Depletion of mammalian target of rapamycin (mTOR) via siRNA mediated knockdown leads to stabilization of beta-catenin and elicits distinct features of cardiomyocyte hypertrophy.
Cardiac myocyte growth is under differential control of mammalian target of rapamycin (mTOR) and glycogen-synthase-kinase-3beta (GSK3beta). Whereas active GSK3beta negatively regulates growth and down-regulates cellular protein synthesis, activation of the mTOR pathway promotes protein expression and cell growth. Here we report that depletion of mTOR via siRNA mediated knockdown causes marked down-regulation of GSK3beta protein in cardiac myocytes. As a result, GSK3beta target protein beta-catenin becomes stabilized and translocates into the nucleus. Moreover, mTOR knockdown leads to increase in cardiac myocyte surface area and produces an up-regulation of the fetal gene program. Our findings suggest a new type of convergence of mTOR and GSK3beta activities, indicating that GSK3beta-dependent stabilization of beta-catenin in cardiac myocytes is influenced by mTOR.
Hagenmueller
Marco
M
Department of Cardiology, University of Heidelberg, Heidelberg, Germany. marco.hagenmueller@med.uni-heidelberg.de
Malekar
Pratima
P
Fieger
Christiane
C
Weiss
Celine S
CS
Buss
Sebastian J
SJ
Wolf
David
D
Katus
Hugo A
HA
Hardt
Stefan E
SE
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D051176:beta Catenin / Q000378:metabolism*
D034741:RNA, Small Interfering; D051176:beta Catenin; D011494:Protein Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus