부산대학교 도서관

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. Author summary: YAP, the major downstream transducer of the Hippo pathway, is a potent inducer of proliferation. Here we show that the Myb-MuvB complex (MMB) mediates cardiomyocyte proliferation by YAP. We find that YAP and MMB regulate an overlapping set of pro-proliferative genes which involves binding of MMB to the promoters of these genes. We also identified a direct interaction between the B-MYB subunit of MMB and YAP. Based on the binding studies, we created a tool called MY-COMP that interferes with the association YAP to B-MYB and strongly inhibits proliferation of cardiomyocytes. Together, our data suggests that the YAP-MMB interaction is essential for division of cardiomyocytes, underscoring the functional relevance of the crosstalk between these two pathways for proper heart development. [ABSTRACT FROM AUTHOR]