title: A C-terminal fragment of Cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
authors.forename: Dragos
authors.initials: D
authors.lastname: Plesca
authors.forename: Suparna
authors.initials: S
authors.lastname: Mazumder
authors.forename: Vivian
authors.initials: V
authors.lastname: Gama
authors.forename: Shigemi
authors.initials: S
authors.lastname: Matsuyama
authors.forename: Alexandru
authors.initials: A
authors.lastname: Almasan
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism*; D019927:Cyclin E; D004268:DNA-Binding Proteins / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D006207:Half-Life; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D000072200:Ku Autoantigen; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; C494826:BAX protein, human; D001897:Boronic Acids; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D007527:Isoenzymes; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D044786:S-Phase Kinase-Associated Proteins; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen
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