The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy.
In cells capable of entering the cell cycle, including cancer cells, beta-catenin has been termed a master switch, driving proliferation over differentiation. However, its role as a transcriptional activator in terminally differentiated cells is relatively unknown. Herein we utilize conditional, cardiac-specific deletion of the beta-catenin gene and cardiac-specific expression of a dominant inhibitory mutant of Lef-1 (Lef-1Delta20), one of the members of the T-cell factor/lymphocyte enhancer factor (Tcf/Lef) family of transcription factors that functions as a coactivator with beta-catenin, to demonstrate that beta-catenin/Tcf/Lef-dependent gene expression regulates both physiologic and pathological growth (hypertrophy) of the heart. Indeed, the profound nature of the growth impairment of the heart in the Lef-1Delta20 mouse, which leads to very early development of heart failure and premature death, suggests beta-catenin/Tcf/Lef targets are dominant regulators of cardiomyocyte growth. Thus, our studies, employing complementary models in vivo, implicate beta-catenin/Tcf/Lef signaling as an essential growth-regulatory pathway in terminally differentiated cells.
Chen
Xin
X
Molecular Cardiology Research Institute, Tufts-New England Medical Center and Tufts University School of Medicine, USA.
Shevtsov
Sergei P
SP
Hsich
Eileen
E
Cui
Lei
L
Haq
Syed
S
Aronovitz
Mark
M
Kerkelä
Risto
R
Molkentin
Jeffery D
JD
Liao
Ronglih
R
Salomon
Robert N
RN
Patten
Richard
R
Force
Thomas
T
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049108:Cell Enlargement; D049109:Cell Proliferation; D017353:Gene Deletion; D006321:Heart / Q000254:growth & development; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051820:TCF Transcription Factors; D051176:beta Catenin