TY - JOUR
T1 - Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity
AU - Wang, Jen Chywan
AU - Shah, Nilesh
AU - Pantoja, Carlos
AU - Meijsing, Sebastiaan H.
AU - Ho, Joseph D.
AU - Scanlan, Thomas S.
AU - Yamamoto, Keith R.
PY - 2006/3/15
Y1 - 2006/3/15
N2 - 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.
AB - 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.
KW - Arylpyrazole compounds
KW - Chromatin immunoprecipitation
KW - Glucocorticoid receptor
KW - Glucocorticoid receptor ligand
KW - Response element
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U2 - 10.1101/gad.1400506
DO - 10.1101/gad.1400506
M3 - Article
C2 - 16543221
AN - SCOPUS:33644996796
SN - 0890-9369
VL - 20
SP - 689
EP - 699
JO - Genes and Development
JF - Genes and Development
IS - 6
ER -