Fig 1: Scheme depicting the mechanism underlying chronic G1-induced cytoprotective effects against H2O2-induced cell death. In cultured H9c2 myoblasts, treatment with the cytotoxic agent, H2O2 increases the reactive oxygen species (ROS, O2.) production, which promotes the phosphorylation of MST1 (p-MST1). p-MST1 initiates activation of cascades that lead to phosphorylation of YAP (p-YAP). p-YAP is sequestered in the cytosol and subsequently degraded. In addition, increase in p-MST1 promotes the phosphorylation of JNK that upregulates proapoptotic genes. On the other hand, chronic GPER1 activation with its agonists E2 or G1 stimulates subcellular signaling that preserves mitochondrial structure and polarization leading to reduced ROS production and delayed mPTP opening. Reduction in ROS production is postulated to mitigate the phosphorylation of MST1, which increases the non-phosphorylated YAP. Thereafter, YAP translocates into the nucleus to upregulate prosurvival genes that, therefore, promote cell survival.