Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL
Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL
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DOI：
10.1038/ncb899
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发表时间：
2003-01-01
影响因子：
21.3
通讯作者：
Krek, W
中科院分区：
文献类型：
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作者：
Hergovich, A;Lisztwan, J;Krek, W
Von Hippel-Lindau (VHL) 肿瘤抑制基因失活与中枢神经系统和视网膜血管母细胞瘤的发展有关，通常与其他肿瘤有关，例如肾透明细胞癌和嗜铬细胞瘤。在这里，我们证明VHL蛋白（pVHL）是一种微管相关蛋白，可以在体内保护微管免于解聚。 pVHL 的微管结合和稳定功能都依赖于 pVHL 的氨基酸 95-123，这是 VHL 疾病中的突变“热点”。从对天然存在的 pVHL 突变体的分析来看，似乎只有 pVHL(Y98H) 和 pVHL(Y112H) 等点突变（易患血管母细胞瘤和嗜铬细胞瘤，但不会患肾细胞癌）会破坏 pVHL 的微管稳定功能。我们的数据确定了 pVHL 在微管动力学调节中的作用，并可能提供 pVHL 的这种功能与 VHL 疾病背景下血管母细胞瘤和嗜铬细胞瘤的发病机制之间的联系。
Von Hippel-Lindau (VHL) tumour suppressor gene inactivation is linked to the development of haemangioblastomas in the central nervous system and retina, often in association with other tumours, such as clear-cell carcinomas of the kidney and phaeochromocytomas. Here we show that the VHL protein (pVHL) is a microtubule-associated protein that can protect microtubules from depolymerization in vivo. Both the microtubule binding and stabilization functions of pVHL depend on amino acids 95-123 of pVHL, a mutational 'hot-spot' in VHL disease. From analysis of naturally occurring pVHL mutants, it seems that only point mutations such as pVHL(Y98H) and pVHL(Y112H) (that predispose to haemangioblastoma and phaeochromocytoma, but not to renal cell carcinoma) disrupt pVHL's microtubule-stabilizing function. Our data identify a role for pVHL in the regulation of microtubule dynamics and potentially provide a link between this function of pVHL and the pathogenesis of haemangioblastoma and phaeochromocytoma in the context of VHL disease.