Constitutive turnover of cyclin E by Cul3 maintains quiescence

Justina D. McEvoy, Uta Kossatz, Nisar Malek, Jeffrey D. Singer

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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, bet 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.

Original languageEnglish (US)
Pages (from-to)3651-3666
Number of pages16
JournalMolecular and cellular biology
Volume27
Issue number10
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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