title: 14-3-3 proteins play a role in the cell cycle by shielding cdt2 from ubiquitin-mediated degradation.
abstract: Cdt2 is the substrate recognition adaptor of CRL4(Cdt2) E3 ubiquitin ligase complex and plays a pivotal role in the cell cycle by mediating the proteasomal degradation of Cdt1 (DNA replication licensing factor), p21 (cyclin-dependent kinase [CDK] inhibitor), and Set8 (histone methyltransferase) in S phase. Cdt2 itself is attenuated by SCF(FbxO11)-mediated proteasomal degradation. Here, we report that 14-3-3 adaptor proteins interact with Cdt2 phosphorylated at threonine 464 (T464) and shield it from polyubiquitination and consequent proteasomal degradation. Depletion of 14-3-3 proteins promotes the interaction of FbxO11 with Cdt2. Overexpressing 14-3-3 proteins shields Cdt2 that has a phospho-mimicking mutation (T464D [change of T to D at position 464]) but not Cdt2(T464A) from ubiquitination. Furthermore, the delay of the cell cycle in the G2/M phase and decrease in cell proliferation seen upon depletion of 14-3-3γ is partly due to the accumulation of the CRL4(Cdt2) substrate, Set8 methyltransferase. Therefore, the stabilization of Cdt2 is an important function of 14-3-3 proteins in cell cycle progression.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dar
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Shibata
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA ad8q@virginia.edu.
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002453:Cell Cycle; D044783:F-Box Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048948:14-3-3 Proteins; C429530:DTL protein, human; D044783:F-Box Proteins; D009687:Nuclear Proteins; D013912:Threonine; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex