Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice.
Genetic instability, which leads to an accumulation of various genetic abnormalities, has been considered an essential component of the human neoplasic transformation process. However, the molecular basis of genomic instability during tumorigenesis remains incompletely understood. Growing evidence indicates that checkpoint with forkhead and ring finger domains (CHFR), a recently identified mitotic checkpoint protein, plays an important role in maintaining chromosome integrity and functions as a tumor suppressor. In this study, we used high-throughput technology to conduct gene expression profiling of human colon cancers and found that loss of CHFR expression frequently occurred in colon cancers with high microsatellite instability (MSI-H). Downregulation of CHFR expression was closely associated with overexpression of Aurora A, an important mitotic kinase. Mice with deficiencies in both Chfr and Mlh1 (the gene that encodes the DNA mismatch-repair protein Mlh1) displayed dramatically higher incidence of spontaneous tumors relative to mice deficient for only one of these genes. These results suggest that defects in both Chfr and Mlh1 synergistically increase predisposition to tumorigenesis.
Fu
Zheng
Z
Department of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. fu.zheng@mayo.edu
Regan
Kevin
K
Zhang
Lizhi
L
Muders
Michael H
MH
Thibodeau
Stephen N
SN
French
Amy
A
Wu
Yanhong
Y
Kaufmann
Scott H
SH
Lingle
Wilma L
WL
Chen
Junjie
J
Tindall
Donald J
DJ
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000368:Aged; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D018816:Genes, cdc; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017931:DNA Primers; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000070957:MutL Protein Homolog 1
Oncogene. 2002 Apr 4;21(15):2328-33
11948416
Jpn J Cancer Res. 2000 May;91(5):504-9
10835495
Cancer Res. 2007 Jul 1;67(13):6064-74
17596595
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870-5
9618505
Cancer Res. 2005 Oct 1;65(19):8662-70
16204034
Cancer Res. 2003 Dec 15;63(24):8606-13
14695171
Hum Mutat. 1997;10(2):89-99
9259192
EMBO Rep. 2002 Mar;3(3):248-54
11850399
Oncol Rep. 2005 Jul;14(1):17-21
15944762
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6443-7
8692834
Science. 1999 Jul 16;285(5426):418-22
10411507
Cancer Cell. 2003 Jan;3(1):51-62
12559175
Oncogene. 1997 May 8;14(18):2195-200
9174055
Cancer Lett. 1999 May 24;139(2):183-7
10395177
Curr Opin Genet Dev. 2001 Feb;11(1):83-90
11163156
Science. 1993 May 7;260(5109):816-9
8484122
Trends Genet. 2000 Apr;16(4):168-74
10729832
Bioinformatics. 2004 Nov 1;20(16):2778-86
15166021
Bioinformatics. 2008 Feb 15;24(4):453-7
18184688
Oncogene. 2005 Apr 14;24(16):2589-98
15674323
Oncogene. 2003 Oct 16;22(46):7101-7
14562038
Cell. 1995 Jul 28;82(2):321-30
7628020
Cancer Res. 2001 Oct 1;61(19):6991-5
11585722
Oncogene. 2006 Jan 5;25(1):139-46
16247484
Cancer Res. 2002 Mar 15;62(6):1797-801
11912157
Nat Genet. 2003 Jan;33(1):80-4
12447371
Oncogene. 1995 Jan 5;10(1):33-7
