A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestineReport as inadecuate




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BMC Cancer

, 8:162

First Online: 05 June 2008Received: 01 February 2008Accepted: 05 June 2008DOI: 10.1186-1471-2407-8-162

Cite this article as: Reed, K.R., Meniel, V.S., Marsh, V. et al. BMC Cancer 2008 8: 162. doi:10.1186-1471-2407-8-162

Abstract

Backgroundp53 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.

MethodsWe 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.

ResultsExpression 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.

Conclusionp53 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.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-8-162 contains supplementary material, which is available to authorized users.

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Author: Karen R Reed - Valerie S Meniel - Victoria Marsh - Alicia Cole - Owen J Sansom - Alan R Clarke

Source: https://link.springer.com/







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