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Molecular and Cellular Biology, June 2001, p. 3692-3703, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3692-3703.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

A Conserved Cyclin-Binding Domain Determines Functional Interplay between Anaphase-Promoting Complex-Cdh1 and Cyclin A-Cdk2 during Cell Cycle Progression

Claus Storgaard Sørensen,1 Claudia Lukas,1 Edgar R. Kramer,2 Jan-Michael Peters,2 Jiri Bartek,1 and Jiri Lukas1,*

Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen Ø, Denmark,1 and Research Institute of Molecular Pathology, A-1030 Vienna, Austria2

Received 11 December 2000/Returned for modification 30 January 2001/Accepted 5 March 2001

Periodic activity of the anaphase-promoting complex (APC) ubiquitin ligase determines progression through multiple cell cycle transitions by targeting cell cycle regulators for destruction. At the G1/S transition, phosphorylation-dependent dissociation of the Cdh1-activating subunit inhibits the APC, allowing stabilization of proteins required for subsequent cell cycle progression. Cyclin-dependent kinases (CDKs) that initiate and maintain Cdh1 phosphorylation have been identified. However, the issue of which cyclin-CDK complexes are involved has been a matter of debate, and the mechanism of how cyclin-CDKs interact with APC subunits remains unresolved. Here we substantiate the evidence that mammalian cyclin A-Cdk2 prevents unscheduled APC reactivation during S phase by demonstrating its periodic interaction with Cdh1 at the level of endogenous proteins. Moreover, we identified a conserved cyclin-binding motif within the Cdh1 WD-40 domain and show that its disruption abolished the Cdh1-cyclin A-Cdk2 interaction, eliminated Cdh1-associated histone H1 kinase activity, and impaired Cdh1 phosphorylation by cyclin A-Cdk2 in vitro and in vivo. Overexpression of cyclin binding-deficient Cdh1 stabilized the APC-Cdh1 interaction and induced prolonged cell cycle arrest at the G1/S transition. Conversely, cyclin binding-deficient Cdh1 lost its capability to support APC-dependent proteolysis of cyclin A but not that of other APC substrates such as cyclin B and securin Pds1. Collectively, these data provide a mechanistic explanation for the mutual functional interplay between cyclin A-Cdk2 and APC-Cdh1 and the first evidence that Cdh1 may activate the APC by binding specific substrates.

* Corresponding author. Mailing address: Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark. Phone: 45 35 25 73 10. Fax: 45 35 25 77 21. E-mail: lukas{at}biobase.dk.

Molecular and Cellular Biology, June 2001, p. 3692-3703, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3692-3703.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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