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The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1.

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 SCF(betaTrCP)-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 betaTrCP 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/SCF(betaTrCP) 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.

Pubmed ID: 16439210

Authors

  • Eldridge AG
  • Loktev AV
  • Hansen DV
  • Verschuren EW
  • Reimann JD
  • Jackson PK

Journal

Cell

Publication Data

January 27, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA09302
  • Agency: NIGMS NIH HHS, Id: R01 GM060439
  • Agency: NIGMS NIH HHS, Id: R01 GM54811
  • Agency: NIGMS NIH HHS, Id: R01 GM73023

Mesh Terms

  • Anaphase
  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Line
  • Cyclin A
  • F-Box Proteins
  • HeLa Cells
  • Humans
  • Interphase
  • Models, Biological
  • Nuclear Proteins
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • SKP Cullin F-Box Protein Ligases
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligase Complexes
  • Xenopus