7824277
Clin Cancer Res. 2003 Mar;9(3):991-7
12631597
Cancer Res. 2005 Jul 1;65(13):5965-73
15994976
Gut. 2005 Mar;54(3):374-84
15710986
J Natl Cancer Inst. 2002 Apr 3;94(7):513-21
11929952
J Biol Chem. 1997 Oct 3;272(40):24727-30
9312062
Genomics. 1999 Jun 1;58(2):181-7
10366450
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10764-9
10485900
Gastroenterology. 2004 Feb;126(2):394-401
14762775
Gut. 2006 Jun;55(6):848-55
16299036
Clin Cancer Res. 2007 Jul 15;13(14):4098-104
17634535
Clin Cancer Res. 2005 Mar 1;11(5):1827-34
15756006
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2698-702
11226302
Cancer Lett. 2001 Jan 26;162(2):201-5
11146226
Am J Hum Genet. 2001 Oct;69(4):780-90
11524701
Carcinogenesis. 2002 Oct;23(10):1695-9
12376479
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6319-23
8022779
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7818-23
12810945
Jpn J Cancer Res. 1999 Aug;90(8):837-40
10543255
Math Biosci. 2002 Mar;176(1):35-51
11867082
Cancer Epidemiol Biomarkers Prev. 2003 Aug;12(8):755-62
12917207
Anticancer Res. 2006 Nov-Dec;26(6B):4267-70
17201143
Cancer Res. 2000 Feb 15;60(4):803-7
10706084
Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12384-8
10535931
Carcinogenesis. 2003 Jan;24(1):47-51
12538348
Cell. 1998 Apr 3;93(1):81-91
9546394
Cell. 1993 Dec 17;75(6):1227-36
8261516
Nature. 1999 Jun 24;399(6738):806-9
10391249
J Cell Biol. 2002 Jan 21;156(2):249-59
11807090
N Engl J Med. 2003 Jul 17;349(3):247-57
12867608
Lab Invest. 2005 Sep;85(9):1130-8
16025146
EMBO J. 2004 Aug 4;23(15):3164-74
15282542
Nat Rev Mol Cell Biol. 2002 Oct;3(10):731-41
12360190
Nature. 1998 Dec 17;396(6712):643-9
9872311
Int J Cancer. 2004 Apr 10;109(3):468-71
14961589
EMBO J. 2002 Feb 15;21(4):483-92
11847097
Clin Cancer Res. 2000 May;6(5):1833-9
10815905
Nature. 1998 Mar 19;392(6673):300-3
9521327
Cell Cycle. 2007 Feb 15;6(4):414-7
17312392
Hybridoma (Larchmt). 2008 Aug;27(4):313-8
18707550
Mol Cell. 2006 May 19;22(4):501-10
16713580
Cancer Sci. 2006 Mar;97(3):226-34
16542220
Nat Genet. 1996 Jul;13(3):336-42
8673133
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4247-52
18337503
Nat Genet. 1998 Mar;18(3):276-9
9500552
Mol Cancer Res. 2003 Nov;1(13):959-69
14638868
Nat Genet. 2005 Apr;37(4):401-6
15793587
Neoplasia. 2008 Jul;10(7):643-52
18592005
Nat Genet. 1998 Oct;20(2):189-93
9771714
Cell. 2000 Dec 22;103(7):997-1000
11163175
PLoS One. 2008 Mar 12;3(3):e1776
18335050
Science. 1989 Apr 14;244(4901):207-11
2565047
EMBO J. 1998 Jun 1;17(11):3052-65
9606188
Genes Chromosomes Cancer. 2000 Nov;29(3):213-8
10992296
Carcinogenesis. 2005 Jun;26(6):1152-6
15760919
Nat Genet. 1995 Sep;11(1):64-70
7550317
Nat Cell Biol. 2009 Mar;11(3):295-302
19182791
Trends Cell Biol. 1999 Nov;9(11):454-9
10511710
Cell. 1996 Jun 28;85(7):1125-34
8674118
Science. 1993 May 7;260(5109):812-6
8484121
JAMA. 1989 Jun 2;261(21):3099-103
2654431
Nature. 2000 Jul 27;406(6794):430-5
10935642
Cancer Res. 2003 Nov 1;63(21):7185-9
14612512
Mol Carcinog. 2004 Jan;39(1):26-33
14694445
Cell. 1997 Nov 14;91(4):467-77
9390556