Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene -: Its possible role in the Warburg effect
Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene -: Its possible role in the Warburg effect
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DOI：
10.1074/jbc.m110978200
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发表时间：
2002-02-22
影响因子：
4.8
通讯作者：
Caro, J
中科院分区：
文献类型：
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作者：
Minchenko, A;Leshchinsky, I;Caro, J
缺氧诱导转录因子-1（HIF-1）复合物是动物细胞缺氧反应的关键介质之一，其中α亚基对氧依赖性降解高度敏感。缺氧反应在肿瘤生长和转移等许多病理生理过程中均有表现。在缺氧期间，细胞转变为主要的糖酵解代谢模式以满足其能量需求。这也表现在许多糖酵解基因的HIF-1依赖性上调中。奇怪的是，在正常氧张力条件下生长的肿瘤细胞也显示出与糖酵解酶和葡萄糖转运蛋白表达增加相关的糖酵解速率升高（瓦尔堡效应）。糖酵解通量的关键调节剂是相对最近发现的果糖-2，6-二磷酸（F-2，6-P2），其是6-磷酸果糖-1-激酶（PFK-1）的变构激活剂。F-2，6-P2的稳态水平由具有激酶和磷酸酶活性的双功能酶PFK-2/F2，6-Bpase维持。在这里，我们表明，一种同工酶，PFKFB 3，是高度诱导缺氧和缺氧模拟钴和去铁胺。这种诱导可以通过使用脯氨酰羟化酶抑制剂来复制，该酶负责von Hippel Lindau（VHL）依赖性去稳定和标记HIF-1 α。PFKFB 3基因对HIF-1的绝对依赖性通过其在VHL缺陷细胞中的过表达和在HIF-1 α条件性失活的小鼠胚胎成纤维细胞中缺乏缺氧诱导得到证实。
One of the key mediators of the hypoxic response in animal cells is the hypoxia-inducible transcription factor-1 (HIF-1) complex, in which the alpha-subunit is highly susceptible to oxygen-dependent degradation. The hypoxic response is manifested in many pathophysiological processes such as tumor growth and metastasis. During hypoxia, cells shift to a primarily glycolytic metabolic mode for their energetic needs. This is also manifested in the HIF-1-dependent up-regulation of many glycolytic genes. Paradoxically, tumor cells growing under conditions of normal oxygen tension also show elevated glycolytic rates that correlate with the increased expression of glycolytic enzymes and glucose transporters (the Warburg effect). A key regulator of glycolytic flux is the relatively recently discovered fructose-2,6-bisphosphate (F-2,6-P2), an allosteric activator of 6-phosphofructo-1-kinase (PFK-1). Steady state levels of F-2,6-P2 are maintained by the bifunctional enzyme PFK-2/F2,6-Bpase, which has both kinase and phosphatase activities. Herein, we show that one isozyme, PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1alpha. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1alpha.