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J. Biol. Chem., Vol. 282, Issue 6, 3672-3679, February 9, 2007

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KEN-Box-dependent Degradation of the Bub1 Spindle Checkpoint Kinase by the Anaphase-promoting Complex/Cyclosome^*

From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The spindle checkpoint is a cell cycle surveillance mechanism that ensures the fidelity of chromosome segregation during mitosis and meiosis. Bub1 is a protein serine-threonine kinase that plays multiple roles in chromosome segregation and the spindle checkpoint. In response to misaligned chromosomes, Bub1 directly inhibits the ubiquitin ligase activity of the anaphase-promoting complex or cyclosome (APC/C) by phosphorylating its activator Cdc20. The protein level and the kinase activity of Bub1 are regulated during the cell cycle; they peak in mitosis and are low in G₁/S phase. Here we show that Bub1 is degraded during mitotic exit and that degradation of Bub1 is mediated by APC/C in complex with its activator Cdh1 (APC/C^Cdh1). Overexpression of Cdh1 reduces the protein levels of ectopically expressed Bub1, whereas depletion of Cdh1 by RNA interference increases the level of the endogenous Bub1 protein. Bub1 is ubiquitinated by immunopurified APC/C^Cdh1 in vitro. We further identify two KEN-box motifs on Bub1 that are required for its degradation in vivo and ubiquitination in vitro. A Bub1 mutant protein with both KEN-boxes mutated is stable in cells but fails to elicit a cell cycle phenotype, indicating that degradation of Bub1 by APC/C^Cdh1 is not required for mitotic exit. Nevertheless, our study clearly demonstrates that Bub1, an APC/C inhibitor, is also an APC/C substrate. The antagonistic relationship between Bub1 and APC/C may help to prevent the premature accumulation of Bub1 during G₁.

Received for publication, October 4, 2006 , and in revised form, December 11, 2006.

^* This work was supported by National Institutes of Health Grant GM61542, the March of Dimes Foundation, the Welch Foundation, and the Leukemia and Lymphoma Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Michael Rosenberg Scholar in Biomedical Research. To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041. Tel.: 214-645-6161; Fax: 214-645-6156; E-mail: hongtao.yu{at}utsouthwestern.edu.

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