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Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas

Nature Medicine volume 6, pages 96–99 (2000)Cite this article

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent1,2. Although inactivation of some tumor suppressor genes such as p53 and p16INK4Ahas been identified3, no known oncogene is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybridization4, and identified an oncoprotein consisting of six ankyrin repeats (gankyrin). The expression of gankyrin was increased in all 34 hepatocellular carcinomas studied. Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells. Gankyrin bound to the product of the retinoblastoma gene (RB1), increasing its phosphorylation and releasing the activity of the transcription factor E2F-1. Gankyrin accelerated the degradation of RB1 in vitro and in vivo, and was identical to or interacted with a subunit of the 26S proteasome5,6. These results demonstrate the importance of ubiquitin–proteasome pathway in the regulation of cell growth and oncogenic transformation, and indicate that gankyrin overexpression contributes to hepatocarcinogenesis by destabilizing RB1.

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Figure 1: Oncogenic activity of gankyrin.
Figure 2: Interaction of gankyrin with RB1.
Figure 3: Effects of gankyrin on phosphorylation and degradation of RB1 and on E2F activity.

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Acknowledgements

This work was supported in part by Grants-in-Aid from the Ministry of Science, Culture, Sports and Education of Japan, and by the European Union Biomedicine and Health Framework IV grant.

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Authors and Affiliations

  1. Department of Clinical Molecular Biology, Faculty of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, 606-8507, Kyoto, Japan

    Hiroaki Higashitsuji, Katsuhiko Itoh, Toshikazu Nagao, Kohsuke Nonoguchi, Tsuneo Kido & Jun Fujita

  2. Laboratory of Intracellular Proteolysis, School of Biomedical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham, NG7 2UH, UK

    Simon Dawson & R. John Mayer

  3. First Department of Surgery, Faculty of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, 606-8507, Kyoto, Japan

    Shigeki Arii

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  1. Hiroaki Higashitsuji
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Correspondence to Jun Fujita.

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Higashitsuji, H., Itoh, K., Nagao, T. et al. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 6, 96–99 (2000). https://doi.org/10.1038/71600

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