Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha.
Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, alpha-ketoglutarate (alpha-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1alpha levels was reversible by an alpha-KG derivative. HIF-1alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.
Zhao
Shimin
S
Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
Lin
Yan
Y
Xu
Wei
W
Jiang
Wenqing
W
Zha
Zhengyu
Z
Wang
Pu
P
Yu
Wei
W
Li
Zhiqiang
Z
Gong
Lingling
L
Peng
Yingjie
Y
Ding
Jianping
J
Lei
Qunying
Q
Guan
Kun-Liang
KL
Xiong
Yue
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D055162:Biocatalysis; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism; D010070:Oxalates / Q000494:pharmacology; D055503:Protein Multimerization
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D050505:Mutant Proteins; D010070:Oxalates; C015407:oxalomalic acid; D007521:Isocitrate Dehydrogenase