Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCF Fbw7 Ubiquitin Ligase

作者：Deanna M. Koepp, Laura Schaefer, Xin Ye, Khandan Keyomarsi, Claire Chu, J. Wade Harper, Stephen J. Elledge · 发表于：Science · 年份：2001 · DOI：10.1126/science.1065203 · 被引用次数：764 · 研究领域：Ubiquitin and proteasome pathways、Cancer-related Molecular Pathways、Protein Degradation and Inhibitors

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.