Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation

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Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation

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Title: Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation
Author: Koivunen, Peppi; Lee, Sungwoo; Duncan, Christopher G.; Lopez, Giselle; Lu, Gang; Ramkissoon, Shakti; Losman, Julie-Aurore; Joensuu, Päivi; Bergmann, Ulrich; Gross, Stefan; Travins, Jeremy; Weiss, Samuel; Looper, Ryan; Ligon, Keith Lloyd; Verhaak, Roel G.W.; Yan, Hai; Kaelin, William George

Note: Order does not necessarily reflect citation order of authors.

Citation: Koivunen, Peppi, Sungwoo Lee, Christopher G. Duncan, Giselle Lopez, Gang Lu, Shakti Ramkissoon, Julie A. Losman, et al. 2013. Transformation by the R enantiomer of 2-hydroxyglutarate linked to EglN activation. Nature 483(7390): 484-488.
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Abstract: The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EglN prolyl 4-hydroxylases that mark the HIF transcription factor for polyubiquitylation and proteasomal degradation 1. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumors but can suppress tumor growth in some other contexts. IDH1 and IDH2, which catalyze the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumors and leukemias. The resulting mutants display the neomorphic ability to convert 2-OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG) 2, 3. Here we show that R-2HG, but not S-2HG, stimulates EglN activity leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes.
Published Version: doi:10.1038/nature10898
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656605/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11177929
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