Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1α and mediates its destabilization in a VHL-independent manner
Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1α and mediates its destabilization in a VHL-independent manner
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DOI：
10.1128/mcb.00015-07
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Kietzmann, Thomas
中科院分区：
文献类型：
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作者：
Fluegel, Daniela;Goerlach, Agnes;Kietzmann, Thomas
缺氧诱导转录因子let（HIF-1 α）是缺氧反应中的关键参与者。此外，HIF-1 α对生长因子和激素有反应，这些生长因子和激素可通过蛋白激酶B（Akt）起作用。然而，HIF-1 α不是这种激酶的直接底物。因此，我们研究了蛋白激酶B靶向糖原合成酶激酶3（GSK-3）是否可能对HIF-1 α产生影响。我们发现，GSK-3的抑制或耗竭诱导HIF-1 α，而GSK-3 β的过表达降低HIF-1 α。这些作用通过HIF-1 α氧依赖性降解结构域中的三个氨基酸残基介导。此外，对von Hippel-Lindau（VHL）缺陷细胞的突变分析和实验表明，GSK-3以VHL非依赖性方式介导HIF-1 α降解。与这些观察结果一致，蛋白酶体的抑制逆转了GSK-3的作用，表明GSK-3可能通过磷酸化将HIF-1 α β靶向蛋白酶体。因此，GSK-3对HIF-1 α稳定性的直接调节可能影响生理过程或病理生理情况，如代谢疾病或肿瘤。
Hypoxia-inducible transcription factor let (HIF-1 alpha) is a key player in the response to hypoxia. Additionally, HIF-1 alpha responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1 alpha is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1 alpha. We found that the inhibition or depletion of GSK-3 induced HIF-1 alpha whereas the overexpression of GSK-3 beta reduced HIF-1 alpha. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1 alpha. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1 alpha degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1 alpha(x to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1 alpha(x stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.