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An ERRbeta/gamma agonist modulates GRalpha expression, and glucocorticoid responsive gene expression in skeletal muscle cells


Wang, S-CM and Myers, S and Dooms, C and Capon, R and Muscat, GEO, An ERRbeta/gamma agonist modulates GRalpha expression, and glucocorticoid responsive gene expression in skeletal muscle cells, Molecular and Cellular Endocrinology, 315, (1-2) pp. 146-152. ISSN 0303-7207 (2010) [Refereed Article]

Copyright Statement

Copyright 2009 Elsevier Ireland Ltd.

DOI: doi:10.1016/j.mce.2009.07.012


Estrogen-related receptors (ERRs) are constitutively active orphan nuclear receptors. Natural ligands have not been identified, however, recent reports have demonstrated the synthetic phenolic acyl hydrazone, GSK4716, functions as a selective ERRbeta/gamma agonist. We demonstrate that ERRbeta is transiently induced, and ERRgamma is dramatically induced (and accumulates) in a differentiation-dependent manner in skeletal muscle cells. Treatment of differentiated skeletal muscle cells with the ERRbeta/gamma agonist (GSK4716) produced a significant increase in the expression of GRalpha (isoform D) protein. Quantitative RT-PCR (Q-RT-PCR) analysis after treatment with GSK4716, revealed induction of the mRNAs encoding the glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), the enzyme that converts inactive cortisone to cortisol and hexose-6-phosphate dehydrogenase expression (H6PDH) that stimulates oxoreduction by 11beta-HSD1. Candidate based expression profiling also demonstrated the mRNAs encoding characterized GR target genes, including C/EBP, ApoD and Monoamine oxidase-A (MAO-A) are induced in GSK4716 treated cells. In concordance with these observations, siRNA-mediated suppression of the mRNA encoding ERRgamma (but not ERRalpha and beta) attenuated the expression of mRNAs encoding GR, 11betaHSD1 and GR target gene(s). Similarly, treatment with the ERRgamma (and ERalpha) antagonist diethylstilbestrol (DES) suppressed glucocorticoid responsive gene expression in skeletal muscle cells. Interestingly, we observed that GSK4716 trans-activated GRE-TK-LUC in a GR-dependent manner. This study highlights the regulatory crosstalk between ERRgamma and GR signaling in skeletal muscle cells, and suggests the ERRgamma agonist modulates the expression of critical genes that control GR signaling and glucocorticoid sensitive gene expression.

Item Details

Item Type:Refereed Article
Keywords:Estrogen-related receptor, Glucocorticoid receptor, GSK4716
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell metabolism
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Myers, S (Dr Stephen Myers)
ID Code:101151
Year Published:2010
Web of Science® Times Cited:24
Deposited By:Health Sciences B
Deposited On:2015-06-11
Last Modified:2015-09-15

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