Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1
Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine p53 mutée, via la voie de signalisation Notch1, inhibe la suppression tumorale induite par les protéines p63 et p73
Despite studies have shown that mutant p53 acquires its GOF by suppressing p63 and p73, the hypothesis has not been tested in vivo and the underlying mechanism is not fully understood. Here, by using mutant p53-R270H knockin and TAp63/p73-deficient mouse models, we showed that KI mutant p53-R270H antagonizes p63/p73 to shorten mouse life span and to promote T lymphoblastic lymphomagenesis. Mechanistically, we showed that mutant p53 collaborates with the Notch1 intracellular domain (NICD) to abrogate p63/p73-mediated repression of HES1 and ECM1. As a result, HES1 and ECM1 are overexpressed, leading to lymphomagenesis. Thus, we identify a context where mutant p53 contributes to pathogenesis of T lymphoblastic lymphoma by collaborating with the Notch1 pathway to hijack the p63/p73-regulated transcriptional program.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.