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topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage

Oncogene volume 24, pages 3385–3396 (2005)Cite this article

Abstract

The RING family zinc-finger protein topors (topoisomerase I-binding protein) binds not only topoisomerase I, but also p53 and the AAV-2 Rep78/68 proteins. topors maps to human chromosome 9p21, which contains candidate tumor suppressor genes implicated in small cell lung cancers. In this study, we isolated the murine counterpart of topors and investigated its impact on p53 function. The deduced amino-acid sequence of mouse topors exhibits extensive similarity to human topors. Overexpressed myc-tagged topors associates with and stabilizes p53, and enhances the p53-dependent transcriptional activities of p21Waf1, MDM2 and Bax promoters and elevates endogenous p21Waf1 mRNA levels. Overexpression of topors consequently results in the suppression of cell growth by cell cycle arrest and/or by the induction of apoptosis. Taken together, these studies identify topors as a positive regulator of p53. The expression of topors is induced by exposure to the genotoxic reagents cisplatin and camptothecin, a DNA topoisomerase I inhibitor. We therefore postulate that topors mediates p53-dependent cellular responses induced by DNA damage, suggesting its physiological role as a tumor suppressor.

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Acknowledgements

We are grateful to Dr M Vidal and Dr O Tetsu for critical reading of the manuscript, Dr O Ohara for providing the mouse cDNA library, Dr T Oda for providing the pBTM116 vector, Ms Sanae Takeda, Dr Jie Liu and Dr Tomomi Kaneko for kind assistance and Dr T Akasaka for initial instructions on yeast two-hybrid screening. This project was supported by a grant-in-aid for Scientific Research on Priority Areas and for Scientific Research (B) and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government to HK and AN.

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Authors and Affiliations

  1. Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Ling Lin, Yuki Takada & Haruhiko Koseki

  2. RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro, Tsurumi-ku, Yokohama, 230-0045, Japan

    Ling Lin, Yuki Takada & Haruhiko Koseki

  3. Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892, USA

    Ling Lin, Jian-Hua Zhang & William F Simonds

  4. Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba, 260-8717, Japan

    Toshinori Ozaki, Hajime Kageyama, Yoko Nakamura & Akira Nakagawara

  5. Department of Public health, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Akira Hata

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  1. Ling Lin
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Correspondence to Haruhiko Koseki.

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Lin, L., Ozaki, T., Takada, Y. et al. topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage. Oncogene 24, 3385–3396 (2005). https://doi.org/10.1038/sj.onc.1208554

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