Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice

The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High...

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Main Authors:	Goh, Amanda M., Xue, Yuezhen, Leushacke, Marc, Li, Ling, Wong, Julin S., Chiam, Poh Cheang, Rahmat, Siti Aishah Binte, Mann, Michael B., Mann, Karen M., Barker, Nick, Lozano, Guillermina, Terzian, Tamara, Lane, David P.
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627229/

id	pubmed-4627229
recordtype	oai_dc
spelling	pubmed-46272292015-11-09 Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice Goh, Amanda M. Xue, Yuezhen Leushacke, Marc Li, Ling Wong, Julin S. Chiam, Poh Cheang Rahmat, Siti Aishah Binte Mann, Michael B. Mann, Karen M. Barker, Nick Lozano, Guillermina Terzian, Tamara Lane, David P. Research Paper: Pathology The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High levels of mutant p53 can be found in tumours and the accumulation of mutant p53 has previously been reported in pathologically normal cells in human skin. We show for the first time that similarly elevated levels of mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model. In fact, in the small intestine, mutant p53 spontaneously accumulates in a manner dependent on gene dosage and cell type. Mutant p53 protein is regulated similarly to wild type p53, which can accumulate rapidly after induction by ionising radiation or Mdm2 inhibitors, however, the clearance of mutant p53 protein is much slower than wild type p53. The accumulation of the protein in the murine small intestine is limited to the cycling, crypt base columnar cells and proliferative zone and is lost as the cells differentiate and exit the cell cycle. Loss of Mdm2 results in even higher levels of p53 expression but p53 is still restricted to proliferating cells in the small intestine. Therefore, the small intestine of these p53 mutant mice is an experimental system in which we can dissect the molecular pathways leading to p53 accumulation, which has important implications for cancer prevention and therapy. Impact Journals LLC 2015-07-22 /pmc/articles/PMC4627229/ /pubmed/26255629 Text en Copyright: © 2015 Goh et al. 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.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Goh, Amanda M. Xue, Yuezhen Leushacke, Marc Li, Ling Wong, Julin S. Chiam, Poh Cheang Rahmat, Siti Aishah Binte Mann, Michael B. Mann, Karen M. Barker, Nick Lozano, Guillermina Terzian, Tamara Lane, David P.
spellingShingle	Goh, Amanda M. Xue, Yuezhen Leushacke, Marc Li, Ling Wong, Julin S. Chiam, Poh Cheang Rahmat, Siti Aishah Binte Mann, Michael B. Mann, Karen M. Barker, Nick Lozano, Guillermina Terzian, Tamara Lane, David P. Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
author_facet	Goh, Amanda M. Xue, Yuezhen Leushacke, Marc Li, Ling Wong, Julin S. Chiam, Poh Cheang Rahmat, Siti Aishah Binte Mann, Michael B. Mann, Karen M. Barker, Nick Lozano, Guillermina Terzian, Tamara Lane, David P.
author_sort	Goh, Amanda M.
title	Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
title_short	Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
title_full	Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
title_fullStr	Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
title_full_unstemmed	Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
title_sort	mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 r172h mutant mice
description	The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High levels of mutant p53 can be found in tumours and the accumulation of mutant p53 has previously been reported in pathologically normal cells in human skin. We show for the first time that similarly elevated levels of mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model. In fact, in the small intestine, mutant p53 spontaneously accumulates in a manner dependent on gene dosage and cell type. Mutant p53 protein is regulated similarly to wild type p53, which can accumulate rapidly after induction by ionising radiation or Mdm2 inhibitors, however, the clearance of mutant p53 protein is much slower than wild type p53. The accumulation of the protein in the murine small intestine is limited to the cycling, crypt base columnar cells and proliferative zone and is lost as the cells differentiate and exit the cell cycle. Loss of Mdm2 results in even higher levels of p53 expression but p53 is still restricted to proliferating cells in the small intestine. Therefore, the small intestine of these p53 mutant mice is an experimental system in which we can dissect the molecular pathways leading to p53 accumulation, which has important implications for cancer prevention and therapy.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627229/
_version_	1613495291325972480

Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice

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