Recent pieces of evidence have shown that the E3 ubiquitin ligase Skp2/fbxl1 might regulate the proliferation of vascular smooth muscle cells (Wu et al., 2006) and cardiomyocytes (Tamamori-Adachi et al., 2004), which suggests that impaired UPS-mediated degradation may impede cardiomyocyte proliferation, while the silencing of RNF181 reduced the cell proliferation induced by the expression of CDK4 and worsened proliferation and deteriorated cardiac efficiency post-ischemia in vivo. Here, CDK4 is linked to ischemia.