title: Role for cyclin-dependent kinase 2 in mitosis exit.
abstract: Mitosis requires cyclin-dependent kinase (cdk) 1-cyclin B activity [1]. Exit from mitosis depends on the inactivation of the complex by the degradation of cyclin B [2]. Cdk2 is also active during mitosis [3, 4]. In Xenopus egg extracts, cdk2 is primarily in complex with cyclin E, which is stable [5]. At the end of mitosis, downregulation of cdk2-cyclin E activity is accompanied by inhibitory phosphorylation of cdk2 [6]. Here, we show that cdk2-cyclin E activity maintains cdk1-cyclin B during mitosis. At mitosis exit, cdk2 is inactivated prior to cdk1. The loss of cdk2 activity follows and depends upon an increase in protein kinase A (PKA) activity. Prematurely inactivating cdk2 advances the time of cyclin B degradation and cdk1 inactivation. Blocking PKA, instead, stabilizes cdk2 activity and inhibits cyclin B degradation and cdk1 inactivation. The stabilization of cdk1-cyclin B is also induced by a mutant cdk2-cyclin E complex that is resistant to inhibitory phosphorylation. P21-Cip1, which inhibits both wild-type and mutant cdk2-cyclin E, reverses mitotic arrest under either condition. Our findings indicate that the proteolysis-independent downregulation of cdk2 activity at the end of mitosis depends on PKA and is required to activate the proteolysis cascade that leads to mitosis exit.
authors.affiliation: Dipartimento di Medicina Sperimentale G. Salvatore, Medical School, University of Catanzaro, Via T. Campanella 5, Catanzaro, Italy.
authors.forename: V
authors.initials: V
authors.lastname: D'Angiolella
authors.forename: V
authors.initials: V
authors.lastname: Costanzo
authors.forename: M E
authors.initials: ME
authors.lastname: Gottesman
authors.forename: E V
authors.initials: EV
authors.lastname: Avvedimento
authors.forename: J
authors.initials: J
authors.lastname: Gautier
authors.forename: D
authors.initials: D
authors.lastname: Grieco
mesh_terms: D000818:Animals; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D014981:Xenopus; D029867:Xenopus Proteins
chemical_list: D029867:Xenopus Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495891:Cdk2 protein, Xenopus; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases