title: Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice.
abstract: 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.
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. fu.zheng@mayo.edu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.forename: Kevin
authors.initials: K
authors.lastname: Regan
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Amy
authors.initials: A
authors.lastname: French
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Wilma L
authors.initials: WL
authors.lastname: Lingle
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
mesh_terms: 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
chemical_list: 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
references.citation: Oncogene. 2002 Apr 4;21(15):2328-33
references.pmid: 11948416
references.citation: Jpn J Cancer Res. 2000 May;91(5):504-9
references.pmid: 10835495
references.citation: Cancer Res. 2007 Jul 1;67(13):6064-74
references.pmid: 17596595
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870-5
references.pmid: 9618505
references.citation: Cancer Res. 2005 Oct 1;65(19):8662-70
references.pmid: 16204034
references.citation: Cancer Res. 2003 Dec 15;63(24):8606-13
references.pmid: 14695171
references.citation: Hum Mutat. 1997;10(2):89-99
references.pmid: 9259192
references.citation: EMBO Rep. 2002 Mar;3(3):248-54
references.pmid: 11850399
references.citation: Oncol Rep. 2005 Jul;14(1):17-21
references.pmid: 15944762
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6443-7
references.pmid: 8692834
references.citation: Science. 1999 Jul 16;285(5426):418-22
references.pmid: 10411507
references.citation: Cancer Cell. 2003 Jan;3(1):51-62
references.pmid: 12559175
references.citation: Oncogene. 1997 May 8;14(18):2195-200
references.pmid: 9174055
references.citation: Cancer Lett. 1999 May 24;139(2):183-7
references.pmid: 10395177
references.citation: Curr Opin Genet Dev. 2001 Feb;11(1):83-90
references.pmid: 11163156
references.citation: Science. 1993 May 7;260(5109):816-9
references.pmid: 8484122
references.citation: Trends Genet. 2000 Apr;16(4):168-74
references.pmid: 10729832
references.citation: Bioinformatics. 2004 Nov 1;20(16):2778-86
references.pmid: 15166021
references.citation: Bioinformatics. 2008 Feb 15;24(4):453-7
references.pmid: 18184688
references.citation: Oncogene. 2005 Apr 14;24(16):2589-98
references.pmid: 15674323
references.citation: Oncogene. 2003 Oct 16;22(46):7101-7
references.pmid: 14562038
references.citation: Cell. 1995 Jul 28;82(2):321-30
references.pmid: 7628020
references.citation: Cancer Res. 2001 Oct 1;61(19):6991-5
references.pmid: 11585722
references.citation: Oncogene. 2006 Jan 5;25(1):139-46
references.pmid: 16247484
references.citation: Cancer Res. 2002 Mar 15;62(6):1797-801
references.pmid: 11912157
references.citation: Nat Genet. 2003 Jan;33(1):80-4
references.pmid: 12447371
references.citation: Oncogene. 1995 Jan 5;10(1):33-7
references.pmid: 7824277
references.citation: Clin Cancer Res. 2003 Mar;9(3):991-7
references.pmid: 12631597
references.citation: Cancer Res. 2005 Jul 1;65(13):5965-73
references.pmid: 15994976
references.citation: Gut. 2005 Mar;54(3):374-84
references.pmid: 15710986
references.citation: J Natl Cancer Inst. 2002 Apr 3;94(7):513-21
references.pmid: 11929952
references.citation: J Biol Chem. 1997 Oct 3;272(40):24727-30
references.pmid: 9312062
references.citation: Genomics. 1999 Jun 1;58(2):181-7
references.pmid: 10366450
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10764-9
references.pmid: 10485900
references.citation: Gastroenterology. 2004 Feb;126(2):394-401
references.pmid: 14762775
references.citation: Gut. 2006 Jun;55(6):848-55
references.pmid: 16299036
references.citation: Clin Cancer Res. 2007 Jul 15;13(14):4098-104
references.pmid: 17634535
references.citation: Clin Cancer Res. 2005 Mar 1;11(5):1827-34
references.pmid: 15756006
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2698-702
references.pmid: 11226302
references.citation: Cancer Lett. 2001 Jan 26;162(2):201-5
references.pmid: 11146226
references.citation: Am J Hum Genet. 2001 Oct;69(4):780-90
references.pmid: 11524701
