title: The G2 checkpoint-a node-based molecular switch.
abstract: Tight regulation of the eukaryotic cell cycle is paramount to ensure genomic integrity throughout life. Cell cycle checkpoints are present in each phase of the cell cycle and prevent cell cycle progression when genomic integrity is compromised. The G2 checkpoint is an intricate signaling network that regulates the progression of G2 to mitosis (M). We propose here a node-based model of G2 checkpoint regulation, in which the action of the central CDK1-cyclin B1 node is determined by the concerted but opposing activities of the Wee1 and cell division control protein 25C (CDC25C) nodes. Phosphorylation of both Wee1 and CDC25C at specific sites determines their subcellular localization, driving them either toward activity within the nucleus or to the cytoplasm and subsequent ubiquitin-mediated proteasomal degradation. In turn, this subcellular balance of the Wee1 and CDC25C nodes is directed by the action of the PLK1 and CHK1 nodes via what we have termed the 'nuclear and cytoplasmic decision states' of Wee1 and CDC25C. The proposed node-based model provides an intelligible structure of the complex interactions that govern the decision to delay or continue G2/M progression. The model may also aid in predicting the effects of agents that target these G2 checkpoint nodes.
authors.affiliation: Division of Pharmacology/Mouse Cancer Clinic The Netherlands Cancer Institute Amsterdam The Netherlands.
authors.forename: Mark C
authors.initials: MC
authors.lastname: de Gooijer
authors.affiliation: Division of Pharmacology/Mouse Cancer Clinic The Netherlands Cancer Institute Amsterdam The Netherlands.
authors.forename: Arnout
authors.initials: A
authors.lastname: van den Top
authors.affiliation: Division of Pharmacology/Mouse Cancer Clinic The Netherlands Cancer Institute Amsterdam The Netherlands.
authors.forename: Irena
authors.initials: I
authors.lastname: Bockaj
authors.affiliation: Department of Pharmacy and Pharmacology The Netherlands Cancer Institute/Slotervaart Hospital Amsterdam The Netherlands; Division of Drug Toxicology Faculty of Pharmacy Utrecht University The Netherlands; Division of Biomedical Analysis Faculty of Science Utrecht University The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Neuro-oncology Research Group Departments of Neurosurgery and Pediatric Oncology/Hematology Cancer Center Amsterdam VU University Medical Center The Netherlands; Molecular Neurogenetics Unit Departments of Neurology and Radiology Massachusetts General Hospital Boston MA USA; Neuroscience Program Harvard Medical School Boston MA USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.affiliation: Division of Pharmacology/Mouse Cancer Clinic The Netherlands Cancer Institute Amsterdam The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
keywords: CDC25C; CHK1; G2 checkpoint; PLK1; Wee1; cell cycle