CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration

Mol Cell. 2013 Mar 28;49(6):1147-58. doi: 10.1016/j.molcel.2013.02.003. Epub 2013 Mar 7.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Cell Movement*
  • Conserved Sequence
  • Cullin Proteins / physiology
  • Cycloheximide / pharmacology
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • F-Box Proteins / physiology*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Leupeptins / pharmacology
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Binding
  • Protein Synthesis Inhibitors / pharmacology
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Protein-Arginine N-Methyltransferases / physiology*
  • Proteolysis
  • RNA, Small Interfering / genetics
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / physiology
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*


  • CUL4A protein, human
  • Cullin Proteins
  • DTL protein, human
  • F-Box Proteins
  • Leupeptins
  • Nuclear Proteins
  • Proteasome Inhibitors
  • Protein Synthesis Inhibitors
  • RNA, Small Interfering
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Cycloheximide
  • FBXO11 protein, human
  • Protein-Arginine N-Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • KMT5A protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde