Constitutive turnover of cyclin E by Cul3 maintains quiescence.
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.
McEvoy
Justina D
JD
Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, 70 Ship Street, Box G-E337, Providence, RI 02903, USA.
Kossatz
Uta
U
Malek
Nisar
N
Singer
Jeffrey D
JD
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
D018797:Cell Cycle Proteins; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D019927:Cyclin E