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Titolo:
A versatile framework for the design of ligand-dependent, transgene-specific transcription factors
Autore:
Xu, L; Zerby, D; Huang, Y; Ji, H; Nyanguile, OF; de los Angeles, JE; Kadan, MJ;
Indirizzi:
Genet Therapy Inc, Gaithersburg, MD 20878 USA Genet Therapy Inc Gaithersburg MD USA 20878 c, Gaithersburg, MD 20878 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 2, volume: 3, anno: 2001,
pagine: 262 - 273
SICI:
1525-0016(200102)3:2<262:AVFFTD>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
ZINC-FINGER PROTEINS; EXPRESSION IN-VIVO; CONTROLLING GENE-EXPRESSION; SITE-SPECIFIC RECOMBINATION; STEROID-HORMONE RECEPTORS; DNA-BINDING DOMAIN; ESTROGEN-RECEPTOR; ADENOVIRAL VECTORS; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS;
Keywords:
cysteine(2)-histidine(2) zinc finger; estrogen receptor; adenovirus; transgene; gene therapy;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Kadan, MJ Genet Therapy Inc, 9 W Watkins Mill Rd, Gaithersburg, MD 20878 USA Genet Therapy Inc 9 W Watkins Mill Rd Gaithersburg MD USA 20878
Citazione:
L. Xu et al., "A versatile framework for the design of ligand-dependent, transgene-specific transcription factors", MOL THER, 3(2), 2001, pp. 262-273

Abstract

The ability to regulate transgene expression will be essential for the safety and efficacy of many gene therapies. Various ligand-dependent transcription factors, including steroid hormone receptors, have been modified to enable transgene-specific regulation. To minimize effects on cellular gene expression, chimeric steroid receptors have been constructed by replacing their native DNA binding domain (DBD) with a heterologous DBD, like that from the yeast transcription factor GAL4. This approach has limitations for human gene therapy, including the potential immunogenicity of the GAL4 domain and the inability to discriminate between different GAL4-linked transgenes in the same cell. To address this, we have constructed chimeric regulators containing the human estrogen receptor (ER) ligand binding domain (LBD) and a Cys(2)-His(2)-type zinc finger DBD. Cys(2)-His(2) zinc finger domains arecommon among human DNA binding proteins and can be engineered to selectively bind different DNA sequences. We demonstrate over 500-fold drug-dependent transgene induction with these chimeric regulators in vitro and the ability to regulate an adenovirus-delivered transgene in mice. Two chimeras containing different Cys(2)-His(2) domains displayed highly sequence-specific binding and regulation. incorporating a point mutation in the ER LBD that ablates estrogen binding enables selective in vivo regulation with the clinically useful anti-estrogen tamoxifen. These Cys(2)-His(2)-ER LBD chimeras represent a versatile framework for creating transgene-specific regulators potentially useful for human gene therapy applications.

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Documento generato il 02/04/20 alle ore 21:08:27