丙酮酸脱氢酶复合物
酶
缺氧诱导因子
生物化学
生物
蛋白质亚单位
转录因子
细胞生物学
缺氧(环境)
磷酸化
新陈代谢
下调和上调
糖酵解
化学
基因
氧气
有机化学
作者
Daisuke Kikuchi,Yoji Andrew Minamishima,Koh Nakayama
标识
DOI:10.1016/j.bbrc.2014.07.114
摘要
Cells are frequently exposed to hypoxia in physiological and pathophysiological conditions in organisms. Control of energy metabolism is one of the critical functions of the hypoxic response. Hypoxia-Inducible Factor (HIF) is a central transcription factor that regulates the hypoxic response. HIF prolyl-hydroxylase PHDs are the enzymes that hydroxylate the α subunit of HIF and negatively regulate its expression. To further understand the physiological role of PHD3, proteomics were used to identify PHD3-interacting proteins, and pyruvate dehydrogenase (PDH)-E1β was identified as such a protein. PDH catalyzes the conversion of pyruvate to acetyl-coA, thus playing a key role in cellular energy metabolism. PDH activity was significantly decreased in PHD3-depleted MCF7 breast cancer cells and PHD3−/− MEFs. PHD3 depletion did not affect the expression of the PDH-E1α, E1β, and E2 subunits, or the phosphorylation status of E1α, but destabilized the PDH complex (PDC), resulting in less functional PDC. Finally, PHD3−/− cells were resistant to cell death in prolonged hypoxia with decreased production of ROS. Taken together, the study reveals that PHD3 regulates PDH activity in cells by physically interacting with PDC.
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