Abstract LB445: Extrinsic induction of apoptosis and tumor suppression via the p53- Reprimo-Hippo-YAP/TAZ-p73 pathway

Abstract The most commonly mutated gene in human cancer is the p53 tumor suppressor gene, which plays a pivotal role in tumor suppression. We have characterized and reported the molecular function of several novel p53 target genes, including Noxa, Reprimo, AEN, FUCA1, IER5 and PHLDA3 (Science, 2000, Cell, 2009, PNAS, 2014, etc). Reprimo is a p53 target gene known to be involved in tumor suppression, but its molecular function has remained elusive. Here we report the Reprimo protein is secreted and extrinsically induces apoptosis in recipient cells. We further identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo induces apoptosis through the Hippo-YAP/TAZ-p73 axis by transactivating pro-apoptotic p73 target genes. In vivo analyses further support the tumor suppressive effects of secreted Reprimo. These findings identify p53-Reprimo-Hippo-YAP/TAZ-p73 as a novel, extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Citation Format: Rieko Ohki. Extrinsic induction of apoptosis and tumor suppression via the p53- Reprimo-Hippo-YAP/TAZ-p73 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB445.