Mdm2 restrains the activity of the CRL4 ^Cdt2 E3 ubiquitin ligase to promote cell cycle progression through the G2/M phase

The canonical function of the Mdm2 oncoprotein is widely recognized as the negative regulation of the p53 tumor suppressor. However, growing evidence indicates that its physiological activities extend far beyond p53. Here, we show that Mdm2 promotes cell cycle progression at the G2/M phase through the ubiquitin-mediated degradation of the substrate recognition adaptor Cdt2 of the CRL4 ^Cdt2 E3 ubiquitin ligase complex, independently of p53. The attenuation of CRL4 ^Cdt2 activity by Mdm2 stabilizes its cell cycle-specific substrates including p21, Set8, and Cdt1, at the G2/M phase following their proteasomal degradation in the S phase. Furthermore, the delay in cell cycle progression at the G2/M phase and the decreased cell proliferation observed in the absence of Mdm2 are largely caused by an increase in Cdt2 and a subsequent decrease in p21. Collectively, our data illustrate a previously unexplored mechanism by which Mdm2 regulates the cell cycle and promotes cellular proliferation by neutralising the CR4 ^Cdt2 E3 ubiquitin ligase activity and subsequently stabilizing p21.