Control of the SCFSkp2-Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligase
T. Bashir, N. V. Dorrello, V. Amador, D. Guardavaccaro and M. Pagano
Nature, 248:190-193, 2004
Skp2 and its cofactor Cks1 are the substrate targeting subunits of the SCFSkp2-Cks1 (Skp1/Cul1/F-box protein) ubiquitin ligase complex that regulates entry into S-phase by inducing the degradation of the CDK inhibitors p21 and p27 (ref.1). Since Skp2 is an oncoprotein whose levels are often elevated in human cancers 2, we investigated the mechanism regulating its cellular abundance. We found that both Skp2 and Cks1 proteins are unstable in G1 and that their degradation is mediated by the ubiquitin ligase APC/CCdh1 (anaphase promoting complex/cyclosome and its activator Cdh1). Silencing of Cdh1 by siRNA in G1 cells stabilizes Skp2 and Cks1 with a consequent enhancement of p21 and p27 proteolysis. Furthermore, Cdh1 depletion increases the percentage of cells in S-phase, whereas concomitant downregulation of Skp2 reverses this effect, showing that Skp2 is a critical target of APC/CCdh1. Importantly, the expression of a stable Skp2 mutant unable to bind APC/CCdh1 induces premature S-phase entry. Thus, the induction of Skp2 and Cks1 degradation during G1 represents a major mechanism by which APC/CCdh1 prevents the unscheduled degradation of SCFSkp2-Cks1 substrates and maintains the G1 state.