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Molecular and Cellular Biology, December 2005, p. 10516-10527, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10516-10527.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Anaphase-Promoting Complex/Cyclosome Controls the Stability of TPX2 during Mitotic Exit

Scott Stewart and Guowei Fang*

Department of Biological Sciences, Stanford University, Stanford, California 94305-5020

Received 5 May 2005/ Returned for modification 15 June 2005/ Accepted 31 August 2005

TPX2, a microtubule-associated protein, is required downstream of Ran-GTP to induce spindle assembly. TPX2 activity appears to be tightly regulated during the cell cycle, and we report here one molecular mechanism for this regulation. We found that TPX2 protein levels are cell cycle regulated, peaking in mitosis and declining sharply during mitotic exit. TPX2 is degraded in mitotic extracts, as well as in HeLa cells exiting from mitosis. This instability depends, both in vitro and in vivo, on the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that controls mitotic progression. In a reconstituted system, TPX2 is efficiently ubiquitinated by APC/C that has been activated by Cdh1. Two discrete elements in TPX2 are required for recognition by APC/CCdh1: a KEN box and a novel element in amino acids 1 to 86. Interestingly, the latter element, which has no known APC/C recognition motifs, is required for the ubiquitination of TPX2 by APC/CCdh1 in vitro and for its degradation in vivo. We conclude that APC/CCdh1 controls the stability of TPX2, thereby ensuring accurate regulation of the spindle assembly in the cell cycle.

* Corresponding author. Mailing address: Department of Biological Sciences, Stanford University, 337 Campus Drive, Room 137, Stanford, CA 94305-5020. Phone: (650) 725-2762. Fax: (650) 724-9945. E-mail: gwfang{at}stanford.edu.

Molecular and Cellular Biology, December 2005, p. 10516-10527, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10516-10527.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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