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J. Biol. Chem., Vol. 283, Issue 16, 10396-10407, April 18, 2008

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Cdc28 and Cdc14 Control Stability of the Anaphase-promoting Complex Inhibitor Acm1^*

Mark C. Hall^¶1, Dah-Eun Jeong, James T. Henderson, Eunyoung Choi, Steven C. Bremmer, Anton B. Iliuk, and Harry Charbonneau²

From the Biochemistry Department, Purdue Cancer Center, and ^¶Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907

The anaphase-promoting complex (APC) regulates the eukaryotic cell cycle by targeting specific proteins for proteasomal degradation. Its activity must be strictly controlled to ensure proper cell cycle progression. The co-activator proteins Cdc20 and Cdh1 are required for APC activity and are important regulatory targets. Recently, budding yeast Acm1 was identified as a Cdh1 binding partner and APC^Cdh1 inhibitor. Acm1 disappears in late mitosis when APC^Cdh1 becomes active and contains conserved degron-like sequences common to APC substrates, suggesting it could be both an inhibitor and substrate. Surprisingly, we found that Acm1 proteolysis is independent of APC. A major determinant of Acm1 stability is phosphorylation at consensus cyclin-dependent kinase sites. Acm1 is a substrate of Cdc28 cyclin-dependent kinase and Cdc14 phosphatase both in vivo and in vitro. Mutation of Cdc28 phosphorylation sites or conditional inactivation of Cdc28 destabilizes Acm1. In contrast, inactivation of Cdc14 prevents Acm1 dephosphorylation and proteolysis. Cdc28 stabilizes Acm1 in part by promoting binding of the 14-3-3 proteins Bmh1 and Bmh2. We conclude that the opposing actions of Cdc28 and Cdc14 are primary factors limiting Acm1 to the interval from G₁/S to late mitosis and are capable of establishing APC-independent expression patterns similar to APC substrates.

Received for publication, December 7, 2007 , and in revised form, February 20, 2008.

^* This work was supported in part by an American Heart Association scientist development grant (to M. C. H.). 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.

² Supported by National Institutes of Health Grant CA59935. This is journal paper 18277 from the Purdue University Agricultural Experiment Station.

¹ Recipient of an institutional research grant from the American Cancer Society to the Purdue Cancer Center. To whom correspondence should be addressed: 175 S. University St., West Lafayette, IN 47907. Tel.: 765-494-0714; Fax: 765-494-7897; E-mail: mchall{at}purdue.edu.

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