title: Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy.
abstract: The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Manchester Academic Health Sciences Centre, Institute of Human Development, Faculty of Medical and Human Sciences.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Matthews
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Manchester Academic Health Sciences Centre, Institute of Human Development, Faculty of Medical and Human Sciences.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Berry
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Manchester Academic Health Sciences Centre, Institute of Human Development, Faculty of Medical and Human Sciences.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgan
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Manchester Academic Health Sciences Centre, Institute of Human Development, Faculty of Medical and Human Sciences.
authors.forename: Toryn M
authors.initials: TM
authors.lastname: Poolman
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bauer
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, 07745 Jena, Germany;
authors.forename: Frederike
authors.initials: F
authors.lastname: Kramer
authors.affiliation: Faculty of Life Sciences, and.
authors.forename: David G
authors.initials: DG
authors.lastname: Spiller
authors.affiliation: University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Richardson
authors.affiliation: University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom;
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Manchester Academic Health Sciences Centre, Institute of Human Development, Faculty of Medical and Human Sciences, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom; and.
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Farrow
authors.affiliation: Division of Medicine, University of Bristol, Bristol BS1 3NY, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Norman
authors.affiliation: Faculty Institute of Cancer Sciences, University University of Manchester, Manchester M13 9PT, United Kingdom;
authors.forename: Andrew J K
authors.initials: AJ
authors.lastname: Williamson
authors.affiliation: Faculty Institute of Cancer Sciences, University University of Manchester, Manchester M13 9PT, United Kingdom;
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.affiliation: Faculty of Life Sciences, and.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Taylor
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany; Leibniz Institute for Age Research, Fritz Lipmann Institute, 07745 Jena, Germany;
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.affiliation: Faculty of Life Sciences, and.
authors.forename: Michael R H
authors.initials: MR
authors.lastname: White
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Manchester Academic Health Sciences Centre, Institute of Human Development, Faculty of Medical and Human Sciences, david.w.ray@manchester.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020090:Chromosome Segregation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011965:Receptors, Glucocorticoid; D025521:Tumor Suppressor Proteins
keywords: DNA damage; aneuploidy; cancer; glucocorticoid receptor; mitosis
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