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Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface

Nickols, Nicholas G. and Jacobs, Claire S. and Farkas, Michelle E. and Dervan, Peter B. (2007) Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface. ACS Chemical Biology, 2 (8). pp. 561-571. ISSN 1554-8929. PMCID PMC3060759. doi:10.1021/cb700110z. https://resolver.caltech.edu/CaltechAUTHORS:20160509-104247919

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Abstract

Transcription mediated by hypoxia-inducible factor (HIF-1) contributes to tumor angiogenesis and metastasis but is also involved in activation of cell-death pathways and normal physiological processes. Given the complexity of HIF-1 signaling, it could be advantageous to target a subset of HIF-1 effectors rather than the entire pathway. We compare the genome-wide effects of three molecules that each interfere with the HIF-1–DNA interaction: a polyamide targeted to the hypoxia response element, small interfering RNA targeted to HIF-1α, and echinomycin, a DNA-binding natural product with a similar but less specific sequence preference than the polyamide. The polyamide affects a subset of hypoxia-induced genes consistent with its binding site preferences. For comparison, HIF-1α siRNA and echinomycin each affect the expression of nearly every gene induced by hypoxia. Remarkably, the total number of genes affected by either polyamide or HIF-1α siRNA over a range of thresholds is comparable. The data show that polyamides can be used to affect a subset of a pathway regulated by a transcription factor. In addition, this study offers a unique comparison of three complementary approaches towards exogenous control of endogenous gene expression.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cb700110zDOIArticle
http://pubs.acs.org/doi/abs/10.1021/cb700110zPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060759/PubMed CentralArticle
http://pubs.acs.org/doi/suppl/10.1021/cb700110zPublisherSupporting Information
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2007 American Chemical Society. Received for review May 18, 2007 and accepted July 26, 2007. Published online August 17, 2007. Accession Codes: Data have been deposited in NCBIs Gene Expression Omnibus (GEO, www.ncbi.nlm.gov/projects/geo), accessible through GEO Series accession number GSE7535.
Issue or Number:8
PubMed Central ID:PMC3060759
DOI:10.1021/cb700110z
Record Number:CaltechAUTHORS:20160509-104247919
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160509-104247919
Official Citation:Modulating Hypoxia-Inducible Transcription by Disrupting the HIF-1–DNA Interface Nicholas G. Nickols, Claire S. Jacobs, Michelle E. Farkas, Peter B. Dervan ACS Chemical Biology 2007 2 (8), 561-571 DOI: 10.1021/cb700110z
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66745
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:17 May 2016 20:58
Last Modified:11 Nov 2021 00:02

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