Bemis Lynne, Chan Denise A, Finkielstein Carla V, Qi Lin, Sutphin Patrick D, Chen Xiaojiang, Stenmark Kurt, Giaccia Amato J, Zundel Wayne
Departments of Medicine and Biochemistry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Genes Dev. 2004 Apr 1;18(7):739-44. doi: 10.1101/gad.1180104.
Mammalian oxygen homeostasis is dependent on the HIF family of transcription factors. The CSN subunit, CSN5, binds both the CODD of HIF-1 alpha and the pVHL tumor suppressor. High CSN5 expression generates a pVHL-independent form of CSN5 that stabilizes HIF-1 alpha aerobically by inhibiting HIF-1 alpha prolyl-564 hydroxylation. Aerobic CSN5 association with HIF-1 alpha occurs independently of the CSN holocomplex, leading to HIF-1 alpha stabilization independent of Cullin 2 deneddylation. CSN5 weakly associates with HIF-1 alpha under hypoxia, but is required for optimal hypoxia-mediated HIF-1 alpha stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1 alpha stability by different mechanisms during oncogenesis.
哺乳动物的氧稳态依赖于转录因子HIF家族。CSN亚基CSN5既能结合HIF-1α的CODD，也能结合pVHL肿瘤抑制因子。高CSN5表达会产生一种不依赖pVHL的CSN5形式，通过抑制HIF-1α脯氨酸-564羟基化在有氧条件下稳定HIF-1α。CSN5与HIF-1α的有氧结合独立于CSN全复合物，导致HIF-1α的稳定独立于Cullin 2去泛素化。在缺氧条件下，CSN5与HIF-1α的结合较弱，但对于最佳的缺氧介导的HIF-1α稳定是必需的。这些结果表明，CSN5在肿瘤发生过程中通过不同机制调节有氧以及缺氧条件下HIF-1α的稳定性。
