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Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist

Olenyuk, Bogdan Z. and Zhang, Guo-Jun and Klco, Jeffery M. and Nickols, Nicholas G. and Kaelin, William G., Jr. and Dervan, Peter B. (2004) Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proceedings of the National Academy of Sciences of the United States of America, 101 (48). pp. 16768-16773. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:OLEpnas04

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Abstract

Vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis that are up-regulated by hypoxia. We evaluated the effects of DNA-binding small molecules on hypoxia-inducible transcription of VEGF. A synthetic pyrrole-imidazole polyamide designed to bind the hypoxia response element (HRE) was found to disrupt hypoxia-inducible factor (HIF) binding to HIRE. In cultured HeLa cells, this resulted in a reduction of VEGF mRNA and secreted protein levels. The observed effects were polyamide-specific and dose-dependent. Analysis of genome-wide effects of the HIRE-specific polyamide revealed that a number of hypoxia-inducible genes were down-regulated. Pathway-based regulation of hypoxia-inducible gene expression with DNA-binding small molecules may represent a new approach for targeting angiogenesis.


Item Type:Article
Additional Information:Copyright © 2004 by the National Academy of Sciences. Contributed by Peter B. Dervan, October 15, 2004. Published online before print November 19, 2004, 10.1073/pnas.0407617101 We thank the National Institutes of Health for support. Mass spectrometry analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering of California Institute of Technology, supported in part by the National Science Foundation Materials Research Science and Engineering program. Oligonucleotide microarray experiments were performed in the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. Author contributions: B.Z.O., G.-J.Z., W.G.K., and P.B.D. designed research; B.Z.O., G.-J.Z., J.M.K., and N.G.N. performed research; B.Z.O., N.G.N., W.G.K., G.-J.Z., and P.B.D. analyzed data; B.Z.O., G.-J.Z., N.G.N., W.G.K., and P.B.D. wrote the paper.
Subject Keywords:GENE REGULATION, HYPOXIA-INDUCIBLE FACTOR, POLYAMIDE, PYRROLE-IMIDAZOLE POLYAMIDES, DNA-BINDING POLYAMIDES, INDUCIBLE FACTOR-I, A BASE-PAIRS, MINOR-GROOVE, GENE-EXPRESSION, TUMOR-GROWTH, NUCLEAR-LOCALIZATION, KINASE INHIBITORS, FACTOR RECEPTOR
Record Number:CaltechAUTHORS:OLEpnas04
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:OLEpnas04
Alternative URL:http://dx.doi.org/10.1073/pnas.0407617101
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:951
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Nov 2005
Last Modified:26 Dec 2012 08:42

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