Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published November 30, 2004 | Published
Journal Article Open

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

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.

Additional Information

© 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.

Attached Files

Published - OLEpnas04.pdf

Files

OLEpnas04.pdf
Files (575.4 kB)
Name Size Download all
md5:2e0fd7f7638f51bca455d7d571871717
575.4 kB Preview Download

Additional details

Created:
August 22, 2023
Modified:
October 13, 2023