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GENES & DEVELOPMENT 20:689-699, 2006
©2006 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Jen-Chywan Wang1, Nilesh Shah1,2,3, Carlos Pantoja1,4, Sebastiaan H. Meijsing1, Joseph D. Ho5, Thomas S. Scanlan1,2 and Keith R. Yamamoto1,6

1 Department of Cellular and Molecular Pharmacology, 2 Department of Pharmaceutical Chemistry, 3 Graduate Group of Biophysics, 4 Graduate Program in Biological Sciences, 5 Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, San Francisco, California 94107-2280, USA

The activities of intracellular receptors are regulated by their cognate ligands. Here we show that a series of related arylpyrazole compounds, which specifically bind the glucocorticoid receptor (GR), selectively modulated GR-regulated biological functions in preadipocyte, preosteoblast, and lung epithelial cell lines. Indeed, when we monitored 17 endogenous GR target genes in one of these cell types, we found that distinct arylpyrazole compounds induced different expression patterns. We showed by chromatin immunoprecipitation that the arylpyrazole compounds regulated, in a gene-specific manner, either GR occupancy of the genomic glucocorticoid response element (GRE) or events after GR association, such as histone modification. Overall, our results establish that subtle differences in ligand chemistry can profoundly influence the transcriptional regulatory activity of GR, and that endogenous genes bearing natural GREs are especially sensitive detectors of these differences.

[Keywords: Glucocorticoid receptor; glucocorticoid receptor ligand; arylpyrazole compounds; response element; chromatin immunoprecipitation]

Received December 13, 2005; revised version accepted January 18, 2006.

6 Corresponding author.

E-MAIL yamamoto{at}cmp.ucsf.edu; FAX (415) 476-6129.

Supplemental material is available at http://www.genesdev.org.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1400506


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