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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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E. S. Yeh, B. O. Lew, and A. R. Means (2006)
J. Biol. Chem. 281, 241-251
   Abstract »    Full Text »    PDF »
CDC4 Mutations Occur in a Subset of Colorectal Cancers but Are Not Predicted to Cause Loss of Function and Are Not Associated with Chromosomal Instability.
Z. Kemp, A. Rowan, W. Chambers, N. Wortham, S. Halford, O. Sieber, N. Mortensen, A. von Herbay, T. Gunther, M. Ilyas, et al. (2005)
Cancer Res. 65, 11361-11366
   Abstract »    Full Text »    PDF »
The Emerging Role of the COP9 Signalosome in Cancer.
K. S. Richardson and W. Zundel (2005)
Mol. Cancer Res. 3, 645-653
   Abstract »    Full Text »    PDF »
A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3{beta}/FBW7 loss of function.
S. Rottmann, Y. Wang, M. Nasoff, Q. L. Deveraux, and K. C. Quon (2005)
PNAS 102, 15195-15200
   Abstract »    Full Text »    PDF »
Ubiquitination of p27Kip1 Requires Physical Interaction with Cyclin E and Probable Phosphate Recognition by SKP2.
D. Ungermannova, Y. Gao, and X. Liu (2005)
J. Biol. Chem. 280, 30301-30309
   Abstract »    Full Text »    PDF »
Control of Genomic Instability and Epithelial Tumor Development by the p53-Fbxw7/Cdc4 Pathway.
J. Perez-Losada, J.-H. Mao, and A. Balmain (2005)
Cancer Res. 65, 6488-6492
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome Pathway and Its Role in Cancer.
A. Mani and E. P. Gelmann (2005)
J. Clin. Oncol. 23, 4776-4789
   Abstract »    Full Text »    PDF »
Ras activity regulates cyclin E degradation by the Fbw7 pathway.
A. C. Minella, M. Welcker, and B. E. Clurman (2005)
PNAS 102, 9649-9654
   Abstract »    Full Text »    PDF »

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