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Updated: May 29, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Extrinsic induction of apoptosis and tumor suppression via the p53-Reprimo-Hippo-YAP/TAZ-p73 pathway

Masahiro Takikawa1,2, Airi Nakano1,3, Jayaraman Krishnaraj1

  • 1Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|February 6, 2025
PubMed

Insights

The tumor suppressor gene p53 targets RPRM, whose protein product Reprimo is secreted to induce apoptosis in cancer cells. This discovery reveals a new extrinsic apoptosis pathway crucial for tumor suppression and potential cancer therapies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Tumor progression is inhibited by cellular mechanisms like apoptosis.
  • The p53 tumor suppressor gene is frequently mutated in human cancers.
  • RPRM is a p53 target gene implicated in tumor suppression, but its function is unclear.

Purpose of the Study:

  • To elucidate the molecular function of Reprimo (RPRM).
  • To identify the mechanism by which Reprimo suppresses tumor progression.
  • To investigate the potential of Reprimo as a therapeutic target for cancer.

Main Methods:

  • Investigated the secretion and apoptotic function of Reprimo.
  • Identified protocadherin family members (FAT1, FAT4, CELSR1-3) as Reprimo receptors.
  • Analyzed the role of Reprimo in the Hippo-YAP/TAZ-p73 signaling pathway.

Main Results:

  • Reprimo is secreted and induces extrinsic apoptosis in recipient cells.
  • Reprimo binds to protocadherin receptors, activating the Hippo-YAP/TAZ-p73 axis.
  • Reprimo transactivates proapoptotic genes, suppressing tumor growth in vivo.

Conclusions:

  • Identified a novel extrinsic apoptosis pathway: p53-Reprimo-Hippo-YAP/TAZ-p73.
  • Reprimo acts as an innate tumor eliminator.
  • The Reprimo pathway presents a promising target for cancer pharmacotherapy.
Keywords:
Hippo pathwayapoptosiscancerp53p73

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