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A C-terminal fragment of cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron

Domenii publicaţii > Biologie + Tipuri publicaţii > Articol în revistã ştiinţificã

Autori: Plesca D, Mazumder S, Gama V, Matsuyama S, Almasan A.

Editorial: J Biol Chemistry, 283, p.30796-803, 2008.


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 26S 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 SCFFbw7 pathway, Ku70 binding that facilitates Hdm2 recruitment may be also 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 various hematopoietic malignancies where p18-Cyclin E is generated.

Cuvinte cheie: Fbw7, cyclin, proteolysis, Ku70