references.citation: Carcinogenesis. 2002 Oct;23(10):1695-9
references.pmid: 12376479
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6319-23
references.pmid: 8022779
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7818-23
references.pmid: 12810945
references.citation: Jpn J Cancer Res. 1999 Aug;90(8):837-40
references.pmid: 10543255
references.citation: Math Biosci. 2002 Mar;176(1):35-51
references.pmid: 11867082
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 Aug;12(8):755-62
references.pmid: 12917207
references.citation: Anticancer Res. 2006 Nov-Dec;26(6B):4267-70
references.pmid: 17201143
references.citation: Cancer Res. 2000 Feb 15;60(4):803-7
references.pmid: 10706084
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12384-8
references.pmid: 10535931
references.citation: Carcinogenesis. 2003 Jan;24(1):47-51
references.pmid: 12538348
references.citation: Cell. 1998 Apr 3;93(1):81-91
references.pmid: 9546394
references.citation: Cell. 1993 Dec 17;75(6):1227-36
references.pmid: 8261516
references.citation: Nature. 1999 Jun 24;399(6738):806-9
references.pmid: 10391249
references.citation: J Cell Biol. 2002 Jan 21;156(2):249-59
references.pmid: 11807090
references.citation: N Engl J Med. 2003 Jul 17;349(3):247-57
references.pmid: 12867608
references.citation: Lab Invest. 2005 Sep;85(9):1130-8
references.pmid: 16025146
references.citation: EMBO J. 2004 Aug 4;23(15):3164-74
references.pmid: 15282542
references.citation: Nat Rev Mol Cell Biol. 2002 Oct;3(10):731-41
references.pmid: 12360190
references.citation: Nature. 1998 Dec 17;396(6712):643-9
references.pmid: 9872311
references.citation: Int J Cancer. 2004 Apr 10;109(3):468-71
references.pmid: 14961589
references.citation: EMBO J. 2002 Feb 15;21(4):483-92
references.pmid: 11847097
references.citation: Clin Cancer Res. 2000 May;6(5):1833-9
references.pmid: 10815905
references.citation: Nature. 1998 Mar 19;392(6673):300-3
references.pmid: 9521327
references.citation: Cell Cycle. 2007 Feb 15;6(4):414-7
references.pmid: 17312392
references.citation: Hybridoma (Larchmt). 2008 Aug;27(4):313-8
references.pmid: 18707550
references.citation: Mol Cell. 2006 May 19;22(4):501-10
references.pmid: 16713580
references.citation: Cancer Sci. 2006 Mar;97(3):226-34
references.pmid: 16542220
references.citation: Nat Genet. 1996 Jul;13(3):336-42
references.pmid: 8673133
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4247-52
references.pmid: 18337503
references.citation: Nat Genet. 1998 Mar;18(3):276-9
references.pmid: 9500552
references.citation: Mol Cancer Res. 2003 Nov;1(13):959-69
references.pmid: 14638868
references.citation: Nat Genet. 2005 Apr;37(4):401-6
references.pmid: 15793587
references.citation: Neoplasia. 2008 Jul;10(7):643-52
references.pmid: 18592005
references.citation: Nat Genet. 1998 Oct;20(2):189-93
references.pmid: 9771714
references.citation: Cell. 2000 Dec 22;103(7):997-1000
references.pmid: 11163175
references.citation: PLoS One. 2008 Mar 12;3(3):e1776
references.pmid: 18335050
references.citation: Science. 1989 Apr 14;244(4901):207-11
references.pmid: 2565047
references.citation: EMBO J. 1998 Jun 1;17(11):3052-65
references.pmid: 9606188
references.citation: Genes Chromosomes Cancer. 2000 Nov;29(3):213-8
references.pmid: 10992296
references.citation: Carcinogenesis. 2005 Jun;26(6):1152-6
references.pmid: 15760919
references.citation: Nat Genet. 1995 Sep;11(1):64-70
references.pmid: 7550317
references.citation: Nat Cell Biol. 2009 Mar;11(3):295-302
references.pmid: 19182791
references.citation: Trends Cell Biol. 1999 Nov;9(11):454-9
references.pmid: 10511710
references.citation: Cell. 1996 Jun 28;85(7):1125-34
references.pmid: 8674118
references.citation: Science. 1993 May 7;260(5109):812-6
references.pmid: 8484121
references.citation: JAMA. 1989 Jun 2;261(21):3099-103
references.pmid: 2654431
references.citation: Nature. 2000 Jul 27;406(6794):430-5
references.pmid: 10935642
references.citation: Cancer Res. 2003 Nov 1;63(21):7185-9
references.pmid: 14612512
references.citation: Mol Carcinog. 2004 Jan;39(1):26-33
references.pmid: 14694445
references.citation: Cell. 1997 Nov 14;91(4):467-77
references.pmid: 9390556