A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer. Mus musculus

The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, we analyzed pancreatic cancer predisposition in mice expressing p53 transactivation domain (TAD) mutants. Surprisingly, we observed that p53 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to suppress pancreatic cancer and to activate a subset of novel p53 target genes. One such gene, Ptpn14, is a direct p53-inducible gene encoding a negative regulator of the Yap oncoprotein. To determine the effects of p53 deficiency on Yap target gene expression in pre-malignant mouse pancreatic intraepithelial neoplasia (PanIN) lesions, we sorted the CD133-positive ductal epithelial cells that make up the PanINs and used these cells for RNA-sequencing analysis. This analysis revealed that a Yap signature is induced upon p53 deficiency, suggesting that p53 loss promotes the induction of a Yap transcriptional program. Overall design: RNA-seq was performed to determine the differentially expressed genes in wild-type and p53-/- PanIN cells, sorted from KrasG12D;Pdx1-Cre;p53+/+ and KrasG12D;Pdx1-Cre;p53-/- mice.