Journal
SCIENCE
Volume 324, Issue 5924, Pages 261-265Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1170944
Keywords
-
Categories
Funding
- Chinese Ministry of Education
- State Key Development Programs of China [2009CB918401, 2006CB806700]
- National 863 Program of China [2006AA02A308]
- China NSF [30600112, 30871255]
- Shanghai Key Basic Research Projects [06JC14086, 07PJ14011, 08JC1400900]
- NIH
Ask authors/readers for more resources
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-1 alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1 alpha levels was reversible by an alpha-KG derivative. HIF-1 alpha 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available