Extrinsic induction of apoptosis and tumor suppression via the p53–Reprimo–Hippo–YAP/TAZ–p73 pathway
Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The <i>p53</i> tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. <i>RPRM</i> is a target gene of p53 known to be involved in tumor suppression, but its molecular function has remained elusive. Here, we report that Reprimo (the protein product of <i>RPRM</i>) is secreted and extrinsically induces apoptosis in recipient cells. We identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis and induces apoptosis by transactivating various proapoptotic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. These findings identify the p53-Reprimo-Hippo-YAP/TAZ-p73 axis as an extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Our finding of the innate tumor eliminator Reprimo and the downstream pathway offers a promising avenue for the pharmacological treatment of cancer.
Authors
- Yuichi Wakabayashi (ORCID: https://orcid.org/0000-0002-8861-2954)
- Atsushi Okabe (ORCID: https://orcid.org/0000-0001-7748-6078)
- Shigeto Matsushita (ORCID: https://orcid.org/0000-0003-2001-5341)
- Yuzo Watanabe
- Masahiro Takikawa (ORCID: https://orcid.org/0009-0003-2261-7992)
- Mahito Sadaie (ORCID: https://orcid.org/0000-0002-3443-5980)
- Yukiko Sakaguchi
- Kimi Araki (ORCID: https://orcid.org/0000-0002-1396-1527)
- Rieko Ohki (ORCID: https://orcid.org/0000-0002-7775-6653)
- Akane Sada (ORCID: https://orcid.org/0000-0002-3541-1323)
- Yuko Tabata (ORCID: https://orcid.org/0000-0003-2999-3635)
- Atsushi Kaneda (ORCID: https://orcid.org/0000-0002-6980-5515)
- Jayaraman Krishnaraj (ORCID: https://orcid.org/0000-0002-0116-0546)
- Ryoji Fujiki
- Airi Nakano (ORCID: https://orcid.org/0009-0001-7372-6369)
- Fuyuki Ishikawa (ORCID: https://orcid.org/0000-0002-5580-2305)
- Tomoko Tajima
- A Mochizuki
Institutions
- Chiba University (JP)
- Tokyo University of Science (JP)
- Kyoto University (JP)
- Chiba Cancer Center (JP)
- Molecular Oncology (United States) (US)
- Nagasaki University (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1073/pnas.2413126122
- Citations
- 8
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 9.21
Funders
- Japan Agency for Medical Research and Development
- Okinaka Memorial Institute for Medical Research
- Ministry of Education, Culture, Sports, Science and Technology
- Princess Takamatsu Cancer Research Fund
- Life Science Foundation of Japan
- Japan Society for the Promotion of Science