Lkb1 is required for TGFbeta-mediated myofibroblast differentiation.
Inactivating mutations of the tumor-suppressor kinase gene LKB1 underlie Peutz-Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomatous polyps with a prominent smooth-muscle and stromal component. Recently, it was noted that PJS-type polyps develop in mice in which Lkb1 deletion is restricted to SM22-expressing mesenchymal cells. Here, we investigated the stromal functions of Lkb1, which possibly underlie tumor suppression. Ablation of Lkb1 in primary mouse embryo fibroblasts (MEFs) leads to attenuated Smad activation and TGFbeta-dependent transcription. Also, myofibroblast differentiation of Lkb1(-/-) MEFs is defective, resulting in a markedly decreased formation of alpha-smooth muscle actin (SMA)-positive stress fibers and reduced contractility. The myofibroblast differentiation defect was not associated with altered serum response factor (SRF) activity and was rescued by exogenous TGFbeta, indicating that inactivation of Lkb1 leads to defects in myofibroblast differentiation through attenuated TGFbeta signaling. These results suggest that tumorigenesis by Lkb1-deficient SM22-positive cells involves defective myogenic differentiation.
Genome-Scale Biology Program, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland.
Kari
K
Vaahtomeri
Eeva
E
Ventelä
Kaisa
K
Laajanen
Pekka
P
Katajisto
Pierre-Jean
PJ
Wipff
Boris
B
Hinz
Tea
T
Vallenius
Marianne
M
Tiainen
Tomi P
TP
Mäkelä
D055372:AMP-Activated Protein Kinases; D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009119:Muscle Contraction; D009132:Muscles / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D026362:Serum Response Factor / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000199:Actins; D026362:Serum Response Factor; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases