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Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability

  • Authors:
    • Shota Kawakami
    • Masaki Michishita
    • Motoharu Sakaue
    • Masami Morimatsu
    • Mitsuki Uemura
    • Nobuaki Kashiwagi
    • Marika Maeda
    • Yukino Machida
    • Daigo Azakami
    • Ai S. Egusa
    • Eri Onozawa
    • Katsumi Ishioka
    • Masami Watanabe
    • Yoshikazu Tanaka
    • Toshinori Omi
    • Kazuhiko Ochiai
  • View Affiliations / Copyright

    Affiliations: School of Veterinary Nursing and Technology, Faculty of Veterinary Science, Musashino, Tokyo 180‑8602, Japan, Laboratory of Veterinary Pathology, School of Veterinary Science, Musashino, Tokyo 180‑8602, Japan, Laboratory of Anatomy II, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa 252‑5201, Japan, Laboratory of Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060‑0818, Japan, Laboratory of Veterinary Hygiene, School of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180‑8602, Japan, Laboratory of Clinical Oncology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183‑8538, Japan, Department of Applied Life Science, Faculty of Food Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180-8602, Japan, Department of Urology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700‑8558, Japan, Research Center for Animal Life Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180‑8602, Japan
    Copyright: © Kawakami et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 351
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    Published online on: October 11, 2020
       https://doi.org/10.3892/ol.2020.12214
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Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations are common in gliomas, acute myeloid leukemia, and chondrosarcoma. The mutation ‘hotspot’ is a single arginine residue, R132. The R132H mutant of IDH1 produces the 2‑hydroxyglutarate (2‑HG) carcinogen from α‑ketoglutarate (α‑KG). The reduction of α‑KG induces the accumulation of hypoxia‑inducible factor‑1α subunit (HIF‑1α) in the cytosol, which is a predisposing factor for carcinogenesis. R132H is the most common IDH1 mutation in humans, but mutations at the R132 residue can also occur in tumor tissues of dogs. The current study reported the discovery of a novel Tyr208Cys (Y208C) mutation in canine IDH1 (cIDH1), which was isolated from 2 of 45 canine chondrosarcoma cases. As the genomic DNA isolated from chondrosarcoma tissue was mutated, but that isolated from blood was not, Y208C mutations were considered to be spontaneous somatic mutations. The isocitrate dehydrogenase activity of the Y208C mutant was attenuated compared with that of wild‑type (WT) cIDH1, but the attenuation of Y208C was less intense than that of the R132H mutation. The induction of HIF‑1α response element activity and cell retention of HIF‑1α were not increased by Y208C overexpression. In silico and cell biological analysis of IDH1 dimerization revealed that the Y208C mutation, but not the R132H mutation, attenuated binding activity with WT cIDH1. These data suggested that the attenuation of dimerization by the Y208C mutation may cause tumorigenesis through different mechanisms other than via 2‑HG production by the IDH1 R132 mutation.
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Copy and paste a formatted citation
Spandidos Publications style
Kawakami S, Michishita M, Sakaue M, Morimatsu M, Uemura M, Kashiwagi N, Maeda M, Machida Y, Azakami D, Egusa AS, Egusa AS, et al: Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability. Oncol Lett 20: 351, 2020.
APA
Kawakami, S., Michishita, M., Sakaue, M., Morimatsu, M., Uemura, M., Kashiwagi, N. ... Ochiai, K. (2020). Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability. Oncology Letters, 20, 351. https://doi.org/10.3892/ol.2020.12214
MLA
Kawakami, S., Michishita, M., Sakaue, M., Morimatsu, M., Uemura, M., Kashiwagi, N., Maeda, M., Machida, Y., Azakami, D., Egusa, A. S., Onozawa, E., Ishioka, K., Watanabe, M., Tanaka, Y., Omi, T., Ochiai, K."Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability". Oncology Letters 20.6 (2020): 351.
Chicago
Kawakami, S., Michishita, M., Sakaue, M., Morimatsu, M., Uemura, M., Kashiwagi, N., Maeda, M., Machida, Y., Azakami, D., Egusa, A. S., Onozawa, E., Ishioka, K., Watanabe, M., Tanaka, Y., Omi, T., Ochiai, K."Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability". Oncology Letters 20, no. 6 (2020): 351. https://doi.org/10.3892/ol.2020.12214
Copy and paste a formatted citation
x
Spandidos Publications style
Kawakami S, Michishita M, Sakaue M, Morimatsu M, Uemura M, Kashiwagi N, Maeda M, Machida Y, Azakami D, Egusa AS, Egusa AS, et al: Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability. Oncol Lett 20: 351, 2020.
APA
Kawakami, S., Michishita, M., Sakaue, M., Morimatsu, M., Uemura, M., Kashiwagi, N. ... Ochiai, K. (2020). Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability. Oncology Letters, 20, 351. https://doi.org/10.3892/ol.2020.12214
MLA
Kawakami, S., Michishita, M., Sakaue, M., Morimatsu, M., Uemura, M., Kashiwagi, N., Maeda, M., Machida, Y., Azakami, D., Egusa, A. S., Onozawa, E., Ishioka, K., Watanabe, M., Tanaka, Y., Omi, T., Ochiai, K."Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability". Oncology Letters 20.6 (2020): 351.
Chicago
Kawakami, S., Michishita, M., Sakaue, M., Morimatsu, M., Uemura, M., Kashiwagi, N., Maeda, M., Machida, Y., Azakami, D., Egusa, A. S., Onozawa, E., Ishioka, K., Watanabe, M., Tanaka, Y., Omi, T., Ochiai, K."Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability". Oncology Letters 20, no. 6 (2020): 351. https://doi.org/10.3892/ol.2020.12214
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