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

Jin Zhang, Wenqiang Sun, Xiangmudong Kong, Yanhong Zhang, Hee Jung Yang, Cong Ren, Yuqian Jiang, Mingyi Chen, Xinbin Chen

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)24259-24267
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Nov 26 2019


  • GOF
  • Mutant p53
  • Notch1
  • P63/p73
  • T-ALL

ASJC Scopus subject areas

  • General


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