The Evi5 Oncogene Regulates Cyclin Accumulation by Stabilizing the Anaphase-Promoting Complex Inhibitor Emi1

• Published in: Cell Vol. 124; no. 2; pp. 367 - 380
• Main Authors: Eldridge, Adam G., Loktev, Alexander V., Hansen, David V., Verschuren, Emmy W., Reimann, Julie D.R., Jackson, Peter K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-01-2006
• Subjects: Anaphase - physiology; Anaphase-Promoting Complex-Cyclosome; Animals; Cell Cycle - physiology; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - pharmacology; Cell Line; Cyclin A - metabolism; F-Box Proteins; GTPase-Activating Proteins; HeLa Cells; Humans; Interphase; Models, Biological; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphorylation; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; SKP Cullin F-Box Protein Ligases - metabolism; Two-Hybrid System Techniques; Ubiquitin-Protein Ligase Complexes - antagonists & inhibitors; Ubiquitin-Protein Ligase Complexes - metabolism; Xenopus
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2005.10.038

The anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 controls progression to S phase and mitosis by stabilizing key APC/C ubiquitination substrates, including cyclin A. Examining Emi1 binding proteins, we identified the Evi5 oncogene as a regulator of Emi1 accumulation. Evi5 antagonizes SCFβTrCP-dependent Emi1 ubiquitination and destruction by binding to a site adjacent to Emi1's DSGxxS degron and blocking both degron phosphorylation by Polo-like kinases and subsequent βTrCP binding. Thus, Evi5 functions as a stabilizing factor maintaining Emi1 levels in S/G2 phase. Evi5 protein accumulates in early G1 following Plk1 destruction and is degraded in a Plk1- and ubiquitin-dependent manner in early mitosis. Ablation of Evi5 induces precocious degradation of Emi1 by the Plk/SCFβTrCP pathway, causing premature APC/C activation; cyclin destruction; cell-cycle arrest; centrosome overduplication; and, finally, mitotic catastrophe. We propose that the balance of Evi5 and Polo-like kinase activities determines the timely accumulation of Emi1 and cyclin, ensuring mitotic fidelity.