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

Jin Zhang1, Wenqiang Sun2, Xiangmudong Kong2

  • 1Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, CA 95616; jinzhang@ucdavis.edu xbchen@ucdavis.edu.

Proceedings of the National Academy of Sciences of the United States of America
|November 13, 2019
PubMed

Insights

Gain-of-function mutant p53 (mutant p53) promotes cancer by suppressing p63 and p73. This study reveals mutant p53 hijacks the Notch1 pathway to overexpress HES1 and ECM1, driving T lymphoblastic lymphomas.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The tumor suppressor p53 is frequently mutated in human cancers, with mutant p53 exhibiting gain-of-function (GOF) activities that promote tumor progression and therapeutic resistance.
  • A key GOF activity of mutant p53 is the suppression of p63 and p73, but the underlying molecular mechanisms remain incompletely understood.

Purpose of the Study:

  • To investigate the in vivo mechanism by which mutant p53 antagonizes p63/p73-mediated tumor suppression.
  • To elucidate the role of the Notch1 pathway in mutant p53-driven lymphomagenesis.

Main Methods:

  • Utilized mutant p53-R270H knockin mouse models and TAp63/p73-deficient mice.
  • Examined protein-protein interactions between mutant p53, Notch1 intracellular domain (NICD), p63, and p73.
  • Analyzed the expression of HES1 and ECM1 in relevant mouse models and lymphomas.

Main Results:

  • Mutant p53-R270H expression shortened the lifespan of p73-deficient mice and induced T lymphoblastic lymphomas (TLBLs) in TAp63 or p73-deficient mice.
  • Mutant p53 formed a complex with NICD, thereby antagonizing p63/p73-mediated repression of HES1 and ECM1.
  • Overexpression of HES1 and ECM1 was observed in TAp63;p53 and p73;p53 TLBLs, indicating hyperactivation of their normal functions in T cell activation.

Conclusions:

  • Gain-of-function mutant p53 utilizes the Notch1 pathway to suppress p63/p73 tumor suppressor functions.
  • This hijacking leads to the overexpression of HES1 and ECM1, ultimately promoting lymphomagenesis.
  • The findings reveal a novel mechanism of oncogenesis driven by GOF mutant p53 through the p63/p73 and Notch1 pathways.
Keywords:
GOFNotch1T-ALLmutant p53p63/p73

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