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Báo cáo khoa học: Gene regulation by tetracyclines Constraints of resistance regulation in bacteria shape TetR for application in eukaryotes Christian Berens and Wolfgang Hillen

The Tet repressor protein (TetR) regulates transcription of a family of tetracycline (tc) resistance determinants in Gram-negative bacteria. The resistance protein TetA, a membrane-spanning H + -[tcÆM]+ antiporter, must be sen-sitively regulated because its expression is harmful in the absence of tc, yet it has to be expressed before the drugs’ concentration reaches cytoplasmic levels inhibitory for protein synthesis. | Eur. J. Biochem. 270 3109-3121 2003 FEBS 2003 doi 10.1046 j.1432-1033.2003.03694.x REVIEW ARTICLE Gene regulation by tetracyclines Constraints of resistance regulation in bacteria shape TetR for application in eukaryotes Christian Berens and Wolfgang Hillen Lehrstuhl fur Mikrobiologie Institut fur Mikrobiologie Biochemie und Genetik Friedrich-Alexander Universitat Erlangen-NUrnberg Germany The Tet repressor protein TetR regulates transcription of a family of tetracycline tc resistance determinants in Gram-negative bacteria. The resistance protein TetA a membrane-spanning H - tc-M antiporter must be sensitively regulated because its expression is harmful in the absence of tc yet it has to be expressed before the drugs concentration reaches cytoplasmic levels inhibitory for protein synthesis. Consequently TetR shows highly specific tetO binding to reduce basal expression and high affinity to tc to ensure sensitive induction. Tc can cross biological membranes by diffusion enabling this inducer to penetrate the majority of cells. These regulatory and pharmacological properties are the basis for application of TetR to selectively control the expression of single genes in lower and higher eukaryotes. TetR can be used for that purpose in some organisms without further modifications. In mammals and in a large variety of other organisms however eukaryotic transcriptional activator or repressor domains are fused to TetR to turn it into an efficient regulator. Mechanistic understanding and the ability to engineer and screen for mutants with specific properties allow tailoring of the DNA recognition specificity the response to inducer tc and the dimerization specificity of TetR-based eukaryotic regulators. This review provides an overview of the TetR properties as they evolved in bacteria the functional modifications necessary to transform it into a convenient specific and efficient regulator for use in eukaryotes and how the interplay between structure - function studies in .