| First Author | Zhang J | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 48 | Pages | 24259-24267 |
| PubMed ID | 31712410 | Mgi Jnum | J:290786 |
| Mgi Id | MGI:6435485 | Doi | 10.1073/pnas.1913919116 |
| Citation | Zhang J, et al. (2019) Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1. Proc Natl Acad Sci U S A 116(48):24259-24267 |
| abstractText | 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. |
