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.
Plesca
Dragos
D
Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
Mazumder
Suparna
S
Gama
Vivian
V
Matsuyama
Shigemi
S
Almasan
Alexandru
A
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
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
Proc Natl Acad Sci U S A. 2005 May 3;102(18):6279-84
15845771
Nat Rev Mol Cell Biol. 2003 Nov;4(11):855-64
14625536
Mol Cell Biol. 2007 May;27(10):3651-66
17339333
Mol Cell Biol. 1995 Jul;15(7):3463-9
7791752
Mol Cancer Res. 2006 Dec;4(12):935-43
17189384
Clin Cancer Res. 2008 Mar 15;14(6):1649-57
18347166
Science. 1996 Dec 6;274(5293):1664-72
8939848
Cell Growth Differ. 1999 Jul;10(7):491-502
10437917
Genes Dev. 1999 Sep 15;13(18):2375-87
10500095
Mol Cell. 2008 Feb 29;29(4):413-5
18313379
Genes Dev. 2008 Jun 15;22(12):1677-89
18559482
Mol Cell. 2007 Apr 13;26(1):131-43
17434132
J Biol Chem. 2002 Oct 18;277(42):39909-18
12149264
Mol Cell. 2006 Jul 7;23(1):37-48
16818231
Cancer Res. 2002 Aug 15;62(16):4535-9
12183400
Mol Cell. 2003 Aug;12(2):381-92
14536078
Nat Rev Cancer. 2006 May;6(5):369-81
16633365
Cell. 2004 Jan 23;116(2):221-34
14744433
Nature. 2001 Sep 20;413(6853):316-22
11565034
Mol Cell Biol. 2007 May;27(9):3511-20
17325036
J Biol Chem. 2004 Nov 26;279(48):50110-9
15364936
Mol Cancer Ther. 2005 Apr;4(4):686-92
15827343
Mol Cell Biol. 1995 May;15(5):2612-24
7739542
Genes Dev. 1996 Aug 15;10(16):1979-90
8769642
Nature. 2001 Nov 29;414(6863):514-21
11734846
Nat Rev Cancer. 2008 Feb;8(2):83-93
18094723
Cancer Cell. 2002 Feb;1(1):19-30
12086884
Genes Dev. 2003 Dec 15;17(24):3062-74
14681206
Nature. 1997 May 15;387(6630):299-303
9153396
J Cell Biol. 1995 Aug;130(4):755-69
7642695
Nature. 2001 Sep 20;413(6853):311-6
11565033
Mol Cell Biol. 2002 Apr;22(7):2398-409
11884622
Oncogene. 2000 Jun 1;19(24):2828-35
10851086
J Cell Biol. 2008 Jun 16;181(6):913-20
18559665
Science. 2001 Oct 5;294(5540):173-7
11533444
Nature. 1997 May 15;387(6630):296-9
9153395
Nat Rev Mol Cell Biol. 2008 Mar;9(3):231-41
18073771
Cell Cycle. 2007 Jun 15;6(12):1437-42
17581275
Annu Rev Biochem. 1998;67:425-79
9759494
EMBO J. 1996 Aug 15;15(16):4182-93
8861947
Nat Rev Cancer. 2004 May;4(5):349-60
15122206
Cancer Res. 2005 Dec 15;65(24):11510-9
16357160