The onconeural antigen cdr2 is a novel APC/C target that acts in mitosis to regulate c-myc target genes in mammalian tumor cells.
Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. Loss of cdr2 leads to functional consequences for dividing cells, as they show aberrant mitotic spindle formation and impaired proliferation. Conversely, cdr2 overexpression is able to drive cell proliferation in tumors. Together, these data indicate that the onconeural antigen cdr2 acts during mitosis in cycling cells, at least in part through interactions with c-myc, to regulate a cascade of actions that may present new targeting opportunities in gynecologic cancer.
O'Donovan
Kevin J
KJ
Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute and The Rockefeller University, New York, New York, United States of America.
Diedler
Jennifer
J
Couture
Graeme C
GC
Fak
John J
JJ
Darnell
Robert B
RB
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination
D000951:Antigens, Neoplasm; C095184:CDR2 protein, human; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D046988:Proteasome Endopeptidase Complex
Cancer Res. 2000 Apr 15;60(8):2136-9
10786675
Genomics. 1997 Oct 15;45(2):313-9
9344654
Cell. 1989 Sep 8;58(5):833-46
2570636
J Cell Sci. 1992 Jul;102 ( Pt 3):401-16
1506423
J Cell Biochem. 2008 Sep 1;105(1):1-8
18459122
Exp Cell Res. 1962 Mar;26:260-8
14488623
Genes Dev. 2008 Aug 15;22(16):2189-203
18662975
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19073-8
18045792
Mol Biol Cell. 1996 May;7(5):791-801
8744951
Mol Cell Biol. 1985 Nov;5(11):3157-67
2427926
Oncogene. 2009 Sep 17;28(37):3274-85
19581925
Mol Cell Biol. 1999 Jan;19(1):1-11
9858526
Genes Dev. 2000 Mar 15;14(6):655-65
10733526
Ann Neurol. 1990 Nov;28(5):692-8
2260856
Genes Dev. 2003 May 1;17(9):1115-29
12695333
Neurology. 1992 Oct;42(10):1931-7
1407575
Curr Opin Immunol. 2004 Oct;16(5):616-22
15342008
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3513-8
19221030
J Neurochem. 1998 Mar;70(3):1241-8
9489747
Genes Dev. 1999 Aug 15;13(16):2087-97
10465786
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16940-5
17939994
Mol Cell Biol. 1983 Apr;3(4):539-50
6406835
Oncogene. 2000 Dec 7;19(52):5964-72
11146547
Philos Trans R Soc Lond B Biol Sci. 2005 Mar 29;360(1455):507-14
15897176
Science. 1998 Aug 28;281(5381):1317-22
9721090
PLoS One. 2009;4(5):e5442
19421315
EMBO J. 2009 Sep 2;28(17):2511-31
19629042
J Cell Biol. 2009 Jul 13;186(1):27-40
19596847
Nat Genet. 2001 Jan;27(1):48-54
11137997
Semin Oncol. 2006 Jun;33(3):270-98
16769417
Genome Biol. 2003;4(10):R69
14519204
FEBS Lett. 2007 Jun 19;581(15):2862-9
17521635
Nucleic Acids Res. 2009 Jan;37(Database issue):D205-10
18984618
Mol Cell Biol. 1999 Jul;19(7):4711-8
10373520
Mol Cell Biol. 2002 Aug;22(16):5946-61
12138204
Annu Rev Cell Dev Biol. 2008;24:475-99
18598214
Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3451-4
2014264
Cell Growth Differ. 1997 Oct;8(10):1039-48
9342182
Mol Biol Cell. 2002 Jun;13(6):1977-2000
12058064
Cell. 1994 Sep 9;78(5):787-98
8087846
Cell. 2009 Jan 23;136(2):322-36
19167333
Pharmacol Ther. 1991;49(1-2):133-52
1852786
Proc Natl Acad Sci U S A. 1987 Jul;84(13):4552-6
3474619
J Neurosci. 1997 Feb 15;17(4):1406-15
9006982
Science. 1996 Nov 15;274(5290):1201-4
8895471
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Genes Dev. 2001 Sep 15;15(18):2381-95
11562348
Am J Pathol. 2007 May;170(5):1793-805
17456782
Neuron. 2001 Aug 30;31(4):557-68
11545715
PLoS Biol. 2008 Nov 11;6(11):e272
18998770
Genes Dev. 1997 Aug 15;11(16):2101-11
9284049
PLoS One. 2008 Mar 12;3(3):e1798
18335064
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11317-22
10500174
Science. 2004 Feb 13;303(5660):1026-30
14716021
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7
18669648
J Biol Chem. 1997 May 23;272(21):13766-71
9153231
Nat Med. 1998 Nov;4(11):1321-4
9809559
Mol Cell Biol. 1993 Jul;13(7):4125-36
8321217
Neuron. 1993 Jan;10(1):1-9
8427698
Exp Cell Res. 2003 Feb 1;283(1):17-21
12565816