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Cited1 deficiency suppresses intestinal tumorigenesis

Meniel, Valerie, Song, Fei, Phesse, Toby, Young, Madeleine, Poetz, Oliver, Parry, Lee, Jenkins, John R., Williams, Geraint Trefor, Dunwoodie, Sally L., Watson, Alastair and Clarke, Alan Richard 2013. Cited1 deficiency suppresses intestinal tumorigenesis. PLoS Genetics 9 (8) , e1003638. 10.1371/journal.pgen.1003638

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Abstract

Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with ApcMin/+ and AhCre+Apcfl/fl mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in ApcMin/+ mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of β-catenin and increased levels of dephosphorylated β-catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of β-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in ApcMin/+ mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1.

Item Type: Article
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Public Library of Science
ISSN: 1553-7404
Date of First Compliant Deposit: 30 March 2016
Last Modified: 15 Oct 2018 03:34
URI: http://orca-mwe.cf.ac.uk/id/eprint/52653

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