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Molecular and Cellular Biology, June 2005, p. 4977-4992, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.4977-4992.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mechanism of Aurora-B Degradation and Its Dependency on Intact KEN and A-Boxes: Identification of an Aneuploidy-Promoting Property

Hao G. Nguyen,1 Dharmaraj Chinnappan,1 Takeshi Urano,2 and Katya Ravid1*

Department of Biochemistry, Department of Medicine, and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118,1 Department of Biochemistry II, Nagoya University School of Medicine, Nagoya 466-0065, Japan2

Received 9 November 2004/ Returned for modification 3 January 2005/ Accepted 7 March 2005

The kinase Aurora-B, a regulator of chromosome segregation and cytokinesis, is highly expressed in a variety of tumors. During the cell cycle, the level of this protein is tightly controlled, and its deregulated abundance is suspected to contribute to aneuploidy. Here, we provide evidence that Aurora-B is a short-lived protein degraded by the proteasome via the anaphase-promoting cyclosome complex (APC/c) pathway. Aurora-B interacts with the APC/c through the Cdc27 subunit, Aurora-B is ubiquitinated, and its level is increased upon treatment with inhibitors of the proteasome. Aurora-B binds in vivo to the degradation-targeting proteins Cdh1 and Cdc20, the overexpression of which accelerates Aurora-B degradation. Using deletions or point mutations of the five putative degradation signals in Aurora-B, we show that degradation of this protein does not depend on its D-boxes (RXXL), but it does require intact KEN boxes and A-boxes (QRVL) located within the first 65 amino acids. Cells transfected with wild-type or A-box-mutated or KEN box-mutated Aurora-B fused to green fluorescent protein display the protein localized to the chromosomes and then to the midzone during mitosis, but the mutated forms are detected at greater intensities. Hence, we identified the degradation pathway for Aurora-B as well as critical regions for its clearance. Intriguingly, overexpression of a stable form of Aurora-B alone induces aneuploidy and anchorage-independent growth.

* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, K225, Boston, MA 02118. Phone: (617) 638-5053. Fax: (617) 638-5054. E-mail: ravid{at}biochem.bumc.bu.edu.

Molecular and Cellular Biology, June 2005, p. 4977-4992, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.4977-4992.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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