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

Satsuki MIYATA; Masashi URABE; Akira GOMI; Mutsumi NAGAI; Takashi YAMAGUCHI; Tomonori TSUKAHARA; Hiroaki MIZUKAMI; Akihiro KUME; Keiya OZAWA; Eiju WATANABE

doi:10.2176/nmc.oa2012-0409

Original Articles

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

Satsuki MIYATA, Masashi URABE, Akira GOMI, Mutsumi NAGAI, Takashi YAMAGUCHI, Tomonori TSUKAHARA, Hiroaki MIZUKAMI, Akihiro KUME, Keiya OZAWA, Eiju WATANABE

Author information

Satsuki MIYATA
Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
Masashi URABE
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
Akira GOMI
Department of Pediatric Neurosurgery, Jichi Children’s Medical Center, Jichi Medical University
Mutsumi NAGAI
Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University
Takashi YAMAGUCHI
Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University
Tomonori TSUKAHARA
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
Hiroaki MIZUKAMI
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
Akihiro KUME
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
Keiya OZAWA
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University
Eiju WATANABE
Department of Neurosurgery, Center for Molecular Medicine, Jichi Medical University

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

JOURNAL OPEN ACCESS

2013 Volume 53 Issue 10 Pages 645-654

DOI https://doi.org/10.2176/nmc.oa2012-0409

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Abstract

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.

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