TAXI/UAS: A molecular switch to control expression of genes in vivo.
Numerous therapies and biological questions could be addressed in mammals by the application of a molecular switch that would allow physicians and/or investigators to turn individual genes on or off during the lifetime of the organism. We have constructed such a switch, composed of three elements: (i) an inducible promoter that is normally absent from mammalian genomes; (ii) a receptor that, when it is bound to an inducer drug, specifically activates transcription from the inducible promoter; and (iii) inducer drugs, such as RU486, whose pharmacological properties in humans and several mammalian species including mouse have been well studied. The molecular switch is functional in transiently and stably transfected cells. Importantly, both the total output and the induction levels of the reporter gene can be finely tuned, with induction levels of over 100-fold being readily attained. Finally, we demonstrate that the molecular switch can be used to regulate a mouse transgene using a gene therapy paradigm. The specificity of the system suggests that it should be useful in the analysis of gene function in transgenic animals and in the design of strategies for human gene therapy.
Delort
J P
JP
Howard Hughes Medical Institute, University of Utah, Salt Lake City 84112, USA.
Capecchi
M R
MR
D000818:Animals; D001665:Binding Sites; D015139:Blotting, Southern; D015153:Blotting, Western; D017690:Cell Transplantation; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002875:Chromosomes; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005656:Fungal Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells / Q000187:drug effects; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics; D006727:Hormone Antagonists / Q000494:pharmacology; D019382:Human Growth Hormone / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015735:Mifepristone / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D029701:Saccharomyces cerevisiae Proteins; D013256:Steroids / Q000494:pharmacology; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D019076:Transgenes
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D017405:Herpes Simplex Virus Protein Vmw65; D006727:Hormone Antagonists; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D013256:Steroids; D014157:Transcription Factors; D019382:Human Growth Hormone; D015735:Mifepristone; D015500:Chloramphenicol O-Acetyltransferase