期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：48
页码：24259-24267
DOI：10.1073/pnas.1913919116
出版社：The National Academy of Sciences of the United States of America
摘要：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..
