Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1

Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24259-24267. doi: 10.1073/pnas.1913919116. Epub 2019 Nov 11.

Abstract

p53 is the most frequently mutated gene in human cancers and mutant p53 has a gain of function (GOF) that promotes tumor progression and therapeutic resistance. One of the major GOF activities of mutant p53 is to suppress 2 other p53 family proteins, p63 and p73. However, the molecular basis is not fully understood. Here, we examined whether mutant p53 antagonizes p63/p73-mediated tumor suppression in vivo by using mutant p53-R270H knockin and TAp63/p73-deficient mouse models. We found that knockin mutant p53-R270H shortened the life span of p73+/- mice and subjected TAp63+/- or p73+/- mice to T lymphoblastic lymphomas (TLBLs). To unravel the underlying mechanism, we showed that mutant p53 formed a complex with Notch1 intracellular domain (NICD) and antagonized p63/p73-mediated repression of HES1 and ECM1. As a result, HES1 and ECM1 were overexpressed in TAp63+/- ;p53R270H/- and p73+/- ;p53R270H/- TLBLs, suggesting that normal function of HES1 and ECM1 in T cell activation is hyperactivated, leading to lymphomagenesis. Together, our data reveal a previously unappreciated mechanism by which GOF mutant p53 hijacks the p63/p73-regulated transcriptional program via the Notch1 pathway.

Keywords: GOF; Notch1; T-ALL; mutant p53; p63/p73.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Mutant Strains
  • Mutation
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Promoter Regions, Genetic
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factor HES-1 / genetics
  • Transcription Factor HES-1 / metabolism
  • Tumor Protein p73 / genetics*
  • Tumor Protein p73 / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Ecm1 protein, mouse
  • Extracellular Matrix Proteins
  • Hes1 protein, mouse
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Trans-Activators
  • Transcription Factor HES-1
  • Trp53 protein, mouse
  • Trp63 protein, mouse
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53