Project description:YAP, a major downstream effector of the Hippo signaling pathway, is an important regulator of cell proliferation. Previous studies have shown that YAP cooperates with the two transcription factors E2F and MYC to mediate G1 to S transition by regulating early cell cycle gene expression. On the other hand, the ability of YAP to regulate G2/M gene expression is dependent on the Myb-MuvB (MMB) complex, consisting of the evolutionary MuvB core complex of five proteins and the facultative subunit B-MYB, a transcription factor. We now carried out interaction studies and found that YAP directly binds to the B-MYB subunit of MMB. Disruption of the YAP/B-MYB interaction by overexpression of the YAP binding domain of B-MYB results in errors in cell division. We also show that YAP and MMB interact in vivo in the developing heart. Genome wide expression and binding studies revealed that YAP and MMB regulate an overlapping set of cell cycle genes in cardiomyocytes. Cardiac specific deletion of the LIN9 subunit of MMB prevents the upregulation of cell cycle genes and the increased proliferation of cardiomyocytes lacking the hippo-signaling component SAV1. Similarly, we find that proliferation of postnatal cardiomyocytes induced by constitutive active YAP depends on MMB. Our findings provide new insights in the mechanisms of cell cycle regulation by the Hippo pathway in cardiomyocytes and suggests that YAP and MMB interact to induce genes critical for cell cycle regulation.
