Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents
Wang, Y. B., de Lartigue, G., & Page, A. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00643 · Cited by 96
Improvement of the reverse tetracycline transactivator by single amino acid substitutions that reduce leaky target gene expression to undetectable levels
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“Upon the addition of tetracycline, rtTA undergoes a conformational change that increases its affinity for a unique 19 base-pair DNA binding site and enhances the recruitment of the machinery required for transcription 1 .”
Animal models of acute myelogenous leukaemia – development, application and future perspectives
McCormack, E., Bruserud, Ø., & Gjertsen, B. T. (2005) · Leukemia · doi:10.1038/sj.leu.2403670 · Cited by 78
Introducing Genes into Mammalian Cells: Viral VectorsPreprint
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“Two transcription factors have been developed, tTA and rtTA, that bind the cognate tet operator (tetO) in the absence (Tet-Off system) (Gossen and Bujard 1992) or presence (Tet-On system) (Gossen et al. 1995) of tetracycline, or derivative antibiotics such as doxycycline.”
Method
Modeling Metastatic Breast Cancer in Mice
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“tetracycline-responsive) elements incorporated in mammary-specific promoters [96, 97].”
Using conditional mutagenesis to study the brain
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Regulated expression of human filaggrin in keratinocytes results in cytoskeletal disruption, loss of cell-cell adhesion, and cell cycle arrest.
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HSV-1-based vectors for gene therapy of neurological diseases and brain tumors: part II. Vector systems and applications.
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Inducible Expression of IκBα Repressor Mutants Interferes with NF-κB Activity and HIV-1 Replication in Jurkat T Cells*
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Practical Use of Immortalized Cells in Medicine: Current Advances and Future Perspectives
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Visualization and genetic manipulation of adult neurogenesis using transgenic mice
Dhaliwal, J., & Lagace, D. C. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07600.x · Cited by 74
“In this dual-transgene system, a specific promoter controls the expression of tTA and a second transgene encodes for a reporter or another gene of interest under the control of the tTA-responsive TetOp promoter (Gossen & Bujard, 1992; Gossen et al., 1995; Chen et al., 1998).”
Background
Expressing short hairpin RNAs in vivo
Snøve, O., & Rossi, J. J. (2006) · Nature Methods · doi:10.1038/nmeth927 · Cited by 64
Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification
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“ESCs expressing the tetracycline-inducible transcriptional activator (rtTA”
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Tight control of gene expression by a helper-dependent adenovirus vector carrying the rtTA2s-M2 tetracycline transactivator and repressor system
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Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by sox9 and msx2
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Regulation of Interleukin-2 Transcription by Inducible Stable Expression of Dominant Negative and Dominant Active Mitogen-activated Protein Kinase Kinase Kinase in Jurkat T Cells
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Inducible gene expression from defective herpes simplex virus vectors using the tetracycline-responsive promoter system
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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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