Fig. 1.

Interactions of cell cycle regulators and signaling proteins model for adult cardiomyocyte proliferation. The cell cycle after G0 is time-phased with four phases of G1, S, G2 and M with the checkpoints at the interphase of G1/S and G2/M. Signaling pathways of Notch, Hippo, Wnt and Akt facilitate or inhibit the transition at checkpoint as shown by the interacting colored arrows. Cyclins, cyclin dependent kinases (CDKs) facilitate the transition at checkpoints which in turn is regulated by inhibitory action of P21, P27, p28 and P57 on cyclin and CDKs. Akt shows a triple response of inactivating GSK-3β, releasing β-catenin to action, activates cyclin D and inhibits P27 leading to disinhibition of cyclins and CDKs. Hippo signaling, on one hand activates Yap proteins to regulate β-catenin and on the other hand, it activates insulin like growth factor-1(IGF-1) to switch on Akt signaling. Wnt signaling activates β-catenin switching on the G1 to S transition. Notch signaling together with Akt inhibits P27 and P57 proteins in order to disinhibit the cyclin-CDK facilitation of cell cycle checkpoints.