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Science 294 (5540): 173-177

Copyright © 2001 by the American Association for the Advancement of Science

Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCFFbw7 Ubiquitin Ligase

Deanna M. Koepp,123 Laura K. Schaefer,123* Xin Ye,1* Khandan Keyomarsi,4 Claire Chu,1 J. Wade Harper,1 Stephen J. Elledge123dagger

Cyclin E binds and activates the cyclin-dependent kinase Cdk2 and catalyzes the transition from the G1 phase to the S phase of the cell cycle. The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro. Depletion of Fbw7 leads to accumulation and stabilization of cyclin E in vivo in human and Drosophila melanogaster cells. Multiple F-box proteins contribute to cyclin E stability in yeast, suggesting an overlap in SCF E3 ligase specificity that allows combinatorial control of cyclin E degradation.

1 Department of Biochemistry and Molecular Biology,
2 Department of Molecular and Human Genetics,
3 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.
4 Department of Experimental Radiation Oncology, M. D. Anderson Cancer Center, Houston, TX 77030, USA
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: selledge{at}bcm.tmc.edu

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FBW2 Targets GCMa to the Ubiquitin-Proteasome Degradation System.
C.-S. Yang, C. Yu, H.-C. Chuang, C.-W. Chang, G.-D. Chang, T.-P. Yao, and H. Chen (2005)
J. Biol. Chem. 280, 10083-10090
   Abstract »    Full Text »    PDF »
The SV40 Large T Antigen Contains a Decoy Phosphodegron That Mediates Its Interactions with Fbw7/hCdc4.
M. Welcker and B. E. Clurman (2005)
J. Biol. Chem. 280, 7654-7658
   Abstract »    Full Text »    PDF »
c-Jun N-Terminal Kinase Contributes to Aberrant Retinoid Signaling in Lung Cancer Cells by Phosphorylating and Inducing Proteasomal Degradation of Retinoic Acid Receptor {alpha}.
H. Srinivas, D. M. Juroske, S. Kalyankrishna, D. D. Cody, R. E. Price, X.-C. Xu, R. Narayanan, N. L. Weigel, and J. M. Kurie (2005)
Mol. Cell. Biol. 25, 1054-1069
   Abstract »    Full Text »    PDF »
Filtering of Ineffective siRNAs and Improved siRNA Design Tool.
S. M. Yiu, P. W. H. Wong, T.W. Lam, Y.C. Mui, H. F. Kung, M. Lin, and Y. T. Cheung (2005)
Bioinformatics 21, 144-151
   Abstract »    Full Text »    PDF »
Molecular and Biochemical Characterization of the Skp2-Cks1 Binding Interface.
W. Wang, D. Ungermannova, L. Chen, and X. Liu (2004)
J. Biol. Chem. 279, 51362-51369
   Abstract »    Full Text »    PDF »
Recognition of Phosphodegron Motifs in Human Cyclin E by the SCFFbw7 Ubiquitin Ligase.
X. Ye, G. Nalepa, M. Welcker, B. M. Kessler, E. Spooner, J. Qin, S. J. Elledge, B. E. Clurman, and J. W. Harper (2004)
J. Biol. Chem. 279, 50110-50119
   Abstract »    Full Text »    PDF »
Systematic analysis and nomenclature of mammalian F-box proteins.
J. Jin, T. Cardozo, R. C. Lovering, S. J. Elledge, M. Pagano, and J. W. Harper (2004)
Genes & Dev. 18, 2573-2580
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Uncovering Novel Cell Cycle Players Through the Inactivation of Securin in Budding Yeast.
S. Sarin, K. E. Ross, L. Boucher, Y. Green, M. Tyers, and O. Cohen-Fix (2004)
Genetics 168, 1763-1771
   Abstract »    Full Text »    PDF »

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