A C-terminal fragment of Cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron.
We have previously shown that caspase-mediated cleavage of Cyclin E generates p18-Cyclin E in hematopoietic tumor cells. Its expression can induce apoptosis or sensitize to apoptotic stimuli in many cell types. However, p18-cyclin E has a much shorter half-life than Cyclin E, being more effectively ubiquitinated and degraded by the ... 26 S proteasome. A two-step process has emerged that regulates accelerated degradation of Cyclin E, with a caspase-mediated cleavage followed by enhanced proteasome-mediated degradation. We show that recognition of p18-Cyclin E by the Skp1-Cul1-Fbw7 (SCF) complex and its interaction with the Fbw7 protein isoforms can take place independently of phosphorylation of p18-Cyclin E at a C-terminal phosphodegron. In addition to the SCF(Fbw7) pathway, Ku70 binding that facilitates Hdm2 recruitment may also be implicated in p18-Cyclin E ubiquitination. Blocking p18-Cyclin E degradation with proteasome inhibitors increases levels of p18-Cyclin E and enhances its association with Ku70, thus leading to Bax release, its activation, and apoptosis. Moreover, cells expressing p18-Cyclin E are more sensitive to treatment with proteasome inhibitors, such as Bortezomib. By preventing its proteasomal degradation, p18-Cyclin E, but not Cyclin E, may become an effective therapeutic target for Bortezomib and apoptotic effectors in hematopoietic malignancies.
Mesh Terms:
Antigens, Nuclear, Apoptosis, Boronic Acids, Caspases, Cell Cycle Proteins, Cell Line, Tumor, Cullin Proteins, Cyclin E, DNA-Binding Proteins, F-Box Proteins, Half-Life, Hematologic Neoplasms, Humans, Isoenzymes, Neoplasm Proteins, Phosphorylation, Protease Inhibitors, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Pyrazines, S-Phase Kinase-Associated Proteins, Ubiquitin-Protein Ligases, Ubiquitination, bcl-2-Associated X Protein
Antigens, Nuclear, Apoptosis, Boronic Acids, Caspases, Cell Cycle Proteins, Cell Line, Tumor, Cullin Proteins, Cyclin E, DNA-Binding Proteins, F-Box Proteins, Half-Life, Hematologic Neoplasms, Humans, Isoenzymes, Neoplasm Proteins, Phosphorylation, Protease Inhibitors, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Pyrazines, S-Phase Kinase-Associated Proteins, Ubiquitin-Protein Ligases, Ubiquitination, bcl-2-Associated X Protein
J. Biol. Chem.
Date: Nov. 07, 2008
PubMed ID: 18784078
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