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:	Sohyoung Kim, Mirit I Aladjem, Geoffrey B McFadden, Kurt W Kohn
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fd949534b1d94bc1b7be6bf9b144f2ab
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spelling	oai:doaj.org-article:fd949534b1d94bc1b7be6bf9b144f2ab2021-11-25T05:42:39ZPredicted functions of MdmX in fine-tuning the response of p53 to DNA damage.1553-734X1553-735810.1371/journal.pcbi.1000665https://doaj.org/article/fd949534b1d94bc1b7be6bf9b144f2ab2010-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20174603/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Tumor 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 p53ratioMdmX and Mdm2ratioMdmX 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.Sohyoung KimMirit I AladjemGeoffrey B McFaddenKurt W KohnPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 2, p e1000665 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Sohyoung Kim Mirit I Aladjem Geoffrey B McFadden Kurt W Kohn Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage.
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 p53ratioMdmX and Mdm2ratioMdmX 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.
format	article
author	Sohyoung Kim Mirit I Aladjem Geoffrey B McFadden Kurt W Kohn
author_facet	Sohyoung Kim Mirit I Aladjem Geoffrey B McFadden Kurt W Kohn
author_sort	Sohyoung Kim
title	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_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_sort	predicted functions of mdmx in fine-tuning the response of p53 to dna damage.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/fd949534b1d94bc1b7be6bf9b144f2ab
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Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage.

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