title: Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules.
abstract: Cdc6 is the bifunctional AAA+ ATPase that assembles prereplicative complexes on origins of replication and activates p21(CIP1)- or p27(KIP1)-bound Cdk2. During the G(1)-S transition, the Cdc6 gene essential for chromosomal replication is activated by the E2F transcriptional factor. Paradoxically, Apaf-1 encoding the central component of the apoptosome is also activated at the same time and by E2F. Consequently, genes for antipodal life and death are regulated in the same manner by the same transcriptional factor. Here we report a striking solution to this paradox. Besides performing prereplicative complex assembly and Cdk2 activation, Cdc6 obstructed apoptosome assembly by forming stable complexes very likely with a monomer of cytochrome c-activated Apaf-1 molecules. This function depended on its own ATPase domain but not on the cyclin-binding motif. In proliferating rodent fibroblasts, Cdc6 continued to block apoptosome assembly induced by a non-cytochrome c or some other mechanism, suppressing seemingly unintended apoptosis when promoting cell proliferation. Thus, Cdc6 is an AAA+ ATPase with three functions, all working for life.
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Niimi
authors.forename: Shiho
authors.initials: S
authors.lastname: Arakawa-Takeuchi
authors.forename: Baasanjav
authors.initials: B
authors.lastname: Uranbileg
authors.forename: Jun-ha
authors.initials: JH
authors.lastname: Park
authors.forename: Shigeki
authors.initials: S
authors.lastname: Jinno
authors.forename: Hiroto
authors.initials: H
authors.lastname: Okayama
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D004789:Enzyme Activation; D006868:Hydrolysis; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: C506593:Apaf1 protein, mouse; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; C502132:CDC6 protein, mouse; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D000255:Adenosine Triphosphate; D053453:Caspase 9