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Methylation-dependent regulation of HIF-1 alpha stability restricts retinal and tumour angiogenesis
- Methylation-dependent regulation of HIF-1 alpha stability restricts retinal and tumour angiogenesis
- Kim, Y[Kim, Yunho]; Nam, HJ[Nam, Hye Jin]; Lee, J[Lee, Junyeop]; Park, DY[Park, Do Young]; Kim, C[Kim, Chan]; Yu, YS[Yu, Young Suk]; Kim, D[Kim, Dongha]; Park, SW[Park, Se Won]; Bhin, J[Bhin, Jinhyuk]; Hwang, D[Hwang, Daehee]; Lee, H[Lee, Ho]; Koh, GY[Koh, Gou Young]; Baek, SH[Baek, Sung Hee]
- DGIST Authors
- Bhin, J[Bhin, Jinhyuk]; Hwang, D[Hwang, Daehee]
- Issue Date
- Nature Communications, 7
- Article Type
- Hypoxia-inducible factor-1 alpha (HIF-1 alpha) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1 alpha posttranslational modifications, HIF-1 alpha methylation and its physiological role have not yet been elucidated. Here we show that HIF-1 alpha is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1 alpha methylation is the modulation of HIF-1 alpha stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1a(KA/KA) allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1 alpha stabilization. Importantly, S28Y and R30Q mutations of HIF-1 alpha, found in human cancers, are involved in the altered HIF-1 alpha stability. Together, these results demonstrate a role for HIF-1 alpha methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.
- Nature Publishing Group
- Related Researcher
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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