In addition, Hsieh et al. and Hsu et al. showed that without the mediation of ER stress, pre-S2 deleted proteins could induce the degradation of cyclin-dependent kinase (Cdk) inhibitor p27 through zinc-dependent interaction with Jun activation domain-binding protein 1 (JAB1), leading to Cdk2-mediated hyperphosphorylation and the inactivation of the tumor suppressor retinoblastoma protein (Rb) in human hepatoma cell lines and in transgenic mouse livers, which promoted cell cycle progression [46,47]. The gene discussed is COPS5; the disease is hepatocellular carcinoma.