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 <i>TAp63/p73</i>-deficient mouse models. We found that knockin mutant p53-R270H shortened the life span of <i>p73</i>^<i>+/-</i> mice and subjected <i>TAp63</i>^<i>+/-</i> or <i>p73</i>^<i>+/-</i> 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 <i>TAp63</i>^<i>+/-</i> ;<i>p53</i>^{<i>R270H/-</i>} and <i>p73</i>^<i>+/-</i> ;<i>p53</i>^{<i>R270H/-</i>} 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 <i>p53</i> hijacks the p63/p73-regulated transcriptional program via the Notch1 pathway.