Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MEK1) in Ileal Enterocytes Leads to Dysplasia and a Predisposition to Cancer

Activation of Mitogen-activated protein kinases (MAPKs) is a key factor in the pathogenesis of cancer, although the specific role of mitogen-activated protein kinase kinase (MEK1) is not well understood. Villin promoter driven cre expression was used to excise a floxed stop cassette from a phosphomimetically constitutively activated MEK1 (caMEK1) expression construct in the intestine of C57BL/6 mice. Zygosity status of caMEK1 afforded assessment of the dose dependence of the effect. The expected mendelian distribution of genotypes and sex was observed in 443 progenies. Between 21 and 63 days of life caMEK1 had no effect on body weight in male mice, but reduced body weight in female mice homozygous for caMEK1. At 10 weeks of age, the ileum of caMEK1 expressing mice was characterized by the finding of dysplasia and profound changes in overall architecture. Paneth cells were nearly absent in caMEK1 homozygotes. Targeted proteomic profiling via reverse phase protein array analyses with confirmatory western blotting revealed significant changes in protein and phosphoprotein expression including up-regulation of proteins downstream of MEK1, associated with enhanced markers of proliferation, diminished apoptosis, alterations in cell-fate determination, cell-cell interactions and tight junctions. Long-term viability of caMEK1 homozygous mice was reduced with no survival beyond one year. Invasive adenocarcinoma developed in three of ten older mice (15 [homozygous], 26 [homozygous] and 35 weeks [heterozygous] of age). Expression of caMEK1 in enterocytes leads to marked derangements in the intestinal epithelium, which is associated with a predisposition to the development of invasive cancer.