Chen Xin, Shevtsov Sergei P, Hsich Eileen, Cui Lei, Haq Syed, Aronovitz Mark, Kerkelä Risto, Molkentin Jeffery D, Liao Ronglih, Salomon Robert N, Patten Richard, Force Thomas
Molecular Cardiology Research Institute, Tufts-New England Medical Center and Tufts University School of Medicine, USA.
Mol Cell Biol. 2006 Jun;26(12):4462-73. doi: 10.1128/MCB.02157-05.
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.
在能够进入细胞周期的细胞（包括癌细胞）中，β-连环蛋白被称为主开关，它促使细胞增殖而非分化。然而，其在终末分化细胞中作为转录激活因子的作用相对未知。在此，我们利用条件性、心脏特异性敲除β-连环蛋白基因以及心脏特异性表达T细胞因子/淋巴细胞增强因子（Tcf/Lef）转录因子家族成员之一Lef-1的显性抑制突变体（Lef-1Delta20）（Lef-1作为与β-连环蛋白协同激活的因子），来证明β-连环蛋白/Tcf/Lef依赖性基因表达调节心脏的生理和病理生长（肥大）。事实上，Lef-1Delta20小鼠心脏生长受损的严重程度导致心力衰竭的早期发展和过早死亡，这表明β-连环蛋白/Tcf/Lef靶标是心肌细胞生长的主要调节因子。因此，我们在体内采用互补模型进行的研究表明，β-连环蛋白/Tcf/Lef信号传导是终末分化细胞中一种重要的生长调节途径。
