Berra E, Richard D E, Gothié E, Pouysségur J
Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, 33 Avenue Valombrose, 06189 Nice, France.
FEBS Lett. 2001 Feb 23;491(1-2):85-90. doi: 10.1016/s0014-5793(01)02159-7.
Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis. In normoxia, HIF-1alpha is a short lived protein, whereas hypoxia rapidly increases HIF-1alpha protein levels by relaxing its ubiquitin-proteasome-dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF-1alpha, does not modulate the degradation/stabilization profile of HIF-1alpha. However, we present evidence that the rate of HIF-1alpha degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF-1alpha is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF-1-dependent transcriptional activity. In keeping with these findings, we postulate that HIF-1alpha is targetted to the proteasome via a HIF-1alpha proteasome targetting factor (HPTF) which expression is directly under the control of HIF-1-mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel-Lindau protein (pVHL).
缺氧诱导因子-1α（HIF-1α）在氧稳态中起核心作用。在常氧条件下，HIF-1α是一种半衰期短的蛋白质，而缺氧通过减轻其泛素-蛋白酶体依赖性降解迅速增加HIF-1α蛋白水平。在本研究中，我们发现已知可磷酸化HIF-1α的p42/p44丝裂原活化蛋白激酶级联反应并不调节HIF-1α的降解/稳定情况。然而，我们提供的证据表明HIF-1α的降解速率取决于缺氧应激的持续时间。我们证明HIF-1α的降解受到以下因素抑制：（i）用放线菌素D抑制一般转录或（ii）特异性阻断HIF-1依赖性转录活性。与这些发现一致，我们推测HIF-1α通过一种HIF-1α蛋白酶体靶向因子（HPTF）被靶向至蛋白酶体，该因子的表达直接受HIF-1介导的转录活性控制。尽管HPTF尚未在分子水平上被鉴定，但它显然不同于冯希佩尔-林道蛋白（pVHL）。
