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Cell Cycle Phase Regulates Glucocorticoid Receptor Function
The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We n...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146484/ https://www.ncbi.nlm.nih.gov/pubmed/21829454 http://dx.doi.org/10.1371/journal.pone.0022289 |
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author | Matthews, Laura Johnson, James Berry, Andrew Trebble, Peter Cookson, Ann Spiller, Dave Rivers, Caroline Norman, Michael White, Mike Ray, David |
author_facet | Matthews, Laura Johnson, James Berry, Andrew Trebble, Peter Cookson, Ann Spiller, Dave Rivers, Caroline Norman, Michael White, Mike Ray, David |
author_sort | Matthews, Laura |
collection | PubMed |
description | The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G(1). This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase. The impact of cell cycle–driven GR trafficking on a panel of glucocorticoid actions was profiled. In G2/M-enriched cells there was marked prolongation of glucocorticoid-induced ERK activation. This was accompanied by DNA template-specific, ligand-independent GR transactivation. Using chimeric and domain-deleted receptors we demonstrate that this transactivation effect is mediated by the AF1 transactivation domain. AF-1 harbours multiple phosphorylation sites, which are consensus sequences for kinases including CDKs, whose activity changes during the cell cycle. In G2/M there was clear ligand independent induction of GR phosphorylation on residues 203 and 211, both of which are phosphorylated after ligand activation. Ligand-independent transactivation required induction of phospho-S211GR but not S203GR, thereby directly linking cell cycle driven GR modification with altered GR function. Cell cycle phase therefore regulates GR localisation and post-translational modification which selectively impacts GR activity. This suggests that cell cycle phase is an important determinant in the cellular response to Gc, and that mitotic index contributes to tissue Gc sensitivity. |
format | Online Article Text |
id | pubmed-3146484 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31464842011-08-09 Cell Cycle Phase Regulates Glucocorticoid Receptor Function Matthews, Laura Johnson, James Berry, Andrew Trebble, Peter Cookson, Ann Spiller, Dave Rivers, Caroline Norman, Michael White, Mike Ray, David PLoS One Research Article The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G(1). This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase. The impact of cell cycle–driven GR trafficking on a panel of glucocorticoid actions was profiled. In G2/M-enriched cells there was marked prolongation of glucocorticoid-induced ERK activation. This was accompanied by DNA template-specific, ligand-independent GR transactivation. Using chimeric and domain-deleted receptors we demonstrate that this transactivation effect is mediated by the AF1 transactivation domain. AF-1 harbours multiple phosphorylation sites, which are consensus sequences for kinases including CDKs, whose activity changes during the cell cycle. In G2/M there was clear ligand independent induction of GR phosphorylation on residues 203 and 211, both of which are phosphorylated after ligand activation. Ligand-independent transactivation required induction of phospho-S211GR but not S203GR, thereby directly linking cell cycle driven GR modification with altered GR function. Cell cycle phase therefore regulates GR localisation and post-translational modification which selectively impacts GR activity. This suggests that cell cycle phase is an important determinant in the cellular response to Gc, and that mitotic index contributes to tissue Gc sensitivity. Public Library of Science 2011-07-29 /pmc/articles/PMC3146484/ /pubmed/21829454 http://dx.doi.org/10.1371/journal.pone.0022289 Text en Matthews et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Matthews, Laura Johnson, James Berry, Andrew Trebble, Peter Cookson, Ann Spiller, Dave Rivers, Caroline Norman, Michael White, Mike Ray, David Cell Cycle Phase Regulates Glucocorticoid Receptor Function |
title | Cell Cycle Phase Regulates Glucocorticoid Receptor Function |
title_full | Cell Cycle Phase Regulates Glucocorticoid Receptor Function |
title_fullStr | Cell Cycle Phase Regulates Glucocorticoid Receptor Function |
title_full_unstemmed | Cell Cycle Phase Regulates Glucocorticoid Receptor Function |
title_short | Cell Cycle Phase Regulates Glucocorticoid Receptor Function |
title_sort | cell cycle phase regulates glucocorticoid receptor function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146484/ https://www.ncbi.nlm.nih.gov/pubmed/21829454 http://dx.doi.org/10.1371/journal.pone.0022289 |
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