title: CyclinD-CDK4/6 complexes phosphorylate CDC25A and regulate its stability.
abstract: The phosphatase CDC25A is a key regulator of cell cycle progression by dephosphorylating and activating cyclin-CDK complexes. CDC25A is an unstable protein expressed from G1 until mitosis. CDC25A overexpression, which can be caused by stabilization of the protein, accelerates the G1/S and G2/M transitions, leading to genomic instability and promoting tumorigenesis. Thus, controlling CDC25A protein levels by regulating its stability is a critical mechanism for timing cell cycle progression and to maintain genomic integrity. Herein, we show that CDC25A is phosphorylated on Ser40 throughout the cell cycle and that this phosphorylation is established during the progression from G1 to S phase. We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. Thus our results identify cyclinD-CDK4/6 complexes as novel regulators of CDC25A stability during G1 phase, generating a negative feedback loop allowing control of the G1/S transition.
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037/Université Toulouse III Paul Sabatier, Toulouse, France.|Equipe labellisée Ligue Contre le Cancer, CNRS ERL5294, Toulouse, France.
authors.forename: C
authors.identifier: 0000-0002-8158-6765
authors.initials: C
authors.lastname: Dozier
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037/Université Toulouse III Paul Sabatier, Toulouse, France.|Equipe labellisée Ligue Contre le Cancer, CNRS ERL5294, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Mazzolini
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037/Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Cénac
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, CNRS UMR5089, Université Toulouse, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Froment
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, CNRS UMR5089, Université Toulouse, Toulouse, France.
authors.forename: O
authors.initials: O
authors.lastname: Burlet-Schiltz
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037/Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: A
authors.identifier: 0000-0002-9599-3943
authors.initials: A
authors.lastname: Besson
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037/Université Toulouse III Paul Sabatier, Toulouse, France.|Equipe labellisée Ligue Contre le Cancer, CNRS ERL5294, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Manenti
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology; D045744:Cell Line, Tumor; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D055550:Protein Stability; D016196:S Phase / Q000502:physiology; D014162:Transfection; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056741:Cyclin D; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases