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Bimodal regulation of p21(waf1) protein as function of DNA damage levels
Human p21(Waf1) protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21(Waf1) protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615108/ https://www.ncbi.nlm.nih.gov/pubmed/25486478 http://dx.doi.org/10.4161/15384101.2014.946852 |
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author | Buscemi, G Ricci, C Zannini, L Fontanella, E Plevani, P Delia, D |
author_facet | Buscemi, G Ricci, C Zannini, L Fontanella, E Plevani, P Delia, D |
author_sort | Buscemi, G |
collection | PubMed |
description | Human p21(Waf1) protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21(Waf1) protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and transiently degraded in response to high doses of DNA lesions. Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis. The initial p21(Waf1) degradation is then counteracted by the ATM-Chk2 pathway, which promotes the p53-dependent accumulation of p21(Waf1) at any dose of damage. We also found that p21(Waf1) ablation favors the activation of an apoptotic program to eliminate otherwise irreparable cells. These findings support a model in which in human cells a balance between ATM-Chk2-p53 and the ATR-Chk1 pathways modulates p21(Waf1) protein levels in relation to cytostatic and cytotoxic doses of DNA damage. |
format | Online Article Text |
id | pubmed-4615108 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-46151082015-11-02 Bimodal regulation of p21(waf1) protein as function of DNA damage levels Buscemi, G Ricci, C Zannini, L Fontanella, E Plevani, P Delia, D Cell Cycle Reports Human p21(Waf1) protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21(Waf1) protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and transiently degraded in response to high doses of DNA lesions. Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis. The initial p21(Waf1) degradation is then counteracted by the ATM-Chk2 pathway, which promotes the p53-dependent accumulation of p21(Waf1) at any dose of damage. We also found that p21(Waf1) ablation favors the activation of an apoptotic program to eliminate otherwise irreparable cells. These findings support a model in which in human cells a balance between ATM-Chk2-p53 and the ATR-Chk1 pathways modulates p21(Waf1) protein levels in relation to cytostatic and cytotoxic doses of DNA damage. Taylor & Francis 2014-10-30 /pmc/articles/PMC4615108/ /pubmed/25486478 http://dx.doi.org/10.4161/15384101.2014.946852 Text en © 2014 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
spellingShingle | Reports Buscemi, G Ricci, C Zannini, L Fontanella, E Plevani, P Delia, D Bimodal regulation of p21(waf1) protein as function of DNA damage levels |
title | Bimodal regulation of p21(waf1) protein as function of DNA damage levels |
title_full | Bimodal regulation of p21(waf1) protein as function of DNA damage levels |
title_fullStr | Bimodal regulation of p21(waf1) protein as function of DNA damage levels |
title_full_unstemmed | Bimodal regulation of p21(waf1) protein as function of DNA damage levels |
title_short | Bimodal regulation of p21(waf1) protein as function of DNA damage levels |
title_sort | bimodal regulation of p21(waf1) protein as function of dna damage levels |
topic | Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615108/ https://www.ncbi.nlm.nih.gov/pubmed/25486478 http://dx.doi.org/10.4161/15384101.2014.946852 |
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