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Reprimo (RPRM): A Tumor Suppressor That Induces Extrinsic Apoptosis via YAP Signaling
Masahiro Takikawa1,2, Rieko Ohki1
1Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
Reprimo (encoded by RPRM) was initially identified as a p53 target gene in 2000 and functions as a tumor suppressor. Promoter hypermethylation of RPRM is frequently observed in various cancers, suggesting that it is transcriptionally silenced during tumorigenesis. Previous studies have reported that overexpression of RPRM induces G2/M cell cycle arrest, inhibits cell proliferation, promotes apoptosis, and increases cellular sensitivity to DNA damage. However, the molecular function of Reprimo is not completely understood. In particular, our recent studies revealed that Reprimo has a novel extracellular function, being secreted outside the cells where it functions to induce apoptosis in its target cells. Furthermore, we found that this apoptosis pathway is novel, mediated by a signaling pathway composed of p53-Reprimo-protocadherin family-Hippo-YAP/TAZ-p73. Reprimo is the first example of an extracellular ligand that induces cell death by modulating YAP activity and is a unique upstream regulator of Hippo signaling. This review summarizes current knowledge of the tumor-suppressive mechanisms of Reprimo, with an emphasis on its unique extracellular function and discusses potential future research directions and clinical applications in cancer therapy.
Insights
Reprimo (RPRM) is a tumor suppressor. It has a novel extracellular function, acting as a ligand that triggers apoptosis by regulating the Hippo-YAP pathway, offering new cancer therapy potential.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Reprimo (RPRM) is a known tumor suppressor and p53 target gene.
- RPRM promoter hypermethylation silences its transcription in various cancers.
- Previous studies linked RPRM overexpression to cell cycle arrest, apoptosis, and DNA damage sensitivity.
Purpose of the Study:
- To elucidate the complete molecular function of Reprimo.
- To highlight Reprimo's novel extracellular role in inducing apoptosis.
- To detail the newly identified p53-Reprimo-protocadherin-Hippo-YAP/TAZ-p73 signaling pathway.
Main Methods:
- Literature review of Reprimo's known functions.
- Analysis of recent studies on Reprimo's extracellular activity.
- Examination of the novel signaling pathway involving Reprimo.
Main Results:
- Reprimo is secreted extracellularly to induce apoptosis in target cells.
- A novel signaling pathway (p53-Reprimo-protocadherin-Hippo-YAP/TAZ-p73) mediates this apoptosis.
- Reprimo is the first identified extracellular ligand modulating YAP activity and regulating Hippo signaling.
Conclusions:
- Reprimo possesses a unique extracellular tumor-suppressive mechanism.
- Reprimo's role as an upstream regulator of Hippo signaling is significant.
- Reprimo presents potential as a therapeutic target and agent in cancer treatment.
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