Atm is a negative regulator of intestinal neoplasia

Oncogene. 2008 Feb 7;27(7):1013-8. doi: 10.1038/sj.onc.1210708. Epub 2007 Aug 13.

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: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoma / metabolism*
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / physiology*
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / physiology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Ligase ATP
  • DNA Ligases / genetics
  • DNA Ligases / metabolism
  • DNA-Binding Proteins / physiology*
  • Intestinal Mucosa / metabolism*
  • Intestinal Neoplasms / metabolism*
  • Loss of Heterozygosity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / physiology*
  • Radiation, Ionizing
  • RecQ Helicases
  • Tumor Suppressor Proteins / physiology*

Substances

  • Adenomatous Polyposis Coli Protein
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • Adenosine Triphosphatases
  • Bloom syndrome protein
  • DNA Helicases
  • RecQ Helicases
  • DNA Ligases
  • DNA Ligase ATP