title: Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle.
abstract: Whereas many components regulating the progression from S phase through G2 phase into mitosis have been identified, the mechanism by which these components control this critical cell cycle progression is still not fully elucidated. Cyclin A/Cdk2 has been shown to regulate the timing of Cyclin B/Cdk1 activation and progression into mitosis although the mechanism by which this occurs is only poorly understood. Here we show that depletion of Cyclin A or inhibition of Cdk2 during late S/early G2 phase maintains the G2 phase arrest by reducing Cdh1 transcript and protein levels, thereby stabilizing Claspin and maintaining elevated levels of activated Chk1 which contributes to the G2 phase observed. Interestingly, the Cyclin A/Cdk2 regulated APC/C(Cdh1) activity is selective for only a subset of Cdh1 targets including Claspin. Thus, a normal role for Cyclin A/Cdk2 during early G2 phase is to increase the level of Cdh1 which destabilises Claspin which in turn down regulates Chk1 activation to allow progression into mitosis. This mechanism links S phase exit with G2 phase transit into mitosis, provides a novel insight into the roles of Cyclin A/Cdk2 in G2 phase progression, and identifies a novel role for APC/C(Cdh1) in late S/G2 phase cell cycle progression.
authors.affiliation: a The University of Queensland Diamantina Institute; Translational Research Institute ; Brisbane , Queensland , Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Oakes
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.forename: Brittney
authors.initials: B
authors.lastname: Harrington
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Heather
authors.initials: H
authors.lastname: Beamish
authors.forename: Kee Ming
authors.initials: KM
authors.lastname: Chia
authors.forename: Alex
authors.initials: A
authors.lastname: Pinder
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Goto
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
authors.forename: Sandra
authors.initials: S
authors.lastname: Pavey
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016196:S Phase / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C513384:CDH1 protein, human; C488158:CLSPN protein, human; D015820:Cadherins; D019925:Cyclin A; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: APC/C, anaphase promoting complex/cyclosome; Cdh1; Cdk, cyclin dependent kinase; Cdk2; Cdki, cyclin dependent kinase inhibitor; Chk1; Chk1, checkpoint kinase 1; Claspin; Cyclin A; G2 phase