LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis

Nat Genet. 2008 Apr;40(4):455-9. doi: 10.1038/ng.98. Epub 2008 Mar 2.

Abstract

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFbeta, and defective TGFbeta signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gastrointestinal Tract / metabolism
  • Gastrointestinal Tract / pathology*
  • Humans
  • Injections, Intraperitoneal
  • Integrases / metabolism
  • Intestinal Polyps / metabolism
  • Intestinal Polyps / pathology*
  • Longevity
  • Male
  • Mesoderm / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / physiology
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology
  • Muscle, Smooth / metabolism*
  • Muscle, Smooth / pathology
  • Peutz-Jeghers Syndrome / metabolism
  • Peutz-Jeghers Syndrome / pathology
  • Peutz-Jeghers Syndrome / prevention & control*
  • Polymerase Chain Reaction
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Selective Estrogen Receptor Modulators / administration & dosage
  • Smad2 Protein
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • TOR Serine-Threonine Kinases
  • Tamoxifen / administration & dosage
  • Transforming Growth Factor beta / metabolism

Substances

  • Microfilament Proteins
  • Muscle Proteins
  • RNA, Messenger
  • SMAD2 protein, human
  • Selective Estrogen Receptor Modulators
  • Smad2 Protein
  • Tagln protein, mouse
  • Transforming Growth Factor beta
  • Tamoxifen
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Stk11 protein, mouse
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cre recombinase
  • Integrases