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Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity
The p53-Mdm2 feedback loop is thought to be the main mechanism by which p53 autoregulates its levels and activity after DNA damage. We tested this paradigm in a genetically engineered mouse model in which the feedback loop was disrupted by point mutations in the p53 binding site of the Mdm2 promoter...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012731/ https://www.ncbi.nlm.nih.gov/pubmed/24658419 |
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author | Pant, Vinod Lozano, Guillermina |
author_facet | Pant, Vinod Lozano, Guillermina |
author_sort | Pant, Vinod |
collection | PubMed |
description | The p53-Mdm2 feedback loop is thought to be the main mechanism by which p53 autoregulates its levels and activity after DNA damage. We tested this paradigm in a genetically engineered mouse model in which the feedback loop was disrupted by point mutations in the p53 binding site of the Mdm2 promoter. We noted that while the p53-Mdm2 feedback loop is required to regulate p53 activity especially in the hematopoietic system in response to DNA damage, its role in development and in regulating the stability of p53 is dispensable. In the present study we have extended our characterization of this mouse model and show that the kinetics of p53 degradation is also unchanged in mouse embryonic fibroblasts (MEFs). Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice. Finally, we show in this system that enhanced acute p53 response does not promote aging or protect against late term tumorigenesis. We also discuss future perspectives for this study. |
format | Online Article Text |
id | pubmed-4012731 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-40127312014-05-09 Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity Pant, Vinod Lozano, Guillermina Oncotarget Research Paper The p53-Mdm2 feedback loop is thought to be the main mechanism by which p53 autoregulates its levels and activity after DNA damage. We tested this paradigm in a genetically engineered mouse model in which the feedback loop was disrupted by point mutations in the p53 binding site of the Mdm2 promoter. We noted that while the p53-Mdm2 feedback loop is required to regulate p53 activity especially in the hematopoietic system in response to DNA damage, its role in development and in regulating the stability of p53 is dispensable. In the present study we have extended our characterization of this mouse model and show that the kinetics of p53 degradation is also unchanged in mouse embryonic fibroblasts (MEFs). Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice. Finally, we show in this system that enhanced acute p53 response does not promote aging or protect against late term tumorigenesis. We also discuss future perspectives for this study. Impact Journals LLC 2014-03-14 /pmc/articles/PMC4012731/ /pubmed/24658419 Text en Copyright: © 2014 Pant and Lozano. http://creativecommons.org/licenses/by/2.5/ 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 credited. |
spellingShingle | Research Paper Pant, Vinod Lozano, Guillermina Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
title | Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
title_full | Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
title_fullStr | Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
title_full_unstemmed | Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
title_short | Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
title_sort | dissecting the p53-mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012731/ https://www.ncbi.nlm.nih.gov/pubmed/24658419 |
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