Clusterin is a secreted marker for a hypoxia-inducible factor- independent function of the von Hippel-Lindau tumor suppressor protein
Clusterin is a secreted marker for a hypoxia-inducible factor- independent function of the von Hippel-Lindau tumor suppressor protein
复制标题
DOI：
10.2353/ajpath.2006.050867
复制
发表时间：
2006-02-01
影响因子：
6
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
--
作者：
Nakamura, E;Abreu-e-Lima, P;Kaelin, WG
VHL肿瘤抑制基因的种系突变以等位基因特异性方式使人易患肾癌、血管母细胞瘤和嗜铬细胞瘤。VHL基因产物（pVHL）的最佳记录功能涉及其聚泛素化的能力，因此靶向破坏异源二聚体转录因子缺氧诱导因子（HIF）的α亚基。与经典VHL疾病相反，与家族性嗜铬细胞瘤（2C型VHL疾病）相关的pVHL突变体似乎在HIF调节方面是正常的。使用一种简单的方法来识别由同基因细胞系对差异分泌的蛋白质，我们证实了HIF靶点IGBP 3和派-1由pVHL缺陷型肾癌细胞过度产生。此外，缺乏野生型pVHL的细胞，包括产生2C型pVHL突变体的细胞，在丛生蛋白的表达和分泌方面是有缺陷的，丛生蛋白的行为不像HIF靶。通过免疫组织化学在体内证实了pVHL缺陷型肿瘤的丛生蛋白分泌减少。因此，clusterin是HIF-独立的pVHL功能的分泌标志物，这可能在嗜铬细胞瘤的发展中特别重要。
Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose people to renal cancer, hemangioblastomas, and pheochromocytomas in an allele-specific manner. The best documented function of the VHL gene product (pVHL) relates to its ability to polyubiquitinate, and hence target for destruction, the a subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF). pVHL mutants linked to familial pheochromocyctoma (type 2C VHL disease), in contrast to classical VHL disease, appear to be normal with respect to HIF regulation. Using a simple method for identifying proteins that are differentially secreted by isogenic cell line pairs, we confirmed that the HIF targets IGBP3 and PAI-1 are overproduced by pVHL-defective renal carcinoma cells. in addition, cells lacking wild-type pVHL, including cells producing type 2C pVHL mutants, were defective with respect to expression and secretion of clusterin, which does not behave like a HIF target. Decreased clusterin secretion by pVHL-defective tumors was confirmed in vivo by immunohistochemistry. Therefore, clusterin is a secreted marker for a HIF-independent pVHL function that might be especially important in pheochromocytoma development.