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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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