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Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage

Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p5...

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Autores principales: Kim, Sohyoung, Aladjem, Mirit I., McFadden, Geoffrey B., Kohn, Kurt W.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824598/
https://www.ncbi.nlm.nih.gov/pubmed/20174603
http://dx.doi.org/10.1371/journal.pcbi.1000665
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author Kim, Sohyoung
Aladjem, Mirit I.
McFadden, Geoffrey B.
Kohn, Kurt W.
author_facet Kim, Sohyoung
Aladjem, Mirit I.
McFadden, Geoffrey B.
Kohn, Kurt W.
author_sort Kim, Sohyoung
collection PubMed
description Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53∶MdmX and Mdm2∶MdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation.
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spelling pubmed-28245982010-02-19 Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage Kim, Sohyoung Aladjem, Mirit I. McFadden, Geoffrey B. Kohn, Kurt W. PLoS Comput Biol Research Article Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53∶MdmX and Mdm2∶MdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation. Public Library of Science 2010-02-05 /pmc/articles/PMC2824598/ /pubmed/20174603 http://dx.doi.org/10.1371/journal.pcbi.1000665 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Kim, Sohyoung
Aladjem, Mirit I.
McFadden, Geoffrey B.
Kohn, Kurt W.
Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage
title Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage
title_full Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage
title_fullStr Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage
title_full_unstemmed Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage
title_short Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage
title_sort predicted functions of mdmx in fine-tuning the response of p53 to dna damage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824598/
https://www.ncbi.nlm.nih.gov/pubmed/20174603
http://dx.doi.org/10.1371/journal.pcbi.1000665
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