Myc deletion rescues Apc deficiency in the small intestine.
The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers, and its loss results in constitutive activity of the beta-catenin-Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; 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 beta-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.
Sansom
Owen J
OJ
The Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK. o.sansom@beatson.gla.ac.uk
Meniel
Valerie S
VS
Muncan
Vanesa
V
Phesse
Toby J
TJ
Wilkins
Julie A
JA
Reed
Karen R
KR
Vass
J Keith
JK
Athineos
Dimitris
D
Clevers
Hans
H
Clarke
Alan R
AR
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D020895:Enterocytes / Q000378:metabolism; D017353:Gene Deletion; D017491:Genes, APC; D016259:Genes, myc / Q000235:genetics*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency* / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D016271:Proto-Oncogene Proteins c-myc