A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

Stephano S Mello; Liz J Valente; Nitin Raj; Jose A Seoane; Brittany M Flowers; Jacob McClendon; Kathryn T Bieging-Rolett; Jonghyeob Lee; Danton Ivanochko; Margaret M Kozak; Daniel T Chang; Teri A Longacre; Albert C Koong; Cheryl H Arrowsmith; Seung K Kim; Hannes Vogel; Laura D Wood; Ralph H Hruban; Christina Curtis; Laura D Attardi

doi:10.1016/j.ccell.2017.09.007

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

Cancer Cell. 2017 Oct 9;32(4):460-473.e6. doi: 10.1016/j.ccell.2017.09.007.

Authors

Stephano S Mello¹, Liz J Valente¹, Nitin Raj¹, Jose A Seoane², Brittany M Flowers¹, Jacob McClendon¹, Kathryn T Bieging-Rolett¹, Jonghyeob Lee³, Danton Ivanochko⁴, Margaret M Kozak¹, Daniel T Chang⁵, Teri A Longacre⁶, Albert C Koong⁵, Cheryl H Arrowsmith⁴, Seung K Kim⁷, Hannes Vogel⁶, Laura D Wood⁸, Ralph H Hruban⁸, Christina Curtis⁹, Laura D Attardi¹⁰

Affiliations

¹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Princess Margaret Cancer Centre, Structural Genomics Consortium and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁵ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁰ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: attardi@stanford.edu.

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 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.

Keywords: Hippo pathway; Ptpn14; YAP; mouse model; p53; pancreas cancer; transactivation domain; tumor suppressor.

MeSH terms

Animals
Cell Cycle Proteins
Cell Proliferation
Cell Transformation, Neoplastic
Gene Expression Profiling
Humans
Mice
Mutation
Nuclear Proteins / physiology*
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / prevention & control
Protein Tyrosine Phosphatases, Non-Receptor / physiology*
Signal Transduction
Transcription Factors / physiology*
Tumor Suppressor Protein p53 / physiology*

Substances

Cell Cycle Proteins
Nuclear Proteins
TP53 protein, human
Transcription Factors
Tumor Suppressor Protein p53
YY1AP1 protein, human
PTPN14 protein, human
Protein Tyrosine Phosphatases, Non-Receptor

Abstract

MeSH terms

Substances

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