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

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.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.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.p53 is implicated in colorectal cancer as the final step of multi-step carcinogenesis leading to carcinoma formation [1]. However, p53 is also postulated to be involved as a critical negative regulator of the Wnt signalling pathway, arguing that it should also have a role in the tumour initiation process. To date, crossing p53 deficient mice to the Apcmin mouse has variably been reported to have no effect or to modify adenoma formation [2-4]. Consequently there is a need to further clarify the role of p53 function in intestinal neoplasia.Increased levels of β-catenin lead to increased transcription of p14ARF (in huma