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

Tarek Abbas1, Adam C Mueller, Etsuko Shibata

  • 1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.

Molecular Cell
|March 13, 2013
PubMed

Insights

The Cul4-Cdt2 E3 ubiquitin ligase

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Biology

Background:

  • The Cul4-Cdt2 (CRL4(Cdt2)) E3 ubiquitin ligase regulates cell-cycle progression and genome stability.
  • CRL4(Cdt2) degrades key regulators like Cdt1, p21, and Pr-Set7/Set8.
  • Regulation of CRL4(Cdt2) activity remains largely uncharacterized.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling the activity of the CRL4(Cdt2) E3 ubiquitin ligase.
  • To elucidate the role of CRL1(FBXO11) in regulating Cdt2 and its downstream targets.
  • To understand the impact of this cross-regulation on cellular responses like TGF-β signaling and epithelial cell migration.

Main Methods:

  • Investigating Cdt2 autoubiquitylation by CRL4(Cdt2).
  • Analyzing polyubiquitylation and degradation of Cdt2 by Cul1-FBXO11 (CRL1(FBXO11)).
  • Assessing the impact of CRL1(FBXO11)-mediated Cdt2 degradation on p21, Set8, Smad2 activation, and epithelial cell migration.

Main Results:

  • Cdt2 undergoes autoubiquitylation mediated by the CRL4A E3 ubiquitin ligase.
  • Cdt2 is polyubiquitylated and degraded by the Cul1-FBXO11 (CRL1(FBXO11)) E3 ubiquitin ligase.
  • CRL1(FBXO11)-mediated degradation of Cdt2 stabilizes p21 and Set8, influencing TGF-β response and Smad2 signaling.
  • Downregulation of Cdt2 by CRL1(FBXO11) promotes epithelial cell migration via Set8 stabilization.

Conclusions:

  • Cdt2 activity is regulated by both CRL4(Cdt2) and CRL1(FBXO11) E3 ubiquitin ligases.
  • Cross-regulation between CRL4 and CRL1 E3 ligases impacts fundamental cellular processes.
  • Ubiquitylation plays a critical role in mediating cellular responses to TGF-β and regulating epithelial cell migration.

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