Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken, Biocenter University of Wuerzburg, Wuerzburg, Germany.
Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
PLoS Genet. 2020 May 29;16(5):e1008818. doi: 10.1371/journal.pgen.1008818. eCollection 2020 May.
The Hippo signalling pathway and its central effector YAP regulate proliferation of cardiomyocytes and growth of the heart. Using genetic models in mice we show that the increased proliferation of embryonal and postnatal cardiomyocytes due to loss of the Hippo-signaling component SAV1 depends on the Myb-MuvB (MMB) complex. Similarly, proliferation of postnatal cardiomyocytes induced by constitutive active YAP requires MMB. Genome studies revealed that YAP and MMB regulate an overlapping set of cell cycle genes in cardiomyocytes. Protein-protein interaction studies in cell lines and with recombinant proteins showed that YAP binds directly to B-MYB, a subunit of MMB, in a manner dependent on the YAP WW domains and a PPXY motif in B-MYB. Disruption of the interaction by overexpression of the YAP binding domain of B-MYB strongly inhibits the proliferation of cardiomyocytes. Our results point to MMB as a critical downstream effector of YAP in the control of cardiomyocyte proliferation.
Hippo 信号通路及其核心效应因子 YAP 调节心肌细胞的增殖和心脏的生长。我们使用小鼠中的遗传模型表明，由于 Hippo 信号成分 SAV1 的缺失导致胚胎期和出生后心肌细胞增殖增加，这取决于 Myb-MuvB（MMB）复合物。同样，由组成性激活的 YAP 诱导的出生后心肌细胞的增殖也需要 MMB。基因组研究表明，YAP 和 MMB 在心肌细胞中调节一组重叠的细胞周期基因。细胞系中的蛋白-蛋白相互作用研究以及使用重组蛋白的研究表明，YAP 以依赖于 YAP WW 结构域和 B-MYB 中的 PPXY 基序的方式直接与 MMB 的 B-MYB 亚基结合。通过过表达 B-MYB 的 YAP 结合域破坏相互作用，强烈抑制心肌细胞的增殖。我们的研究结果表明，MMB 是 YAP 在控制心肌细胞增殖中的关键下游效应因子。
