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Identification of SCN3B as a novel p53-inducible proapoptotic gene

Oncogene volume 23, pages 7791–7798 (2004)Cite this article

Abstract

Tumor suppressor p53 is a transcription factor that induces growth arrest and/or apoptosis in response to cellular stress. To identify novel p53-inducible genes, we compared the expression of genes in normal mouse embryo fibroblasts (MEFs) to p53-null cells by cDNA representational difference analysis. We report here that expression of endogenous sodium channel subunit beta 3 (SCN3B) is upregulated in mouse embryonic fibroblasts by DNA damage in a p53-dependent manner. In addition, we found that SCN3B levels are upregulated in human cancer cell lines by DNA damaging agents, as well as by overexpression of p53, but not significantly by p63 or p73. Furthermore, we identified two putative p53-binding sites upstream of the first exon (RE1) and in the third intron (RE2). The p53 protein can directly interact with the putative p53-binding sites in vivo, as assessed by chromatin immunoprecipitation. A reporter gene assay revealed that these two p53-binding sites are functional response elements. The SCN3B protein appears to be localized to the endoplasmic reticulum (ER). Introduction of the SCN3B gene into T98G and Saos2 cells potently suppressed colony formation. Furthermore, we found that adenovirus-mediated transfer of SCN3B induced apoptosis when combined with anticancer agents. The results presented here suggest that SCN3B mediates a p53-dependent apoptotic pathway and may be a candidate for gene therapy combined with anticancer drugs.

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Acknowledgements

We are grateful to Dr Motoya Katsuki for MEFs from p53 nullizygote mice and Dr Bert Vogelstein for HCT116-p53(−/−) cell lines. We also thank Dr Joseph F. Costello for valuable discussion in this study. This study was supported in part by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology (MT, YH, KI and TT).

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Author notes

  1. Katsuya Adachi, Minoru Toyota and Yasushi Sasaki: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan

    Katsuya Adachi, Minoru Toyota, Yasushi Sasaki, Toshiharu Yamashita, Setsuko Ishida, Mutsumi Ohe-Toyota & Takashi Tokino

  2. First Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Minoru Toyota, Reo Maruyama, Yuji Hinoda & Kohzoh Imai

  3. Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Katsuya Adachi, Tsuyoshi Saito & Ryuichi Kudo

  4. Division of Clinical Laboratory, Yamaguchi University School of Medicine, 1-1-1, Minami-Kogushi, 755-8505, Ube, Japan

    Yuji Hinoda

Authors
  1. Katsuya Adachi
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  2. Minoru Toyota
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  12. Takashi Tokino
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Corresponding author

Correspondence to Takashi Tokino.

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Adachi, K., Toyota, M., Sasaki, Y. et al. Identification of SCN3B as a novel p53-inducible proapoptotic gene. Oncogene 23, 7791–7798 (2004). https://doi.org/10.1038/sj.onc.1208067

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  • DOI: https://doi.org/10.1038/sj.onc.1208067

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