title: APC/C and SCF(cyclin F) Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry.
abstract: The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase and core component of the cell-cycle oscillator. During G1 phase, APC/C binds to its substrate receptor Cdh1 and APC/C(Cdh1) plays an important role in restricting S-phase entry and maintaining genome integrity. We describe a reciprocal feedback circuit between APC/C and a second ubiquitin ligase, the SCF (Skp1-Cul1-F box). We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. These data indicate that the coordinated, temporal ordering of cyclin F and Cdh1 degradation, organized in a double-negative feedback loop, represents a fundamental aspect of cell-cycle control. This mutual antagonism could be a feature of other oscillating systems.
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Choudhury
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bonacci
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Arceci
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.
authors.forename: Debojyoti
authors.initials: D
authors.lastname: Lahiri
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Mills
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kernan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Branigan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burke
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: emanuele@email.unc.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Emanuele
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016196:S Phase / Q000502:physiology*
chemical_list: C503669:CCNF protein, human; D016213:Cyclins; D064173:Anaphase-Promoting Complex-Cyclosome