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p53RDL1 regulates p53-dependent apoptosis

Nature Cell Biology volume 5, pages 216–223 (2003)Cite this article

Abstract

Although a number of targets for p53 have been reported, the mechanism of p53-dependent apoptosis still remains to be elucidated. Here we report a new p53 target-gene, designated p53RDL1 (p53-regulated receptor for death and life; also termed UNC5B). The p53RDL1 gene product contains a cytoplasmic carboxy-terminal death domain that is highly homologous to rat Unc5H2, a dependence receptor involved in the regulation of apoptosis, as well as in axon guidance and migration of neural cells1. We found that p53RDL1 mediated p53-dependent apoptosis. Conversely, when p53RDL1 interacted with its ligand, Netrin-1, p53-dependent apoptosis was blocked. Therefore, p53RDL1 seems to be a previously un-recognized target of p53 that may define a new pathway for p53-dependent apoptosis. We suggest that p53 might regulate the survival of damaged cells by balancing the regulation of Netrin–p53RDL1 signalling, and cell death through cleavage of p53RDL1 for apoptosis.

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Figure 1: Cloning of p53RDL1 as a direct target of p53.
Figure 2: p53RDL1 as a mediator of p53-dependent apoptosis.
Figure 3: Induction of apoptosis by Ad-p53RDL1 in glioblastoma cell lines.
Figure 4: Netrin-1 inhibits p53-induced apoptosis.
Figure 5: Netrin-1 inhibits p53-induced neuronal cell death.

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Acknowledgements

We thank B. Vogelstein for the p53-deficient cancer cell lines, and P. Mehlen for the recombinant netrin protein. We also thank K. Matsui and S. Onoue for their excellent technical assistance. This work was supported in part by Grants #13216031 & #14028018 from the Ministry of Education, Culture, Sports, Science and Technology (to H.A.), in part by Research Grant #01-23301 of the Princess Takamatsu Cancer Research Fund (to H.A.) and in part by “Research for the Future” Program Grant #00L01402 from the Japan Society for the Promotion of Science (to Y.N.).

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  1. Hirofumi Arakawa

    Present address: Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuou-ku, Tokyo, 104-0045, Japan

  2. Chizu Tanikawa, Koichi Matsuda and Hirofumi Arakawa: These authors equally contributed to this work.

Authors and Affiliations

  1. Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Chizu Tanikawa, Koichi Matsuda, Seisuke Fukuda, Yusuke Nakamura & Hirofumi Arakawa

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  1. Chizu Tanikawa
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Correspondence to Hirofumi Arakawa.

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Supplementary information

Supplementary Figures

Figure S1 Comparison of the amino-acid sequences of p53RDL1 and rat Unc5H2. (PDF 574 kb)

Figure S2 Expression of p53RDL1.

Figure S3 β-gal staining of NHNP cells or PC-12 cells.

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Tanikawa, C., Matsuda, K., Fukuda, S. et al. p53RDL1 regulates p53-dependent apoptosis. Nat Cell Biol 5, 216–223 (2003). https://doi.org/10.1038/ncb943

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