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Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing

In response to DNA damage, the transcription factor p53 accumulates in a series of pulses. While p53 dynamics play a critical role in regulating stress responses, how p53 pulsing affects target protein expression is not well understood. Recently, we showed that p53 pulses generate diversity in targe...

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Detalles Bibliográficos
Autores principales: Hanson, Ryan L., Porter, Joshua R., Batchelor, Eric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446860/
https://www.ncbi.nlm.nih.gov/pubmed/30745421
http://dx.doi.org/10.1083/jcb.201803063
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author Hanson, Ryan L.
Porter, Joshua R.
Batchelor, Eric
author_facet Hanson, Ryan L.
Porter, Joshua R.
Batchelor, Eric
author_sort Hanson, Ryan L.
collection PubMed
description In response to DNA damage, the transcription factor p53 accumulates in a series of pulses. While p53 dynamics play a critical role in regulating stress responses, how p53 pulsing affects target protein expression is not well understood. Recently, we showed that p53 pulses generate diversity in target mRNA expression dynamics; however, given that mRNA and protein expression are not necessarily well correlated, it remains to be determined how p53 pulses impact target protein expression. Using computational and experimental approaches, we show that target protein decay rates filter p53 pulses: Distinct target protein expression dynamics are generated depending on the relationship between p53 pulse frequency and target mRNA and protein stability. Furthermore, by mutating the targets MDM2 and PUMA to alter their stabilities, we show that downstream pathways are sensitive to target protein decay rates. This study delineates the mechanisms by which p53 dynamics play a crucial role in orchestrating the timing of events in the DNA damage response network.
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spelling pubmed-64468602019-10-01 Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing Hanson, Ryan L. Porter, Joshua R. Batchelor, Eric J Cell Biol Research Articles In response to DNA damage, the transcription factor p53 accumulates in a series of pulses. While p53 dynamics play a critical role in regulating stress responses, how p53 pulsing affects target protein expression is not well understood. Recently, we showed that p53 pulses generate diversity in target mRNA expression dynamics; however, given that mRNA and protein expression are not necessarily well correlated, it remains to be determined how p53 pulses impact target protein expression. Using computational and experimental approaches, we show that target protein decay rates filter p53 pulses: Distinct target protein expression dynamics are generated depending on the relationship between p53 pulse frequency and target mRNA and protein stability. Furthermore, by mutating the targets MDM2 and PUMA to alter their stabilities, we show that downstream pathways are sensitive to target protein decay rates. This study delineates the mechanisms by which p53 dynamics play a crucial role in orchestrating the timing of events in the DNA damage response network. Rockefeller University Press 2019-04-01 2019-02-11 /pmc/articles/PMC6446860/ /pubmed/30745421 http://dx.doi.org/10.1083/jcb.201803063 Text en This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Hanson, Ryan L.
Porter, Joshua R.
Batchelor, Eric
Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
title Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
title_full Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
title_fullStr Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
title_full_unstemmed Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
title_short Protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
title_sort protein stability of p53 targets determines their temporal expression dynamics in response to p53 pulsing
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446860/
https://www.ncbi.nlm.nih.gov/pubmed/30745421
http://dx.doi.org/10.1083/jcb.201803063
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