Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5
Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5
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DOI：
10.1101/gad.1180104
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发表时间：
2004-04-01
影响因子：
10.5
通讯作者：
Zundel, W
中科院分区：
文献类型：
--
作者：
Bemis, L;Chan, DA;Zundel, W
哺乳动物的氧稳态依赖于转录因子的HIF家族。CSN亚基CSN 5结合HIF-1 α的CODD和pVHL肿瘤抑制因子。高CSN 5表达产生一种pVHL非依赖性形式的CSN 5，通过抑制HIF-1 α脯氨酰-564羟基化在有氧条件下稳定HIF-1 α。有氧CSN 5与HIF-1 α的结合独立于CSN全复合物发生，导致HIF-1 α稳定化独立于Cullin 2去卷曲化。CSN 5在缺氧条件下与HIF-1 α弱相关，但对于最佳缺氧介导的HIF-1 α稳定化是必需的。这些结果表明，CSN 5调节有氧以及缺氧HIF-1 α的稳定性在肿瘤发生过程中通过不同的机制。
Mammalian oxygen homeostasis is dependent on the HIF family of transcription factors. The CSN subunit, CSN5, binds both the CODD of HIF-1alpha and the pVHL tumor suppressor. High CSN5 expression generates a pVHL-independent form of CSN5 that stabilizes HIF-1alpha aerobically by inhibiting HIF-1alpha prolyl-564 hydroxylation. Aerobic CSN5 association with HIF-1alpha occurs independently of the CSN holocomplex, leading to HIF-1alpha stabilization independent of Cullin 2 deneddylation. CSN5 weakly associates with HIF-1alpha under hypoxia, but is required for optimal hypoxia-mediated HIF-1alpha stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1alpha stability by different mechanisms during oncogenesis.