Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Atm is a negative regulator of intestinal neoplasia

Oncogene volume 27, pages 1013–1018 (2008)Cite this article

Abstract

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: ApcMin/+ and Apc1638N/+. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Amos-Landgraf JM, Kwong LN, Kendziorski CM, Reichelderfer M, Torrealba J, Weichert J et al. (2007). A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA 104: 4036–4041.

    Article  CAS  Google Scholar 

  • Bai AHC, Tong JHM, To KF, Chan MWY, Man EPS, Lo KW et al. (2004). Promoter hypermethylation of tumor-related genes in the progression of colorectal neoplasia. Int J Cancer 112: 846–853.

    Article  CAS  Google Scholar 

  • Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F et al. (1996). Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86: 159–171.

    Article  CAS  Google Scholar 

  • Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K et al. (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–870.

    Article  CAS  Google Scholar 

  • Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444: 633–637.

    Article  CAS  Google Scholar 

  • Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B et al. (1994). A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA 91: 8969–8973.

    Article  CAS  Google Scholar 

  • Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C et al. (2000). DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 5: 993–1002.

    Article  CAS  Google Scholar 

  • Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T et al. (2005). Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434: 907–913.

    Article  CAS  Google Scholar 

  • Goss KH, Risinger MA, Kordich JJ, Sanz MM, Straughen JE, Slovek LE et al. (2002). Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297: 2051–2053.

    Article  Google Scholar 

  • Grabsch H, Dattani M, Barker L, Maughan N, Maude K, Hansen O et al. (2006). Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer. Clin Cancer Res 12: 1494–1500.

    Article  CAS  Google Scholar 

  • Haigis KM, Caya JG, Reichelderfer M, Dove WF . (2002). Intestinal adenomas can develop with a stable karyotype and stable microsatellites. Proc Natl Acad Sci USA 99: 8927–8931.

    Article  CAS  Google Scholar 

  • Haigis KM, Hoff PD, White A, Shoemaker AR, Halberg RB, Dove WF . (2004). Tumor regionality in the mouse intestine reflects the mechanism of loss of Apc function. Proc Natl Acad Sci USA 101: 9769–9773.

    Article  CAS  Google Scholar 

  • Halberg RB, Katzung DS, Hoff PD, Moser AR, Cole CE, Lubet RA et al. (2000). Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers. Proc Natl Acad Sci USA 97: 3461–3466.

    Article  CAS  Google Scholar 

  • Hill R, Song Y, Cardiff RD, Van Dyke T . (2005). Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell 123: 1001–1011.

    Article  CAS  Google Scholar 

  • Janssen KP, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P et al. (2006). APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131: 1096–1109.

    Article  CAS  Google Scholar 

  • Luo G, Santoro IM, McDaniel LD, Nishijima I, Mills M, Youssoufian H et al. (2000). Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet 26: 424–429.

    Article  CAS  Google Scholar 

  • Luongo C, Dove WF . (1996). Somatic genetic events linked to the Apc locus in intestinal adenomas of the Min mouse. Genes Chromosomes Cancer 17: 194–198.

    Article  CAS  Google Scholar 

  • Mann MB, Hodges CA, Barnes E, Vogel H, Hassold TJ, Luo G . (2005). Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund–Thomson syndrome. Hum Mol Genet 14: 813–825.

    Article  CAS  Google Scholar 

  • Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ . (2000). Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci USA 97: 10389–10394.

    Article  CAS  Google Scholar 

  • Rao CV, Yang YM, Swamy MV, Liu T, Fang Y, Mahmood R et al. (2005). Colonic tumorigenesis in BubR1+/−ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci USA 102: 4365–4370.

    Article  CAS  Google Scholar 

  • Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M et al. (2006). ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38: 873–875.

    Article  CAS  Google Scholar 

  • Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L et al. (1995). A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268: 1749–1753.

    Article  CAS  Google Scholar 

  • Sharpless NE, Ferguson DO, O'Hagan RC, Castrillon DH, Lee C, Farazi PA et al. (2001). Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol Cell 8: 1187–1196.

    Article  CAS  Google Scholar 

  • Sugai T, Habano W, Uesugi N, Jiao YF, Nakamura S, Yoshida T et al. (2001). Frequent allelic imbalance at the ATM locus in DNA multiploid colorectal carcinomas. Oncogene 20: 6095–6101.

    Article  CAS  Google Scholar 

  • Taketo MM . (2006). Mouse models of gastrointestinal tumors. Cancer Sci 97: 355–361.

    Article  CAS  Google Scholar 

  • Westphal CH, Rowan S, Schmaltz C, Elson A, Fisher DE, Leder P . (1997). atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat Genet 16: 397–401.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Caroline Alexander for discussions and Linda Clipson for critical reading and editing of the manuscript. Allan Bradley and Frederick Alt generously provided key mouse strains. This work was supported by the National Cancer Institute (NCI) training grant CA009135 to LNK and by NCI grant R37CA63677.

Author information

Author notes

  1. L N Kwong

    Present address: 2Current address: Dana-Farber Cancer Institute, Boston, MA 02115, USA.,

Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, WI, USA

    L N Kwong, K R Weiss, K M Haigis & W F Dove

Authors
  1. L N Kwong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K R Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K M Haigis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W F Dove
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W F Dove.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kwong, L., Weiss, K., Haigis, K. et al. Atm is a negative regulator of intestinal neoplasia. Oncogene 27, 1013–1018 (2008). https://doi.org/10.1038/sj.onc.1210708

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210708

Keywords

This article is cited by

Search

Advanced search

Quick links