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Myc deletion rescues Apc deficiency in the small intestine

2007; Nature Portfolio; Volume: 446; Issue: 7136 Linguagem: Inglês

10.1038/nature05674

1476-4687

Owen J. Sansom, Valérie S. Méniel, Vanesa Muncan, Toby J. Phesse, Julie A. Wilkins, Karen R. Reed, J. Keith Vass, Dimitris Athineos, Hans Clevers, Alan R. Clarke,

Cancer-related gene regulation

Deregulation of the Wnt signalling pathway has been implicated in the development of cancer, including colorectal tumours. This paper shows that regulation of the transcription factor c-Myc is the most critical target for Wnt signalling in the early stages of intestinal neoplasias. The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome1. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers2,3, and its loss results in constitutive activity of the β-catenin–Tcf4 transcription complex3. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro4, in normal crypts in vivo5 and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene6; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear β-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.