Gut pathophysiology due to expression of mutant p53 in a mouse model

The TP53 gene is the most important tumor suppressor in the cell. Due to its crucial role in cellular response to stress, p53 is also the most mutated protein in human cancers, with more than 50% of tumors exhibiting a mutation at this locus. The vast majority of cancer-associated mutations in TP53 are missense mutations, resulting in the translation of an erroneous amino acid in the full-length protein. When mutated, p53 not only loses its tumor suppressive activity, but also gains new tumor-promotive features. p53 mutation is frequent in colorectal cancer, and is thought to mediate the transition from a benign polyp into an invasive carcinoma. To characterize the role of mutant p53 in gut tumorigenesis, we use the CKIα^fl/fl model established in our lab, in which gut-specific CKIα ablation (CKIα^Δgut) results in hyperactivation of the Wnt pathway with simultaneous activation of p53. Upon deletion of both CKIα and p53 (CKIα/p53^Δgut), intestinal homeostasis is disrupted and mice develop invasive tumors. By breeding the CKIα^fl/fl mice with mice carrying the p53 mutant allele R172H (corresponding to the human hot-spot mutation R175H), we were able to examine and compare the tissue effects of WT and mutant p53. We found that compared to CKIα^Δgut mice, which showed robust activation of WT p53, p53 target-genes expression was completely absent in the homozygous mutant mice (CKIα^Δgut/p53^R172H). Surprisingly, CKIα^Δgut/p53^R172H mice had less carcinomas and lower proliferation rate in the small bowel, compared to CKIα/p53^Δgut mice. Indeed, while many Wnt target-genes were highly expressed in the CKIα/p53^Δgut mice, most of them were significantly downregulated in the CKIα^Δgut and the CKIα^Δgut/p53^R172H mice, indicating that mutant p53 may surprisingly act in the small bowel, similarly to WT p53, as Wnt- and tumor-suppressor. Further investigation showed this suppression is mediated by chromatin condensation and less binding of the Wnt transcription factor TCF4, and is executed in a tissue-dependent fashion.