title: CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration.
abstract: The Cul4-Cdt2 (CRL4(Cdt2)) E3 ubiquitin ligase is a master regulator of cell-cycle progression and genome stability. Despite its central role in the degradation of many cell-cycle regulators, e.g., Cdt1, p21, and Pr-Set7/Set8, little is known about the regulation of its activity. We report that Cdt2 is autoubiquitylated by the CRL4A E3 ubiquitin ligase. Cdt2 is additionally polyubiquitylated and degraded by Cul1-FBXO11 (CRL1(FBXO11)). CRL1(FBXO11)-mediated degradation of Cdt2 stabilizes p21 and Set8, and this is important during the response to TGF-β, with the Set8 induction being important for turning off the activation of Smad2. The migration of epithelial cells is also stimulated by CRL1(FBXO11)-mediated downregulation of Cdt2 and the consequent stabilization of Set8. This is an interesting example of cross-regulation between specific Cullin 4 and Cullin 1 E3 ubiquitin ligases and highlights the role of ubiquitylation in regulating cellular responses to TGF-β and the migration of epithelial cells.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Abbas
authors.forename: Adam C
authors.initials: AC
authors.lastname: Mueller
authors.forename: Etsuko
authors.initials: E
authors.lastname: Shibata
authors.forename: Mignon
authors.initials: M
authors.lastname: Keaton
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002465:Cell Movement; D017124:Conserved Sequence; D044842:Cullin Proteins / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; C429530:DTL protein, human; D044783:F-Box Proteins; D007976:Leupeptins; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D003513:Cycloheximide; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde