Selak Mary A, Durán Raul V, Gottlieb Eyal
Apoptosis and Tumour Physiology Laboratory, Cancer Research UK, Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland, UK.
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):567-72. doi: 10.1016/j.bbabio.2006.05.015. Epub 2006 May 17.
HIFalpha prolyl hydroxylases (PHDs) are a family of enzymes that regulate protein levels of the alpha subunit of the hypoxia inducible transcription factor (HIF) under different oxygen levels. PHDs catalyse the conversion of a prolyl residue, molecular oxygen and alpha-ketoglutarate to hydroxy-prolyl, carbon dioxide and succinate in a reaction dependent on ferrous iron and ascorbate as cofactors. Recently it was shown that pseudo-hypoxia, HIF induction under normoxic conditions, is an important feature of tumours generated as a consequence of inactivation of the mitochondrial tumour suppressor 'succinate dehydrogenase' (SDH). Two models have been proposed to describe the link between SDH inhibition and HIF activation. Both models suggest that a mitochondrial-generated signal leads to the inhibition of PHDs in the cytosol, however, the models differ in the nature of the proposed messenger. The first model postulates that mitochondrial-generated hydrogen peroxide mediates signal transduction while the second model implicates succinate as the molecular messenger which leaves the mitochondrion and inhibits PHDs in the cytosol. Here we show that pseudo-hypoxia can be observed in SDH-suppressed cells in the absence of oxidative stress and in the presence of effective antioxidant treatment.
缺氧诱导因子α脯氨酰羟化酶（PHDs）是一类酶，可在不同氧水平下调节缺氧诱导转录因子（HIF）α亚基的蛋白质水平。PHDs在依赖亚铁离子和抗坏血酸作为辅因子的反应中，催化脯氨酰残基、分子氧和α-酮戊二酸转化为羟脯氨酸、二氧化碳和琥珀酸。最近研究表明，假性缺氧，即在常氧条件下的HIF诱导，是线粒体肿瘤抑制因子“琥珀酸脱氢酶”（SDH）失活所产生肿瘤的一个重要特征。已提出两种模型来描述SDH抑制与HIF激活之间的联系。两种模型均表明线粒体产生的信号导致胞质中PHDs的抑制，然而，这两种模型在所提出的信使的性质上有所不同。第一种模型假定线粒体产生的过氧化氢介导信号转导，而第二种模型认为琥珀酸是分子信使，它离开线粒体并抑制胞质中的PHDs。在此我们表明，在没有氧化应激且存在有效抗氧化剂处理的情况下，可在SDH抑制的细胞中观察到假性缺氧。
