The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene

1 Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California; 2 European Molecular Biology Laboratory, Heidelberg; 3 Department of Molecular Oncology, Göttingen Center for Molecular Biosciences; and 4 Department of Cellular and Molecular Immunology, University...

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Published in:American journal of physiology: endocrinology and metabolism 2008-10, Vol.295 (4), p.E785-E797
Main Authors: Waddell, David S, Baehr, Leslie M, van den Brandt, Jens, Johnsen, Steven A, Reichardt, Holger M, Furlow, J. David, Bodine, Sue C
Format: Article
Language:English
Subjects:
Animals
Blotting, Northern
Cells, Cultured
Chromatin - metabolism
Dexamethasone - pharmacology
Endocrinology
Forkhead Box Protein O1
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - physiology
Genes
Genes, Reporter - genetics
Glucose
Humans
Immunoprecipitation
Luciferases - genetics
Mice
Mice, Inbred BALB C
Muscle Proteins - genetics
Muscle Proteins - physiology
Muscular Atrophy - genetics
Muscular Atrophy - pathology
Musculoskeletal system
Plasmids - genetics
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - physiology
Rodents
Tripartite Motif Proteins
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - physiology
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Summary:1 Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California; 2 European Molecular Biology Laboratory, Heidelberg; 3 Department of Molecular Oncology, Göttingen Center for Molecular Biosciences; and 4 Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany Submitted 4 October 2007 ; accepted in final form 27 June 2008 The muscle specific ubiquitin E3 ligase MuRF1 has been implicated as a key regulator of muscle atrophy under a variety of conditions, such as during synthetic glucocorticoid treatment. FOXO class transcription factors have been proposed as important regulators of MuRF1 expression, but its regulation by glucocorticoids is not well understood. The MuRF1 promoter contains a near-perfect palindromic glucocorticoid response element (GRE) 200 base pairs upstream of the transcription start site. The GRE is highly conserved in the mouse, rat, and human genes along with a directly adjacent FOXO binding element (FBE). Transient transfection assays in HepG2 cells and C 2 C 12 myotubes demonstrate that the MuRF1 promoter is responsive to both the dexamethasone (DEX)-activated glucocorticoid receptor (GR) and FOXO1, whereas coexpression of GR and FOXO1 leads to a dramatic synergistic increase in reporter gene activity. Mutation of either the GRE or the FBE significantly impairs activation of the MuRF1 promoter. Consistent with these findings, DEX-induced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C 2 C 12 myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding. These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle. forkhead transcription factor class O; muscle RING finger 1; glucocorticoid receptor Address for reprint requests and other correspondence: J. D. Furlow or S. C. Bodine, Section of Neurobiology, Physiology & Behavior, Univ. of California Davis, One Shields Ave., Davis, CA 95616 (e-mail: jdfurlow{at}ucdavis.edu )
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00646.2007