title: Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production.
abstract: The glucocorticoid receptor (GR), a nuclear receptor and major drug target, has a highly conserved minor splice variant, GRγ, which differs by a single arginine within the DNA binding domain. GRγ, which comprises 10% of all GR transcripts, is constitutively expressed and tightly conserved through mammalian evolution, suggesting an important non-redundant role. However, to date no specific role for GRγ has been reported. We discovered significant differences in subcellular localisation, and nuclear-cytoplasmic shuttling in response to ligand. In addition the GRγ transcriptome and protein interactome was distinct, and with a gene ontology signal for mitochondrial regulation which was confirmed using Seahorse technology. We propose that evolutionary conservation of the single additional arginine in GRγ is driven by a distinct, non-redundant functional profile, including regulation of mitochondrial function.
authors.affiliation: School of Computer Sciences, University of Manchester, Kilburn Building, Oxford Road, Manchester, Uk, M13 9PL.|Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgan
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Manchester Centre for Nuclear Hormone Research in Disease, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Manchester Academic Health Sciences Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.
authors.forename: Toryn M
authors.initials: TM
authors.lastname: Poolman
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Manchester Academic Health Sciences Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.
authors.forename: Andrew J K
authors.initials: AJ
authors.lastname: Williamson
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
authors.forename: Zichen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Clark
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Manchester Academic Health Sciences Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Stoller Biomarker Discovery Centre, University of Manchester, Wolfson Molecular Imaging Centre, Palatine Road, Manchester, UK, M20 3LJ.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.affiliation: School of Computer Sciences, University of Manchester, Kilburn Building, Oxford Road, Manchester, Uk, M13 9PL.|Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.
authors.forename: Andrew
authors.initials: A
authors.lastname: Brass
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Faculty of Medicine and Health, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, UK, LS9 7TF.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Matthews
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Manchester Centre for Nuclear Hormone Research in Disease, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.|Manchester Academic Health Sciences Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK, M13 9PT.
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
mesh_terms: D000072283:A549 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D040901:Proteomics; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*
chemical_list: C497471:GRgamma protein, human; D011965:Receptors, Glucocorticoid; D000255:Adenosine Triphosphate