Atm is a negative regulator of intestinal neoplasia

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/ þ and Apc 1638N/ þ . 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.

DNA Damage Activates TGF-β Signaling via ATM-c-Cbl-Mediated Stabilization of the Type II Receptor TβRII

“…Disruption of this axis by gene deletion leads to hyperproliferation of the epithelium upon X-ray irradiation. In accordance with our results, ATM has been reported to be a negative regulator of intestinal neoplasia by inhibiting cell proliferation at the early stage of intestinal tumor development (Kwong et al, 2008). Tgfbr2 inactivation in intestinal epithelium promotes the progression of colon cancer (Biswas et al, 2004).…”

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

“…The pathways that were specifically enriched in adenomas in our analysis are known to be activated in colorectal carcinogenesis (causal, resulting or compensatory) such as the Wnt pathway (Midgley and Kerr, 1999), cell cycle routes (Hao et al, 1998), DNA base metabolism, transcription, ATM (Kwong et al, 2008;Paulson et al, 2008), ARF, p27 (Payne et al, 2008) and p53 (Einspahr et al, 2006) signaling routes. In addition, we found novel pathways unique to adenomas, among which are the Rb pathway, the Src pathway, folate biosynthesis and the PTC1 pathway.…”

ATM signalling and cancer

“…ATM-null mice develop T-cell lymphomas with high penetrance due to defective V(D)J recombination, [86][87][88][89] and loss of ATM doubles the incidence of intestinal tumours in APC mutants. 90 Notably, although patients with mutations in NBS1 frequently develop lymphoid malignancies, NBS1-deficient mice, or mice expressing a humanised mutant NBS1 allele found in Nijmegen breakage syndrome patients, do not. 44,91 This suggests that NBS1 is not required for ATM's tumour-suppressive function in mice.…”