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Molecular and Cellular Biology, May 2007, p. 3651-3666, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.00720-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Constitutive Turnover of Cyclin E by Cul3 Maintains Quiescence{triangledown} ,{dagger}

Justina D. McEvoy,1 Uta Kossatz,2 Nisar Malek,2 and Jeffrey D. Singer1*

Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, Providence, Rhode Island 02903,1 Department of Gastroenterology, Hepatology and Endocrinology and Institute for Molecular Biology, Hannover Medical School, Hannover, Germany2

Received 26 April 2006/ Returned for modification 12 June 2006/ Accepted 22 February 2007

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.

* Corresponding author. Mailing address: Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, 70 Ship St., Box G-E337, Providence, RI 02903. Phone: (401) 863-9778. Fax: (410) 863-6087. E-mail: Jeffrey_Singer{at}brown.edu

{triangledown} Published ahead of print on 5 March 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2007, p. 3651-3666, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.00720-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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