Specific inhibition of c-fos proto-oncogene expression by triple-helix-forming oligonucleotides

Journal of Cellular Biochemistry
Y LavrovskyN G Abraham

Abstract

The promoter region of the c-fos oncogene 5' flanking sequence contains enhancer elements crucial for binding nuclear factors that regulate transcription following cell proliferation and differentiation. Single-stranded deoxyoligonucleotides were chosen for modulation of c-fos protooncogene expression because of their high-affinity binding to specific nucleotide sequences. We designed two oligonucleotides that form a triple-helix complex on the retinoblastoma gene product-responsible element of the c-fos oncogene. Modification of the DNA triplex with dimethyl sulfate and affinity cleaving assays demonstrate that the predicted oligonucleotides form a DNA triplex structure with the c-fos promoter in a sequence-specific manner. Tumorigenic and non-tumorigenic fibroblasts were transiently transfected with fos-CAT plasmid modified with alkylating triplex-forming oligonucleotide reagents. A dramatic depression of CAT activity was found when the cross-linked triple helix complex at the retinoblastoma gene product-related site of the c-fos promoter was used. These experiments suggest that transcription of individual genes can be selectively modulated in cell culture by sequence specific triplex formation in regulatory enhancer sequences.

References

Dec 11, 1992·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·L J Maher
Jan 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·G Duval-ValentinC Hélène
Jan 1, 1988·Cold Spring Harbor Symposia on Quantitative Biology·R PrywesR G Roeder

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