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Research Article
The Peutz-Jeghers kinase LKB1 suppresses polyp growth from intestinal cells of a proglucagon-expressing lineage
Sagen Zac-Varghese, Stefan Trapp, Paul Richards, Sophie Sayers, Gao Sun, Stephen R. Bloom, Frank Reimann, Fiona M. Gribble, Guy A. Rutter
Disease Models & Mechanisms 2014 : dmm.014720 doi: 10.1242/dmm.014720 Published 13 October 2014
Sagen Zac-Varghese
Imperial College London, UK;
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Stefan Trapp
Imperial College London, UK;
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Paul Richards
University of Cambridge, UK
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Sophie Sayers
Imperial College London, UK;
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Gao Sun
Imperial College London, UK;
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Stephen R. Bloom
Imperial College London, UK;
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Frank Reimann
University of Cambridge, UK
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Fiona M. Gribble
University of Cambridge, UK
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Guy A. Rutter
Imperial College London, UK;
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Abstract

Liver kinase B1 (LKB1; also known as STK11) is a serine/threonine kinase and tumour suppressor that is mutated in Peutz-Jeghers syndrome (PJS), a premalignant syndrome associated with the development of gastrointestinal polyps. Proglucagon-expressing enteroendocrine cells are involved in the control of glucose homeostasis and the regulation of appetite through the secretion of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) (incretins). To determine the role of LKB1 in these cells, we bred mice bearing floxed alleles of Lkb1 against animals carrying Cre recombinase under proglucagon promoter control. These mice (GluLKB1KO) were viable and displayed near-normal growth rates and glucose homeostasis. However, they developed large polyps at the gastro-duodenal junction, and displayed premature mortality (death from 120 days of age). Histological analysis of the polyps demonstrated that they had a PJS-like appearance with an arborising smooth-muscle core. Circulating GLP-1 levels were normal in GluLKB1KO mice and the polyps expressed low levels of the peptide, similar to levels in the neighbouring duodenum. Lineage tracing using a Rosa26tdRFP transgene revealed, unexpectedly, that enterocytes within the polyps were derived from non-proglucagon-expressing precursors, whereas connective tissue was largely derived from proglucagon-expressing precursors. Developmental studies in wild-type mice suggested that a subpopulation of proglucagon-expressing cells undergo epithelial-mesenchymal transition (EMT) to become smooth-muscle-like cells. Thus, it is likely that polyps in the GluLKB1KO mice developed from a unique population of smooth-muscle-like cells derived from a proglucagon-expressing precursor. The loss of LKB1 within this subpopulation seems to be sufficient to drive tumorigenesis.

  • Received November 1, 2013.
  • Accepted September 3, 2014.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Research Article
The Peutz-Jeghers kinase LKB1 suppresses polyp growth from intestinal cells of a proglucagon-expressing lineage
Sagen Zac-Varghese, Stefan Trapp, Paul Richards, Sophie Sayers, Gao Sun, Stephen R. Bloom, Frank Reimann, Fiona M. Gribble, Guy A. Rutter
Disease Models & Mechanisms 2014 : dmm.014720 doi: 10.1242/dmm.014720 Published 13 October 2014
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Research Article
The Peutz-Jeghers kinase LKB1 suppresses polyp growth from intestinal cells of a proglucagon-expressing lineage
Sagen Zac-Varghese, Stefan Trapp, Paul Richards, Sophie Sayers, Gao Sun, Stephen R. Bloom, Frank Reimann, Fiona M. Gribble, Guy A. Rutter
Disease Models & Mechanisms 2014 : dmm.014720 doi: 10.1242/dmm.014720 Published 13 October 2014

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