Controlling mammalian gene expression with small molecules

Current Opinion in Chemical Biology

Volumn 1, Issue 2, 1997, Pages 210-218

  Clackson, Tim ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALIA; MAMMALIA;

ECDYSONE; MIFEPRISTONE; POLYENE; PROTEIN SYNTHESIS INHIBITOR; RAPAMYCIN; TETRACYCLINE;

CHEMICAL STRUCTURE; DRUG EFFECT; GENETIC TRANSCRIPTION; GENETICS; HUMAN; REVIEW;

ECDYSONE; HUMANS; MIFEPRISTONE; MODELS, MOLECULAR; POLYENES; PROTEIN SYNTHESIS INHIBITORS; SIROLIMUS; TETRACYCLINE; TRANSCRIPTION, GENETIC;

EID: 0031197176     PISSN: 13675931     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1367-5931(97)80012-9     Document Type: Article

References (44)

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38. Ho SN, Biggar SR, Spencer DM, Schreiber SL, Crabtree GR: Dimeric ligands define a role for transcriptional activation domains in reinitiation. Nature 1996, 382:822-826. Describes the use of the semisynthetic FK506 homodimer FK1012 to activate reporter transcription using DNA binding and activation domain proteins each including triplicated FKBP. Disruption of the bipartite transcription factor with a monomeric FK506 ligand was used to show that activation domains must remain localized to the promoter to maintain transcription.
39. Belshaw PJ, Ho SN, Crabtree GR, Schreiber SL: Controlling protein association and subcellular location with a synthetic ligand that induces heterodimerization of proteins. Proc Natl Acad Sci USA 1996, 93:4604-4607. FK-CsA, a heterodimer between FK506 and CsA, was used to activate transcription from a reporter introduced transiently into mammalian cells, using the GAL4 DNA binding domain fused to three FKBPs and the VP16 activation domain fused to two CyP modules. There was no background expression in the absence of the drug. This paper also illustrates the use of dimerizers to control other cellular signaling and localization events.
40. Rivera VM, Clackson T, Natesan S, Pollock R, Amara JF, Keenan T, Magari SR, Phillips T, Courage NL, Cerasoli F Jr et al.: A humanized system for pharmacologic control of gene expression. Nat Med 1996, 2:1028-1032. Describes the development of a dimerizer-based system appropriate for use in human gene therapy. Rapamycin was used to control reporter gene expression in stably transfected cells. Rapamycin was also used to control secretion of hGH from cells implanted into mice, using transcription factor domains fused to FKBP and FRB. Background transcription in the absence of rapamycin was negligible. All protein components used were of human origin, including the DNA binding domain [41], and the activation domain, which was from human NF-κB.
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43. Wang J, Takagaki Y, Mankey JL: Targeted disruption of an essential vertebrate gene: ASF/SF2 is required for cell viability. Genes Dev 1996, 10:2588-2599. Uses the tTA system to conditionally express the essential splice factor ASF/SF2, or mutants thereof, in a chicken B cell line lacking both endogenous genes.
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