Journal
CANCER CELL
Volume 32, Issue 4, Pages 460-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.09.007
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Funding
- Canadian Natural Sciences and Engineering Research Council
- NIH grants [R21 CA169673, R01 CA140875, R35 CA197591, DK10261201, CA21192701]
- Susan G. Komen Postdoctoral Fellowship [PDF16377256]
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The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53 53,54 TAD2 mutant behaves as a super-tumor suppressor,'' with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.
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