Constitutive turnover of cyclin E by Cul3 maintains quiescence

Mol Cell Biol. 2007 May;27(10):3651-66. doi: 10.1128/MCB.00720-06. Epub 2007 Mar 5.


Two distinct pathways for the degradation of mammalian cyclin E have previously been described. One pathway is induced by cyclin E phosphorylation and is dependent on the Cul1/Fbw7-based E3 ligase. The other pathway is dependent on the Cul3-based E3 ligase, but the mechanistic details of this pathway have yet to be elucidated. To establish the role of Cul3 in the degradation of cyclin E in vivo, we created a conditional knockout of the Cul3 gene in mice. Interestingly, the biallelic loss of Cul3 in primary fibroblasts derived from these mice results in increased cyclin E expression and reduced cell viability, paralleling the loss of Cul3 protein expression. Cell cycle analysis of viable, Cul3 hypomorphic cells shows that decreasing the levels of Cul3 increases both cyclin E protein levels and the number of cells in S phase. In order to examine the role of Cul3 in an in vivo setting, we determined the effect of deletion of the Cul3 gene in liver. This gene deletion resulted in a dramatic increase in cyclin E levels as well as an increase in cell size and ploidy. The results we report here show that the constitutive degradation pathway for cyclin E that is regulated by the Cul3-based E3 ligase is essential to maintain quiescence in mammalian cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Survival
  • Cells, Cultured
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Cyclin E / genetics
  • Cyclin E / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Hepatocytes / cytology
  • Hepatocytes / physiology
  • Mice
  • Mice, Knockout
  • Phenotype


  • Cell Cycle Proteins
  • Cul3 protein, mouse
  • Cullin Proteins
  • Cyclin E