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Published September 29, 2009 | Published + Supplemental Material
Journal Article Open

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

Abstract

The glucocorticoid receptor (GR) affects the transcription of genes involved in diverse processes, including energy metabolism and the immune response, through DNA-binding dependent and independent mechanisms. The DNA-binding dependent mechanism occurs by direct binding of GR to glucocorticoid response elements (GREs) at regulatory regions of target genes. The DNA-binding independent mechanism involves binding of GR to transcription factors and coactivators that, in turn, contact DNA. A small molecule that competes with GR for binding to GREs could be expected to affect the DNA-dependent pathway selectively by interfering with the protein-DNA interface. We show that a DNA-binding polyamide that targets the consensus GRE sequence binds the glucocorticoid-induced zipper (GILZ) GRE, inhibits expression of GILZ and several other known GR target genes, and reduces GR occupancy at the GILZ promoter. Genome-wide expression analysis of the effects of this polyamide on a set of glucocorticoid-induced and -repressed genes could help to elucidate the mechanism of GR regulation for these genes.

Additional Information

© 2009 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Peter B. Dervan, August 13, 2009 (received for review June 4, 2009); published online before print September 15, 2009. We thank Keith Yamamoto for his kind gift of GR antibody. Mass spectrometry analyses were performed in the Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering at the 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 the California Institute of Technology. This work was supported by National Institutes of Health Grant GM051747. Author contributions: K.A.M., N.G.N., and P.B.D. designed research; K.A.M. and N.G.N. performed research; K.A.M., N.G.N., and P.B.D. analyzed data; and K.A.M., N.G.N., 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. GSE17307). This article contains supporting information online at www.pnas.org/cgi/content/full/0909192106/DCSupplemental.

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Published - Muzikar2009p6077P_Natl_Acad_Sci_Usa.pdf

Supplemental Material - 0909192106SI.pdf

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August 21, 2023
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