Tissue-Specific, Cell Cycle-Regulated Chimeric Transcription Factors for the Targeting of Gene Expression to Tumor Cells

Titelangaben

Jérôme, Valérie ; Müller, Rolf:
Tissue-Specific, Cell Cycle-Regulated Chimeric Transcription Factors for the Targeting of Gene Expression to Tumor Cells.
In: Human Gene Therapy. Bd. 9 (1998) Heft 18 . - S. 2653-2659.
ISSN 1557-7422
DOI: https://doi.org/10.1089/hum.1998.9.18-2653

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Abstract

A major challenge in the gene therapy of proliferative diseases is the specific targeting of gene expression. Here we describe a new approach based on the development of dual-specificity promoters that are both cell type specific and cell cycle regulated. The gene of interest is driven by an artificial heterodimeric transcription factor, whose DNA-binding subunit is expressed from a tissue-specific promoter, whereas the trans-activating subunit is transcribed from a cell cycle-regulated promoter. As a result gene expression occurs preferentially in the proliferating cells of a specific type of tissue. The selectivity of this strategy is demonstrated for the expression of a transgene in proliferating melanoma cells, using a combination of cyclin A and tyrosinase promoter elements. We also show that the level of expression that can be achieved by this system is sufficient to induce a clear biological effect in a TNF-alpha cytotoxicity assay.