Nur77通过抑制pVHL介导的降解来上调缺氧诱导因子α（HIF-α）。
Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation.
作者信息
Kim Bu Yeon, Kim Hyungsoo, Cho Eun Jung, Youn Hong Duk
机构信息
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
出版信息
Exp Mol Med. 2008 Feb 29;40(1):71-83. doi: 10.3858/emm.2008.40.1.71.
In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-alpha transcriptional activity. We found that Nur77 associates and stabilizes HIF-1alpha via indirect interaction. Nur77 was found to interact with pVHL in vivo via the alpha-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1alpha and ultimately increased the stability and transcriptional activity of HIF-1alpha. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1alpha. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-alpha. Moreover, Nur77 could not further stabilize HIF-2alpha in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-alpha by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-alpha transcriptional activity under the non-hypoxic conditions.
在本研究中，我们调查了孤儿核受体Nur77在缺氧诱导因子-α（HIF-α）转录活性中的作用。我们发现Nur77通过间接相互作用与HIF-1α结合并使其稳定。研究发现，Nur77在体内通过VHL蛋白（pVHL）的α结构域与pVHL相互作用。通过与pVHL结合，Nur77与延伸蛋白C竞争pVHL的结合。此外，Nur77与pVHL的结合抑制了pVHL介导的HIF-1α泛素化，最终增加了HIF-1α的稳定性和转录活性。发现Nur77的配体结合结构域与pVHL相互作用，并且该配体结合结构域的表达足以稳定和反式激活HIF-1α。在氯化钴处理或pVHL敲低的条件下，Nur77无法稳定HIF-α。此外，在A498/VHL稳定细胞中，Nur77无法进一步稳定HIF-2α，这与我们发现Nur77通过与pVHL结合间接稳定HIF-α的结果一致。因此，我们的结果表明，孤儿核受体Nur77与pVHL结合，从而在非缺氧条件下稳定并增加HIF-α的转录活性。
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