LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis.
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.
Katajisto
Pekka
P
Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, 00014 University of Helsinki, Finland.
Vaahtomeri
Kari
K
Ekman
Niklas
N
Ventelä
Eeva
E
Ristimäki
Ari
A
Bardeesy
Nabeel
N
Feil
Robert
R
DePinho
Ronald A
RA
Mäkelä
Tomi P
TP
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007274:Injections, Intraperitoneal; D019426:Integrases / Q000378:metabolism; D007417:Intestinal Polyps / Q000378:metabolism / Q000473:pathology*; D008136:Longevity; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D010580:Peutz-Jeghers Syndrome / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage; D051899:Smad2 Protein; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000008:administration & dosage; D016212:Transforming Growth Factor beta / Q000378:metabolism
D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C497782:SMAD2 protein, human; D020845:Selective Estrogen Receptor Modulators; D051899:Smad2 Protein; C058992:Tagln protein, mouse; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases