Editors' ChoiceCell Cycle

Dueling E3 Ligases

Science's STKE  16 Mar 2004:
Vol. 2004, Issue 224, pp. tw97-TW97
DOI: 10.1126/stke.2242004TW97

Protein degradation plays a key role in progression through the cell cycle. The anaphase-promoting complex (APC) is best known for its role as an E3 ubiquitin ligase that contributes to the degradation of proteins that allow exit from mitosis. The substrate specificity of E3 ligases is controlled by which subunits they contain, and two groups (Bashir et al. and Wei et al.) report that components of the E3 ligase that acts in the transition from G1 to S phase (SCFSkp2) are substrates for APC when it is activated by Cdh1. Both groups report that the destruction box motif in Skp2 is essential for degradation by APC and that RNAi treatment of cells to decrease the abundance of Cdh1 stabilized Skp2, which resulted in a decrease in the abundance of the cyclin-dependent protein kinase inhibitor, p27. Bashir et al. also showed that the SCF component Cks1 was stabilized after silencing of Cdh1. Wei et al. confirmed that Skp2 was a substrate for APC in the presence of Cdh1 in vitro. Both groups reported that, in cultured cells, in the absence of Skp2 degradation (due to knockdown of Cdh1 by RNAi), there was accelerated progression through the cell cycle. Thus, there is a complex interplay of E3 ligases and protein degradation in addition to the kinase cycle controlling cell cycle progression and kinetics.

T. Bashir, N. V. Dorrello, V. Amador, D. Guardavaccaro, M. Pagano, Control of the SCFSkp2-Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligase. Nature 428, 190-193 (2004). [Online Journal]

W. Wei, N. G Ayad, Y. Wan, G.-J. Zhang, M. W. Kirshner, W. G. Kaelin Jr., Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428, 194-198 (2004). [Online Journal]