Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation

Catherine H Wilson, Catriona Crombie, Louise van der Weyden, George Poulogiannis, Alistair G Rust, Mercedes Pardo, Tannia Gracia, Lu Yu, Jyoti Choudhary, Gino B Poulin, Rebecca E McIntyre, Douglas J Winton, H Nikki March, Mark J Arends, Andrew G Fraser, David J Adams

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression.
Original languageEnglish
Pages (from-to)2486-97
Number of pages12
JournalEMBO Journal
Volume31
Issue number11
DOIs
Publication statusPublished - 30 May 2012

Keywords

  • Animals
  • Carrier Proteins
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • DNA-Binding Proteins
  • Female
  • Gene Deletion
  • Homeostasis
  • Humans
  • Intestines
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Neoplasms
  • Prognosis
  • Receptors, Cytoplasmic and Nuclear
  • Stem Cells
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitination
  • Vesicular Transport Proteins

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