The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma
The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma
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DOI：
10.1016/s1535-6108(02)00044-2
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发表时间：
2002-04-01
期刊：
影响因子：
50.3
通讯作者：
Klausner, RD
中科院分区：
文献类型：
--
作者：
Maranchie, JK;Vasselli, JR;Klausner, RD
透明细胞肾癌与von Hippel-Lindau （VHL）肿瘤抑制基因失活有关。VHL是E3连接酶的底物识别亚基，已知在常氧条件下靶向HIF异二聚体转录因子的α亚基进行泛素介导的降解。我们证明，来自HIF1alpha氧降解区域的肽竞争性抑制VHL底物识别位点概括了VHL缺陷肿瘤细胞的致瘤表型。这些研究证明VHL底物识别对VHL的抑瘤功能至关重要。我们进一步证明，虽然能够模拟VHL损失的某些方面，但仅HIF1alpha的常模稳定不足以再现肿瘤发生，这表明它不是VHL的关键致癌底物。
Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the alpha subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1alpha recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1alpha alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL.