Gene expression changes in a tumor xenograft by a pyrrole-imidazole polyamide
Abstract
Gene regulation by DNA binding small molecules could have important therapeutic applications. This study reports the investigation of a DNA-binding pyrrole-imidazole polyamide targeted to bind the DNA sequence 5′-WGGWWW-3′ with reference to its potency in a subcutaneous xenograft tumor model. The molecule is capable of trafficking to the tumor site following subcutaneous injection and modulates transcription of select genes in vivo. An FITC-labeled analogue of this polyamide can be detected in tumor-derived cells by confocal microscopy. RNA deep sequencing (RNA-seq) of tumor tissue allowed the identification of further affected genes, a representative panel of which was interrogated by quantitative reverse transcription-PCR and correlated with cell culture expression levels.
Additional Information
© 2012 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Peter B. Dervan, August 20, 2012 (sent for review July 10, 2012). Published online before print September 17, 2012. J.A.R. is grateful to the Alexander von Humboldt foundation for the award of a Feodor Lynen postdoctoral fellowship. We thank Michael J. Waring for careful editing of the manuscript. N.G.N. would like to acknowledge the National Institutes of Health (NIH) and the Jonsson Cancer Center Foundation (JCCF) at UCLA for postdoctoral support. A.E.H. thanks the California Tobacco-Related Disease Research Program (19FT-0105) and the NIH (NRSA 1F32CA156833) for postdoctoral support. Sequencing was conducted at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. We are grateful for support by The Ellison Medical Foundation (AG-SS-2256-09) and the National Institutes of Health (GM051747). Author contributions: J.A.R., and P.B.D. designed research; J.A.R., N.G.N., and A.E.H. performed research; J.A.R., N.G.N., A.E.H., G.K.M., B.W., and P.B.D. analyzed data; and J.A.R., and P.B.D. wrote the paper. The authors declare no conflict of interest. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE40218). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1214267109/-/DCSupplemental.Attached Files
Published - PNAS-2012-Raskatov-16041-5.pdf
Supplemental Material - pnas.1214267109_SI.pdf
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Additional details
- PMCID
- PMC3479560
- Eprint ID
- 35304
- Resolver ID
- CaltechAUTHORS:20121106-105719691
- Alexander von Humboldt Foundation
- UCLA Jonsson Cancer Center Foundation
- California Tobacco-Related Disease Research Program
- 19FT-0105
- NIH Postdoctoral Fellowship
- 1F32CA156833
- Ellison Medical Foundation
- AG-SS-2256-09
- NIH
- GM-051747
- Created
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2012-11-06Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field