Regulation of HIF-1 alpha stability by lysine methylationopen access
- Authors
- Baek, Sung Hee; Kim, Keun Il
- Issue Date
- May-2016
- Publisher
- KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY
- Keywords
- HIF-1 alpha; LSD1; Lysine methylation; SET7/9; Ubiquitin
- Citation
- BMB REPORTS, v.49, no.5, pp 245 - 246
- Pages
- 2
- Journal Title
- BMB REPORTS
- Volume
- 49
- Number
- 5
- Start Page
- 245
- End Page
- 246
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/9807
- DOI
- 10.5483/BMBRep.2016.49.5.053
- ISSN
- 1976-6696
1976-670X
- Abstract
- The level and activity of critical regulatory proteins in cells are tightly controlled by several tiers of post-translational modifications. HIF-1 alpha 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 alpha 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 alpha, which triggers degradation of the protein by the ubiquitin-proteasome system, whereas LSD1 removes the methyl group, leading to stabilization of HIF-1 alpha under hypoxia conditions. In cells from knock-in mice with a mutation preventing HIF-1 alpha methylation (Hif1 alpha(KA/KA)), HIF-1 alpha levels were increased in both normoxic and hypoxic conditions. Hif1 alpha(KA/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 alpha(KA/KA) knock-in mice. Certain human cancer cells exhibit mutations that cause defects in HIF-1 alpha methylation. In summary, this newly identified methylation-based regulation of HIF-1 alpha stability constitutes another layer of regulation that is independent of previously identified mechanisms.
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