Role of c-Myc in intestinal tumorigenesis of the ApcMin/+ mouse.
The c-MYC oncogene plays an important role in tumorigenesis and is commonly highly expressed in gastrointestinal cancers. In colon cells, c-MYC is regulated by the adenomatous polyposis coli (Apc) tumor suppressor gene. Multiple intestinal neoplasia (ApcMin/+ or Min) mice are heterozygous for a truncating Apc mutation and serve as a model of familial adenomatous polyposis (FAP) disease. To study the role of c-Myc in the mutant Apc-mediated colon tumorigenesis, we have developed a transgenic mouse with the conditional deletion of the floxed c-Myc alleles in the intestinal crypts of ApcMin/+ mice (ApcMin/+; c-Mycfl/fl). The floxed c-Myc deletion was initiated via a Cre recombinase controlled by the intestine-specific transcriptional regulatory elements of the liver fatty acid-binding protein gene (Fabpl4xat-132). Fabpl4xat-132-mediated Cre expression and recombination resulted in a two-fold decrease in c-MYC protein expression with no effect on intestinal tract morphology. Small intestinal tumorigenesis was significantly suppressed throughout the small intestinal tract of ApcMin/+; c-Mycfl/fl mice compared to c-Myc wild type littermates. In ApcMin/+; c-Mycfl/fl mice, the intestinal apoptosis was higher in the areas of the small intestine with the decreased c-Myc protein expression (P=0.0016, compared to their littermates with the wild type c-Myc). Thus, conditional inactivation of c-Myc, mediated by Fabpl4xat-132-driven Cre-recombinase, suppresses Apc-dependent intestinal tumorigenesis in adult ApcMin/+ mice, without apparent effect on normal intestinal mucosa.
Ignatenko
Natalia A
NA
Department of Cell Biology and Anatomy, The University of Arizona, Tucson, Arizona 85724, USA. nai@email.arizona.edu
Holubec
Hana
H
Besselsen
David G
DG
Blohm-Mangone
Karen A
KA
Padilla-Torres
Jose L
JL
Nagle
Raymond B
RB
de Alboránç
Ignacio Moreno
IM
Guillen-R
Jose M
JM
Gerner
Eugene W
EW
D000818:Animals; D017209:Apoptosis; D003062:Codon / Q000235:genetics; D017353:Gene Deletion; D017491:Genes, APC; D016259:Genes, myc; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D007421:Intestine, Small / Q000166:cytology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D017384:Sequence Deletion
D003062:Codon; D016271:Proto-Oncogene Proteins c-myc