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Inhibition of Ets-1 DNA Binding and Ternary Complex Formation between Ets-1, NF-kappa B, and DNA by a Designed DNA-binding Ligand

Dickinson, Liliane A. and Trauger, John W. and Baird, Eldon E. and Dervan, Peter B. and Graves, Barbara J. and Gottesfeld, Joel M. (1999) Inhibition of Ets-1 DNA Binding and Ternary Complex Formation between Ets-1, NF-kappa B, and DNA by a Designed DNA-binding Ligand. Journal of Biological Chemistry, 274 (18). pp. 12765-12773. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:DICjbc99

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Abstract

Sequence-specific pyrrole-imidazole polyamides can be designed to interfere with transcription factor binding and to regulate gene expression, both in vitro and in living cells. Polyamides bound adjacent to the recognition sites for TBP, Ets-1, and LEF-1 in the human immunodeficiency virus, type 1 (HIV-1), long terminal repeat inhibited transcription in cell-free assays and viral replication in human peripheral blood lymphocytes. The DNA binding activity of the transcription factor Ets-1 is specifically inhibited by a polyamide bound in the minor groove. Ets-1 is a member of the winged-helix-turn-helix family of transcription factors and binds DNA through a recognition helix bound in the major groove with additional phosphate contacts on either side of this major groove interaction. The inhibitory polyamide possibly interferes with phosphate contacts made by Ets-1, by occupying the adjacent minor groove. Full-length Ets-1 binds the HIV-1 enhancer through cooperative interactions with the p50 subunit of NF-kappa B, and the Ets-inhibitory polyamide also blocks formation of ternary Ets-1·NF-kappa B·DNA complexes on the HIV-1 enhancer. A polyamide bound adjacent to the recognition site for NF-kappa B also inhibits NF-kappa B binding and ternary complex formation. These results broaden the application range of minor groove-binding polyamides and demonstrate that these DNA ligands are powerful inhibitors of DNA-binding proteins that predominantly use major groove contacts and of cooperative protein-DNA ternary complexes.


Item Type:Article
Additional Information:Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc. (Received for publication, January 22, 1999) This work was supported by Grant GM-57148 from the National Institutes of Health (to J.M.G. and P.B.D.), the National Science Foundation, the Ralph M. Parsons Foundation for predoctoral fellowships (to J.W.T.), and the Howard Hughes Medical Institute for a predoctoral fellowship (to E.E.B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Record Number:CaltechAUTHORS:DICjbc99
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:DICjbc99
Alternative URL:http://www.jbc.org/cgi/content/abstract/274/18/12765
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5961
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:09 Nov 2006
Last Modified:26 Dec 2012 09:16

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