The glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Research output: Contribution to journalArticle

  • External authors:
  • Andrew Berry
  • Toryn Poolman
  • K Bauer
  • F Kramer
  • David G Spiller
  • RV Richardson
  • KE Chapman
  • Stuart Farrow
  • MR Norman
  • AJK Williamson
  • AD Whetton
  • SS Taylor
  • JP Tuckermann
  • MRH White

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.

Bibliographical metadata

Original languageEnglish
Article number1411356112
Pages (from-to)5479-5484
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume112
Issue number17
DOIs
Publication statusPublished - 28 Apr 2015

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