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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / analysis
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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DNA-Binding Proteins / analysis
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Female
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Gene Deletion
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Homeostasis / physiology*
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Humans
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Intestines / cytology
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Intestines / physiology*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / physiology*
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Male
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Mice
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Oxidoreductases
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Prognosis
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / physiology*
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Stem Cells / cytology
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Stem Cells / physiology*
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Transcription Factors / analysis
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / physiology
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Ubiquitination / genetics
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Ubiquitination / physiology
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / physiology*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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NRBP1 protein, human
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Receptors, Cytoplasmic and Nuclear
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SALL4 protein, human
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Sall4 protein, mouse
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TSC22D2 protein, human
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TSC22D2 protein, mouse
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Transcription Factors
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Tumor Suppressor Proteins
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Vesicular Transport Proteins
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Nrbf1 protein, mouse
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Oxidoreductases