title: Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry.
abstract: Proliferating cells must cross a point of no return before they replicate their DNA and divide. This commitment decision plays a fundamental role in cancer and degenerative diseases and has been proposed to be mediated by phosphorylation of retinoblastoma (Rb) protein. Here, we show that inactivation of the anaphase-promoting complex/cyclosome (APC(Cdh1)) has the necessary characteristics to be the point of no return for cell-cycle entry. Our study shows that APC(Cdh1) inactivation is a rapid, bistable switch initiated shortly before the start of DNA replication by cyclin E/Cdk2 and made irreversible by Emi1. Exposure to stress between Rb phosphorylation and APC(Cdh1) inactivation, but not after APC(Cdh1) inactivation, reverted cells to a mitogen-sensitive quiescent state, from which they can later re-enter the cell cycle. Thus, APC(Cdh1) inactivation is the commitment point when cells lose the ability to return to quiescence and decide to progress through the cell cycle.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: scappell@stanford.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Cappell
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Chung
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Jaimovich
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sabrina L
authors.initials: SL
authors.lastname: Spencer
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: tobias1@stanford.edu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D064200:Cdh1 Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000378:metabolism; D006801:Humans; D008934:Mitogens / Q000633:toxicity; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C498960:FBXO5 protein, human; C577584:FZR1 protein, human; D008934:Mitogens; D016160:Retinoblastoma Protein; D064173:Anaphase-Promoting Complex-Cyclosome