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A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine

BACKGROUND: p53 is an important tumour suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of the...

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Autores principales: Reed, Karen R, Meniel, Valerie S, Marsh, Victoria, Cole, Alicia, Sansom, Owen J, Clarke, Alan R
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443808/
https://www.ncbi.nlm.nih.gov/pubmed/18533991
http://dx.doi.org/10.1186/1471-2407-8-162
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author Reed, Karen R
Meniel, Valerie S
Marsh, Victoria
Cole, Alicia
Sansom, Owen J
Clarke, Alan R
author_facet Reed, Karen R
Meniel, Valerie S
Marsh, Victoria
Cole, Alicia
Sansom, Owen J
Clarke, Alan R
author_sort Reed, Karen R
collection PubMed
description BACKGROUND: p53 is an important tumour suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of β-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development.
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spelling pubmed-24438082008-07-08 A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine Reed, Karen R Meniel, Valerie S Marsh, Victoria Cole, Alicia Sansom, Owen J Clarke, Alan R BMC Cancer Research Article BACKGROUND: p53 is an important tumour suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of β-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development. BioMed Central 2008-06-05 /pmc/articles/PMC2443808/ /pubmed/18533991 http://dx.doi.org/10.1186/1471-2407-8-162 Text en Copyright © 2008 Reed et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Reed, Karen R
Meniel, Valerie S
Marsh, Victoria
Cole, Alicia
Sansom, Owen J
Clarke, Alan R
A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine
title A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine
title_full A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine
title_fullStr A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine
title_full_unstemmed A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine
title_short A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine
title_sort limited role for p53 in modulating the immediate phenotype of apc loss in the intestine
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443808/
https://www.ncbi.nlm.nih.gov/pubmed/18533991
http://dx.doi.org/10.1186/1471-2407-8-162
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