Extrinsic induction of apoptosis and tumor suppression via the p53-Reprimo-Hippo-YAP/TAZ-p73 pathway
成果类型：
Article
署名作者：
Takikawa, Masahiro; Nakano, Airi; Krishnaraj, Jayaraman; Tabata, Yuko; Watanabe, Yuzo; Okabe, Atsushi; Sakaguchi, Yukiko; Fujiki, Ryoji; Mochizuki, Ami; Tajima, Tomoko; Sada, Akane; Matsushita, Shu; Wakabayashi, Yuichi; Araki, Kimi; Kaneda, Atsushi; Ishikawa, Fuyuki; Sadaie, Mahito; Ohki, Rieko
署名单位：
National Cancer Center - Japan; Tokyo University of Science; Nagasaki University; Kyoto University; Chiba University; Chiba University; Chiba Cancer Center; Kumamoto University; Kumamoto University; Kyoto University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-11077
DOI：
10.1073/pnas.241312612
发表日期：
2025-02-11
关键词：
yes-associated protein
aberrant methylation
candidate mediator
reprimo
gene
p73
promoter
yap
p53
phosphorylation
摘要：
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 fur-ther 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 pharmaco-logical treatment of cancer.