A conserved family of prolyl-4-hydroxylases that modify HIF
A conserved family of prolyl-4-hydroxylases that modify HIF
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DOI：
10.1126/science.1066373
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发表时间：
2001-11-09
期刊：
影响因子：
56.9
通讯作者：
McKnight, SL
中科院分区：
文献类型：
--
作者：
Bruick, RK;McKnight, SL
哺乳动物细胞通过由缺氧诱导因子（HIF）调节的保守途径对氧可用性的变化做出反应。HIF的α亚基在常氧条件下被识别HIF中羟化脯氨酸残基的泛素-连接酶复合物降解。我们确定了一个保守的HIF脯氨酰羟化酶（HPH）家族的酶，似乎是负责这种翻译后修饰。在培养的哺乳动物细胞中，在常氧条件下强制表达HIF-1 α亚基引起的HIF的不适当积累通过共表达HPH而减弱。在正常氧条件下，通过RNA干扰抑制培养的果蝇细胞中的HPH导致低氧诱导基因（LDH，编码乳酸脱氢酶）的表达升高。这些发现表明，HPH是细胞感知氧气的途径的重要组成部分。
Mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. We identified a conserved family of HIF prolyl hydoxylase (HPH) enzymes that appear to be responsible for this posttranslational modification. In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1 alpha subunit under normoxic conditions was attenuated by coexpression of HPH. Suppression of HPH in cultured Drosophila melanogaster cells by RNA interference resulted in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen.