KMID : 0624620160490050245
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BMB Reports 2016 Volume.49 No. 5 p.245 ~ p.246
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Regulation of HIF-1¥á stability by lysine methylation
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Baek Sung-Hee
Kim Keun-Il
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Abstract
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The level and activity of critical regulatory proteins in cells are tightly controlled by several tiers of post-translational modifications. HIF-1¥á is maintained at low levels under normoxia conditions by the collaboration between PHD proteins and the VHL-containing E3 ubiquitin ligase complex. We recently identified a new physiologically relevant mechanism that regulates HIF-1¥á stability in the nucleus in response to cellular oxygen levels. This mechanism is based on the collaboration between the SET7/9 methyltransferase and the LSD1 demethylase. SET7/9 adds a methyl group to HIF-1¥á, which triggers degradation of the protein by the ubiquitin-proteasome system, whereas LSD1 removes the methyl group, leading to stabilization of HIF-1¥á under hypoxia conditions. In cells from knock-in mice with a mutation preventing HIF-1¥á methylation (Hif1¥áKA/KA), HIF-1¥á levels were increased in both normoxic and hypoxic conditions. Hif1¥áKA/KA knock-in mice displayed increased hematological parameters, such as red blood cell count and hemoglobin concentration. They also displayed pathological phenotypes; retinal and tumor-associated angiogenesis as well as tumor growth were increased in Hif1¥áKA/KA knock-in mice. Certain human cancer cells exhibit mutations that cause defects in HIF-1¥á methylation. In summary, this newly identified methylation-based regulation of HIF-1¥á stability constitutes another layer of regulation that is independent of previously identified mechanisms.
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KEYWORD
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HIF-1¥á, LSD1, Lysine methylation, SET7/9, Ubiquitin
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