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Molecular and Cellular Biology, August 2001, p. 5190-5199, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5190-5199.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of an Overlapping Binding Domain on Cdc20 for Mad2 and Anaphase-Promoting Complex: Model for Spindle Checkpoint Regulation

Yongke Zhang and Emma Lees*

Department of Oncology, DNAX Research Institute, Palo Alto, California 94304-1104

Received 8 December 2000/Returned for modification 29 January 2001/Accepted 24 April 2001

Activation of the anaphase-promoting complex (APC) is required for anaphase initiation and for exit from mitosis in mammalian cells. Cdc20, which specifically recognizes APC substrates involved in the metaphase-to-anaphase transition, plays a pivotal role in APC activation through direct interaction with the APC. The activation of the APC by Cdc20 is prevented by the interaction of Cdc20 with Mad2 when the spindle checkpoint is activated. Using deletion mutagenesis and peptide mapping, we have identified the sequences in Cdc20 that target it to Mad2 and the APC, respectively. These sequences are distinct but overlapping, providing a possible structural explanation for the internal modulation of the APC-Cdc20 complex by Mad2. In the course of these studies, a truncation mutant of Cdc20 (1-153) that constitutively binds Mad2 but fails to bind the APC was identified. Overexpression of this mutant induces the formation of multinucleated cells and increases their susceptibility to undergoing apoptosis when treated with microtubule-inhibiting drugs. Our experiments demonstrate that disruption of the Mad2-Cdc20 interaction perturbs the mitotic checkpoint, leading to premature activation of the APC, sensitizing the cells to the cytotoxic effects of microtubule-inhibiting drugs.

* Corresponding author. Mailing address: DNAX Research Institute, 901 California Ave., Palo Alto, CA 94304. Phone: (650) 496-1257. Fax: (650) 496-1200. E-mail: emma.lees{at}dnax.org.

Molecular and Cellular Biology, August 2001, p. 5190-5199, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5190-5199.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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