Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression.
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.
Muzikar
Katy A
KA
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Nickols
Nicholas G
NG
Dervan
Peter B
PB
D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009757:Nylons / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D009757:Nylons; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA