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J. Biol. Chem., Vol. 283, Issue 45, 30796-30803, November 7, 2008

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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^*

Dragos Plesca, Suparna Mazumder, Vivian Gama^¶||, Shigemi Matsuyama^¶||**, and Alexandru Almasan¹

From the Department of Cancer Biology, Lerner Research Institute and the Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio 44195, the School of Biomedical Sciences, Kent State University, Kent, Ohio 44240, the Departments of ^¶Medicine (Division of Hematology-Oncology) and ^||Pharmacology, Case Western Reserve University and the ^**Division of General Medical Science-Oncology, Case Comprehensive Cancer Center, Cleveland, Ohio 44106

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.

Received for publication, June 18, 2008 , and in revised form, September 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA-81504. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. 9500 Euclid Ave., NB4-, Cleveland, OH 44195. Fax: 216-445-6269; E-mail: almasaa{at}ccf.org.

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