Homotypic association between tumour-associated VHL proteins leads to the restoration of HIF pathway
Homotypic association between tumour-associated VHL proteins leads to the restoration of HIF pathway
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DOI：
10.1038/sj.onc.1209328
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发表时间：
2006-05-18
期刊：
影响因子：
8
通讯作者：
Ohh, M.
中科院分区：
文献类型：
--
作者：
Chung, J.;Roberts, A. M.;Ohh, M.
von Hippel-Lindau (VHL) 肿瘤抑制基因编码 E3 泛素连接酶的底物特异性成分，该成分以缺氧诱导因子 (HIF) α 亚基为目标，在常氧条件下降解。 VHL 蛋白由 N 端 HIF α 结合 ss 结构域和 C 端 α 结构域组成，这对于 E3 多蛋白酶的形成是必要且充分的。 α 或 ss 结构域中的大量致病突变使 HIF α 稳定，无论氧张力如何，从而导致许多 HIF 靶基因的上调，例如 GLUT1 和 VEGF。在这里，我们证明 VHL 在体内形成自相关复合体，但在体外则不然，并证明两种不同的 VHL 错义突变体（一种在 a 结构域，另一种在 ss 结构域）的共表达可以恢复 HIF 介导的基因表达谱。这些发现表明，VHL 同型复合物可以在体内以互补的方式发挥作用，以靶向 HIF α 进行泛素介导的蛋白水解，并可能解释为什么具有携带错义突变的 VHL 等位基因的 VHL 相关肿瘤几乎总是伴随着第二个带有总体截短或缺失的 VHL 等位基因。
The von Hippel-Lindau (VHL) tumour suppressor gene encodes a substrate-specifying component of an E3 ubiquitin ligase that targets hypoxia-inducible factor (HIF) alpha subunits for degradation under normoxia. The VHL protein is composed of an N-terminal HIF alpha-binding ss domain and a C-terminal alpha domain, which is necessary and sufficient for the formation of the E3 multiprotein enzyme. A large number of disease-causing mutations in either the alpha or ss domain renders HIF alpha stable irrespective of oxygen tension, leading to the upregulation of numerous HIF-target genes, such as GLUT1 and VEGF. Here, we show that VHL forms a self-associated complex in vivo, but not in vitro, and demonstrate that coexpression of two different VHL missense mutants - one in the a domain and the other in the ss domain - restores HIF-mediated gene expression profile. These findings indicate that VHL homotypic complexes can function in vivo in a complementary fashion to target HIF alpha for ubiquitinmediated proteolysis, and potentially explain why VHL-associated tumours witha missense mutation-carrying VHL allele is almost invariably accompanied by a second VHL allele harbouring a gross truncation or deletion.