Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1
Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1
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DOI：
10.1074/jbc.m508718200
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发表时间：
2005-12-23
影响因子：
4.8
通讯作者：
Verma, A
中科院分区：
文献类型：
--
作者：
Lu, HS;Dalgard, CL;Verma, A
HIF-1转录因子α亚基通过氧和2-酮戊二酸依赖性双加氧酶的连续羟基化促进该蛋白质的衰变，从而阻止参与能量代谢、血管生成、细胞存活和基质修饰的许多基因的转录激活。缺氧阻断HIF-1 α羟基化，从而激活HIF-1 α介导的基因表达。几种非缺氧刺激也可以激活HIF-1，尽管所涉及的机制尚不清楚。在这里，我们表明，葡萄糖代谢产物丙酮酸和草酰乙酸的HIF-1 α衰减的方式选择性可逆的抗坏血酸，半胱氨酸，组氨酸，亚铁，但不是2-酮戊二酸或氧。丙酮酸和草酰乙酸与HIF-1 α脯氨酰羟化酶的2-酮戊二酸位点结合，但它们对HIF-1的作用不被其他克雷布斯循环中间体（包括琥珀酸和富马酸）模仿。我们发现，葡萄糖衍生的2-含氧酸对HIF-1羟基化的失活是许多高度糖酵解的癌细胞中常见的突出的基础HIF-1活性的基础。由于HIF-1本身促进糖酵解代谢，葡萄糖代谢产物对HIF-1的增强可能构成了恶性进展中涉及的一种新的前馈信号机制。
Continuous hydroxylation of the HIF-1 transcription factor alpha subunit by oxygen and 2-oxoglutarate-dependent dioxygenases promotes decay of this protein and thus prevents the transcriptional activation of many genes involved in energy metabolism, angiogenesis, cell survival, and matrix modification. Hypoxia blocks HIF-1 alpha hydroxylation and thus activates HIF-1 alpha-mediated gene expression. Several nonhypoxic stimuli can also activate HIF-1, although the mechanisms involved are not well known. Here we show that the glucose metabolites pyruvate and oxaloacetate inactivate HIF-1 alpha decay in a manner selectively reversible by ascorbate, cysteine, histidine, and ferrous iron but not by 2-oxoglutarate or oxygen. Pyruvate and oxaloacetate bind to the 2-oxoglutarate site of HIF-1 alpha prolyl hydroxylases, but their effects on HIF-1 are not mimicked by other Krebs cycle intermediates, including succinate and fumarate. We show that inactivation of HIF-1 hydroxylation by glucose-derived 2-oxoacids underlies the prominent basal HIF-1 activity commonly seen in many highly glycolytic cancer cells. Since HIF-1 itself promotes glycolytic metabolism, enhancement of HIF-1 by glucose metabolites may constitute a novel feed-forward signaling mechanism involved in malignant progression.