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Early growth response 2 (EGR2) is a novel regulator of the senescence programme
Senescence, a state of stable growth arrest, plays an important role in ageing and age‐related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening fo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963333/ https://www.ncbi.nlm.nih.gov/pubmed/33547862 http://dx.doi.org/10.1111/acel.13318 |
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author | Tyler, Eleanor J. Gutierrez del Arroyo, Ana Hughes, Bethany K. Wallis, Ryan Garbe, James C. Stampfer, Martha R. Koh, Jim Lowe, Robert Philpott, Michael P. Bishop, Cleo L. |
author_facet | Tyler, Eleanor J. Gutierrez del Arroyo, Ana Hughes, Bethany K. Wallis, Ryan Garbe, James C. Stampfer, Martha R. Koh, Jim Lowe, Robert Philpott, Michael P. Bishop, Cleo L. |
author_sort | Tyler, Eleanor J. |
collection | PubMed |
description | Senescence, a state of stable growth arrest, plays an important role in ageing and age‐related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up‐regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down‐regulates p16 levels and increases the pool of p16− p21− ‘reversed’ cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence. |
format | Online Article Text |
id | pubmed-7963333 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79633332021-03-19 Early growth response 2 (EGR2) is a novel regulator of the senescence programme Tyler, Eleanor J. Gutierrez del Arroyo, Ana Hughes, Bethany K. Wallis, Ryan Garbe, James C. Stampfer, Martha R. Koh, Jim Lowe, Robert Philpott, Michael P. Bishop, Cleo L. Aging Cell Original Articles Senescence, a state of stable growth arrest, plays an important role in ageing and age‐related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up‐regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down‐regulates p16 levels and increases the pool of p16− p21− ‘reversed’ cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence. John Wiley and Sons Inc. 2021-02-06 2021-03 /pmc/articles/PMC7963333/ /pubmed/33547862 http://dx.doi.org/10.1111/acel.13318 Text en © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Tyler, Eleanor J. Gutierrez del Arroyo, Ana Hughes, Bethany K. Wallis, Ryan Garbe, James C. Stampfer, Martha R. Koh, Jim Lowe, Robert Philpott, Michael P. Bishop, Cleo L. Early growth response 2 (EGR2) is a novel regulator of the senescence programme |
title | Early growth response 2 (EGR2) is a novel regulator of the senescence programme |
title_full | Early growth response 2 (EGR2) is a novel regulator of the senescence programme |
title_fullStr | Early growth response 2 (EGR2) is a novel regulator of the senescence programme |
title_full_unstemmed | Early growth response 2 (EGR2) is a novel regulator of the senescence programme |
title_short | Early growth response 2 (EGR2) is a novel regulator of the senescence programme |
title_sort | early growth response 2 (egr2) is a novel regulator of the senescence programme |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963333/ https://www.ncbi.nlm.nih.gov/pubmed/33547862 http://dx.doi.org/10.1111/acel.13318 |
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