An R132H Mutation in Isocitrate Dehydrogenase 1 Enhances p21 Expression and Inhibits Phosphorylation of Retinoblastoma Protein in Glioma Cells
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概要
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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 IDH1R132H-expression plasmid. Small interfering ribonucleic acid (siRNA) for SREBP1 specifically decreased p21 messenger RNA (mRNA) levels independent of the p53 pathway. In IDH1R132H-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.
- 社団法人 日本脳神経外科学会の論文
著者
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Watanabe Eiju
Department Of Neurosurgery Jichi Medical School
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Nagai Mutsumi
Department Of Neurosurgery Sano Kousei General Hospital
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Yamaguchi Takashi
Department Of Cardiology Saitama Medical School
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Urabe Masashi
Division Of Genetic Therapeutics Center For Molecular Medicine
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Kume Akihiro
Division Of Genetic Therapeutics Center For Molecular Medicine
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Mizukami Hiroaki
Division Of Functional Genomics Jichi Medical School
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Gomi Akira
Department Of Neurosurgery Jichi Medical University
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Ozawa Keiya
Division of Cell Therapy, Jichi Medical University Hospital, Shimotsuke
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WATANABE Eiju
Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University
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MIYATA Satsuki
Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University
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TSUKAHARA Tomonori
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
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GOMI Akira
Department of Pediatric Neurosurgery, Jichi Children's Medical Center, Jichi Medical University
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URABE Masashi
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
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KUME Akihiro
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
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