A strategy for enhancing the transcriptional activity of weak cell type-specific promoters

Titelangaben

Nettelbeck, Dirk M. ; Jérôme, Valérie ; Müller, Rolf:
A strategy for enhancing the transcriptional activity of weak cell type-specific promoters.
In: Gene Therapy. Bd. 5 (1998) Heft 12 . - S. 1656-1664.
ISSN 1476-5462

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Abstract

Cell type- and tissue-specific promoters play an important role in the development of site-selective vectors for gene therapy. A large number of highly specific promoters has been described, but their applicability is often hampered by their inefficient transcriptional activity. In this study, we describe a new strategy for enhancing the activity of weak promoters without loss of specificity. The basic principle of this strategy is to establish a positive feedback loop which is initiated by transcription from a cell type-specific promoter. This was achieved by using a cell type-specific promoter to drive the simultaneous expression of the desired effector/reporter gene product and a strong artificial transcriptional activator which stimulates transcription through appropriate binding sites in the promoter. Using a VP16-LexA chimeric transcription factor, we show that this approach leads to a 14- to > 100-fold enhancement of both the endothelial cell-specific von Willebrand factor promoter and the gastrointestinal-specific sucrase-isomaltase promoter while maintaining approximately 30- to > 100-fold cell type specificity.