Extrinsic induction of apoptosis and tumor suppression via the p53–Reprimo–Hippo–YAP/TAZ–p73 pathway
Abstract
Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. RPRM 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 RPRM ) 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Masahiro Takikawa
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Airi Nakano
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Jayaraman Krishnaraj
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Yuko Tabata
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Yuzo Watanabe
Proteomics Facility, Graduate School of Biostudies, Kyoto University
Atsushi Okabe
Department of Molecular Oncology, Graduate School of Medicine, Chiba University
Yukiko Sakaguchi
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Ryoji Fujiki
Ami Mochizuki
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Tomoko Tajima
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Akane Sada
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Shu Matsushita
Laboratory of Fundamental Oncology, National Cancer Center Research Institute
Yuichi Wakabayashi
Cancer Genome Center, Division of Experimental Animal Research, Chiba Cancer Center Research Institute
Kimi Araki
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University
Atsushi Kaneda
Fuyuki Ishikawa
Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University
Mahito Sadaie
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
Rieko Ohki
Laboratory of Fundamental Oncology, National Cancer Center Research Institute