Atm is a negative regulator of intestinal neoplasia.
The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc(Min/+) and Apc(1638N/+). These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability.
Kwong
L N
LN
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
Weiss
K R
KR
Haigis
K M
KM
Dove
W F
WF
D000236:Adenoma / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism*; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011839:Radiation, Ionizing; D053484:RecQ Helicases; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D025601:Adenomatous Polyposis Coli Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; D011088:DNA Ligases; D000072481:DNA Ligase ATP
Genes Chromosomes Cancer. 1996 Nov;17(3):194-8
8946200
Nat Genet. 1997 Aug;16(4):397-401
9241281
Hum Mol Genet. 2005 Mar 15;14(6):813-25
15703196
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4365-70
15767571
Clin Cancer Res. 2006 Mar 1;12(5):1494-500
16533773
Cancer Sci. 2006 May;97(5):355-61
16630131
Nat Genet. 2006 Aug;38(8):873-5
16832357
Gastroenterology. 2006 Oct;131(4):1096-109
17030180
Nature. 2006 Nov 30;444(7119):633-7
17136093
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4036-41
17360473
Nature. 2005 Apr 14;434(7035):864-70
15829956
Nature. 2005 Apr 14;434(7035):907-13
15829965
Cell. 2005 Dec 16;123(6):1001-11
16360031
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3461-6
10716720
Mol Cell. 2000 Jun;5(6):993-1002
10911993
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10389-94
10973490
Nat Genet. 2000 Dec;26(4):424-9
11101838
Oncogene. 2001 Sep 20;20(42):6095-101
11593417
Mol Cell. 2001 Dec;8(6):1187-96
11779495
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8927-31
12060718
Science. 2002 Sep 20;297(5589):2051-3
12242442
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9769-73
15210940
Int J Cancer. 2004 Dec 10;112(5):846-53
15386372
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8969-73
8090754
Science. 1995 Jun 23;268(5218):1749-53
7792600
Cell. 1996 Jul 12;86(1):159-71
8689683