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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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