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Molecular and Cellular Biology, July 2000, p. 4614-4625, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hsl1p, a Swe1p Inhibitor, Is Degraded via the Anaphase-Promoting Complex

Janet L. Burton and Mark J. Solomon*

Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut 06520-8114

Received 24 November 1999/Returned for modification 10 January 2000/Accepted 15 March 2000

Ubiquitination and subsequent degradation of critical cell cycle regulators is a key mechanism exploited by the cell to ensure an irreversible progression of cell cycle events. The anaphase-promoting complex (APC) is a ubiquitin ligase that targets proteins for degradation by the 26S proteasome. Here we identify the Hsl1p protein kinase as an APC substrate that interacts with Cdc20p and Cdh1p, proteins that mediate APC ubiquitination of protein substrates. Hsl1p is absent in G1, accumulates as cells begin to bud, and disappears in late mitosis. Hsl1p is stabilized by mutations in CDH1 and CDC23, both of which result in compromised APC activity. Unlike Hsl1p, Gin4p and Kcc4p, protein kinases that have sequence homology to Hsl1p, were stable in G1-arrested cells containing active APC. Mutation of a destruction box motif within Hsl1p (Hsl1pdb-mut) stabilized Hsl1p. Interestingly, this mutation also disrupted the Hsl1p-Cdc20p interaction and reduced the association between Hsl1p and Cdh1p in coimmunoprecipitation studies. These findings suggest that the destruction box motif is required for Cdc20p and, to a lesser extent, for Cdh1p to target Hsl1p to the APC for ubiquitination. Hsl1p has been previously shown to inhibit Swe1p, a protein kinase that negatively regulates the cyclin-dependent kinase Cdc28p, by promoting Swe1p degradation via SCFMet30 in a bud morphogenesis checkpoint. Results of the present work indicate that Hsl1p is degraded in an APC-dependent manner and suggest a link between the SCF (Skp1-cullin-F box) and APC-proteolytic systems that may help to coordinate the proper progression of cell cycle events.

* Corresponding author. Mailing address: Department of Molecular Biophysics & Biochemistry, Yale University, 266 Whitney Ave., New Haven, CT 06520-8114. Phone: (203) 436-4388. Fax: (203) 432-3104. E-mail: Mark.Solomon{at}Yale.edu.

Molecular and Cellular Biology, July 2000, p. 4614-4625, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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