Nature Medicine
6, 96 - 99 (2000)
doi:10.1038/71600
Reduced stability of retinoblastoma protein by gankyrin, an oncogenic
ankyrin-repeat protein overexpressed in hepatomasHiroaki Higashitsuji1, Katsuhiko Itoh1, Toshikazu Nagao1, Simon Dawson2, Kohsuke Nonoguchi1, Tsuneo Kido1, R. John Mayer2, Shigeki Arii3
& Jun Fujita11
Department of Clinical Molecular Biology, Faculty of
Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
2
Laboratory of Intracellular Proteolysis, School of
Biomedical Sciences, University of Nottingham Medical School, Queens Medical
Centre, Nottingham, NG7 2UH, UK
3
First Department of Surgery, Faculty of Medicine, Kyoto
University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
Correspondence should be addressed to Jun Fujita jfujita@virus.kyoto-u.ac.jpHepatocellular 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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