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Nucleic Acids Research, 2003, Vol. 31, No. 14 e71
© 2003 Oxford University Press

Streptomyces-derived quorum-sensing systems engineered for adjustable transgene expression in mammalian cells and mice

Wilfried Weber, Ronald Schoenmakers1, Manuela Spielmann, Marie Daoud El-Baba2, Marc Folcher3, Bettina Keller, Cornelia C. Weber1, Nils Link, Petra van de Wetering1, Christoph Heinzen4, Benoît Jolivet5, Urs Séquin5, Dominique Aubel2, Charles J. Thompson3 and Martin Fussenegger*

Institute of Biotechnology, Swiss Federal Institute of Technology, ETH Hoenggerberg, CH-8093 Zurich, Switzerland, 1 Institute for Biomedical Engineering, Swiss Federal Institute of Technology, ETH Zurich, CH-8044 Zurich, Switzerland, 2 Institut Universitaire de Technologie, IUTA, Département Génie Biologique, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France, 3 Biocenter, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland, 4 Inotech Encapsulation AG, Kirchstrasse 1, CH-5605 Dottikon, Switzerland and 5 Department of Chemistry, University of Basel, St Johanns-Ring 19, CH-4056 Basel, Switzerland

*To whom correspondence should be addressed. Tel: +41 1 633 3448; Fax: +41 1 633 1234; fussenegger{at}biotech.biol.ethz.ch

Prokaryotic transcriptional regulatory elements have been adopted for controlled expression of cloned genes in mammalian cells and animals, the cornerstone for gene-function correlations, drug discovery, biopharmaceutical manufacturing as well as advanced gene therapy and tissue engineering. Many prokaryotes have evolved specific molecular communication systems known as quorum-sensing to coordinate population-wide responses to physiological and/or physicochemical signals. A generic bacterial quorum-sensing system is based on a diffusible signal molecule that prevents binding of a repressor to corresponding operator sites thus resulting in derepression of a target regulon. In Streptomyces, a family of butyrolactones and their corresponding receptor proteins, serve as quorum-sensing systems that control morphological development and antibiotic biosynthesis. Fusion of the Streptomyces coelicolor quorum-sensing receptor (ScbR) to a eukaryotic transactivation domain (VP16) created a mammalian transactivator (SCA) which binds and adjusts transcription from chimeric promoters containing an SCA-specific operator module (PSPA). Expression of erythropoietin or the human secreted alkaline phosphatase (SEAP) by this quorum-sensor-regulated gene expression system (QuoRex) could be fine-tuned by non-toxic butyrolactones in a variety of mammalian cells including human primary and mouse embryonic stem cells. Following intraperitoneal implantation of microencapsulated Chinese hamster ovary cells transgenic for QuoRex-controlled SEAP expression into mice, the serum levels of this model glycoprotein could be adjusted to desired concentrations using different butyrolactone dosing regimes.


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