Journal article
A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer
Cancer cell, Vol.32(4), pp.460-473.e6
10/09/2017
DOI: 10.1016/j.ccell.2017.09.007
PMCID: PMC5659188
PMID: 29017057
Abstract
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 p5353,54 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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•The p5353,54 TAD2 mutant is a super-tumor suppressor in pancreatic cancer•p5353,54 hyperactivates Ptpn14, a p53 target gene involved in tumor suppression•p53 negatively regulates Yap through Ptpn14 activation•p53-Ptpn14-Yap is a key tumor suppressive axis in mice and humans
Mello et al. find that a p53 mutant harboring mutations in the second transcriptional activation domain has enhanced tumor suppression capacities due to hyperactivation of the p53 target gene Ptpn14. Ptpn14 suppresses Yap activity and is required for p53 tumor suppressor activity in pancreatic cancer.
Details
- Title: Subtitle
- A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer
- Creators
- Stephano S. Mello - Stanford UniversityLiz J. Valente - Stanford UniversityNitin Raj - Stanford UniversityJose A. Seoane - Stanford UniversityBrittany M. Flowers - Stanford UniversityJacob McClendon - Stanford UniversityKathryn T. Bieging-Rolett - Stanford UniversityJonghyeob Lee - Stanford UniversityDanton Ivanochko - Princess Margaret Cancer CentreMargaret M. Kozak - Stanford UniversityDaniel T. Chang - Stanford UniversityTeri A. Longacre - Stanford UniversityAlbert C. Koong - Stanford UniversityCheryl H. Arrowsmith - Princess Margaret Cancer CentreSeung K. Kim - Stanford UniversityHannes Vogel - Stanford UniversityLaura D. Wood - Department of Pathology The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine Baltimore MD USARalph H. Hruban - Johns Hopkins University School of MedicineChristina Curtis - Stanford UniversityLaura D. Attardi - Stanford University
- Resource Type
- Journal article
- Publication Details
- Cancer cell, Vol.32(4), pp.460-473.e6
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ccell.2017.09.007
- PMID
- 29017057
- PMCID
- PMC5659188
- ISSN
- 1535-6108
- eISSN
- 1878-3686
- Grant note
- DOI: 10.13039/501100000038, name: Canadian Natural Sciences and Engineering Research Council; DOI: 10.13039/100000002, name: NIH, award: R21 CA169673, R01 CA140875, R35 CA197591, DK10261201, CA21192701; name: Susan G. Komen Postdoctoral Fellowship, award: PDF16377256
- Language
- English
- Date published
- 10/09/2017
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984312966002771
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