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

Stephano S Mello1, Liz J Valente1, Nitin Raj1

  • 1Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Cancer Cell
|October 11, 2017
PubMed

Insights

The p53 tumor suppressor protein guards against pancreatic cancer. A specific p53 mutant, p5353,54 TAD2, acts as a super-tumor suppressor by enhancing the p53-Ptpn14-Yap pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The p53 transcription factor is a crucial tumor suppressor, particularly in preventing pancreatic cancer progression.
  • The precise mechanisms underlying p53-mediated tumor suppression remain incompletely understood.

Purpose of the Study:

  • To investigate the role of p53 transcriptional activation domain (TAD) mutants in pancreatic cancer development.
  • To elucidate the molecular pathways involved in p53-mediated pancreatic tumor suppression.

Main Methods:

  • Analysis of pancreatic cancer development in mice engineered to express p53 TAD mutants.
  • Examination of p53 target gene activation, specifically Ptpn14.
  • Investigation of the relationship between p53, Ptpn14, and Yap signaling in cancer.

Main Results:

  • A specific p53 mutant, p5353,54 TAD2, exhibited enhanced tumor suppressive activity in pancreatic cancer.
  • This mutant demonstrated superior transactivation of select p53 target genes, including Ptpn14.
  • Ptpn14, a negative regulator of the Yap oncoprotein, was found to be essential for p53-mediated pancreatic cancer suppression.
  • p53 deficiency was observed to promote Yap signaling, and mutations in TP53 and PTPN14 are mutually exclusive in human cancers.

Conclusions:

  • A novel p53-Ptpn14-Yap signaling pathway is identified as integral to p53-mediated tumor suppression in pancreatic cancer.
  • The p5353,54 TAD2 mutant functions as a 'super-tumor suppressor' by enhancing this pathway.
  • Understanding this pathway offers new insights into therapeutic strategies for pancreatic cancer.
Keywords:
Hippo pathwayPtpn14YAPmouse modelp53pancreas cancertransactivation domaintumor suppressor

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