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

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 +/- ;p53 R270H/- and p73 +/- ;p53 R270H/- 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.

authors

Zhang J,Sun W,Kong X,Zhang Y,Yang HJ,Ren C,Jiang Y,Chen M,Chen X

doi

10.1073/pnas.1913919116

subject

Has Abstract

pub_date

2019-11-26 00:00:00

pages

24259-24267

issue

48

eissn

0027-8424

issn

1091-6490

pii

1913919116

journal_volume

116

pub_type

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