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History of the GeneSwitch System


The standard GeneSwitch® system for regulated transgene expression exhibits positive control – transgene expression is OFF in the absence of inducing drug, but ON in its presence. The GeneSwitch® system consists of two genes: one codes for the GeneSwitch regulator protein, the other codes for the inducible transgene of interest. Expression of the GeneSwitch regulator protein is typically driven by a constitutive promoter. The GeneSwitch regulator protein is a chimeric transcription factor that is allosterically activated by synthetic antiprogestin drugs. The functional components of the chimeric protein are (1) a mutant form of the ligand binding domain of the human progesterone receptor, (2) the DNA binding domain from the yeast GAL4 protein, and (3) the transcriptional activation domain from the VP16 protein of herpes simplex virus or from the p65 subunit of human NF-kB. The inducible transgene has a promoter that consists of a minimal promoter (typically a simple TATA box) linked to multiple copies of the 17 bp palindromic GAL4 DNA binding site. Each 17 bp binding site is capable of binding a homodimer of the GeneSwitch regulator protein. Many antiprogestin drugs activate the GeneSwitch regulator protein. The most commonly used antiprogestin drug is mifepristone (MFP). The GeneSwitch regulator protein is not activated by progesterone or other natural steroids.

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