An R132H Mutation in Isocitrate Dehydrogenase 1 Enhances p21 Expression and Inhibits Phosphorylation of Retinoblastoma Protein in Glioma Cells

• MIYATA Satsuki

  Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University

• URABE Masashi

  Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University

• GOMI Akira

  Department of Pediatric Neurosurgery, Jichi Children’s Medical Center, Jichi Medical University

• NAGAI Mutsumi

  Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University

• YAMAGUCHI Takashi

  Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University

• TSUKAHARA Tomonori

  Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University

• MIZUKAMI Hiroaki

  Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University

• KUME Akihiro

  Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University

• OZAWA Keiya

  Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University

• WATANABE Eiju

  Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University

抄録

Cytosolic isocitrate dehydrogenase 1 (IDH1) with an R132H mutation in brain tumors loses its enzymatic activity for catalyzing isocitrate to α-ketoglutarate (α-KG) and acquires new activity whereby it converts α-KG to 2-hydroxyglutarate. The IDH1 mutation induces down-regulation of tricarboxylic acid cycle intermediates and up-regulation of lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) regulate not only the synthesis of cholesterol and fatty acids but also acyclin-dependent kinase inhibitor p21 that halts the cell cycle at G1. Here we show that SREBPs were up-regulated in U87 human glioblastoma cells transfected with an IDH1^R132H-expression plasmid. Small interfering ribonucleic acid (siRNA) for SREBP1 specifically decreased p21 messenger RNA (mRNA) levels independent of the p53 pathway. In IDH1^R132H-expressing U87 cells, phosphorylation of Retinoblastoma (Rb) protein also decreased. We propose that metabolic changes induced by the IDH1 mutation enhance p21 expression via SREBP1 and inhibit phosphorylation of Rb, which slows progression of the cell cycle and may be associated with non-aggressive features of gliomas with an IDH1 mutation.

収録刊行物

• Neurologia medico-chirurgica

  Neurologia medico-chirurgica 53 (10), 645-654, 2013

  一般社団法人 日本脳神経外科学会

キーワード

• isocitrate dehydrogenase 1 (IDH1) mutation
• sterol regulatory element-binding proteins (SREBP)
• p21
• lipid metabolism
• tricarboxylic acid (TCA) cycle

詳細情報

• CRID: 1390001205055967744
• NII論文ID: 10031191634
• NII書誌ID: AN00358613
• DOI: 10.2176/nmc.oa2012-0409
• COI: 1:STN:280:DC%2BC2c%2FitFShuw%3D%3D
• ISSN: 13498029
• ISSN: 04708105
• PubMed: 24077277
• Web Site: https://www.jstage.jst.go.jp/article/nmc/53/10/53_oa2012-0409/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2014315990
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • PubMed
  • CiNii Articles
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