The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma
The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma
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DOI：
10.1158/1078-0432.ccr-06-1865
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发表时间：
2007-01-15
影响因子：
11.5
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Kaelin, William G., Jr.
生殖系VHL肿瘤抑制基因功能丧失突变导致von Hippel-Lindau病，其与中枢神经系统血管母细胞瘤、透明细胞肾癌和嗜铬细胞瘤的风险增加相关。体细胞VHL突变在散发性透明细胞肾癌中也很常见。VHL基因产物pVHL是泛素连接酶复合物的一部分，该复合物靶向异源二聚体转录因子缺氧诱导因子（HIF）的α-亚基，用于多泛素化，因此，当氧气可用时，蛋白酶体降解。pVHL缺陷型肾透明细胞癌过度产生多种受HIF控制的mRNA，包括编码血管内皮生长因子、血小板衍生生长因子B和转化生长因子α的mRNA。在临床前模型中，HIF-α，特别是HIF-2 α的下调对于pVHL抑制肾肿瘤是必要的和充分的。这些观察结果可能与已证实的血管内皮生长因子拮抗剂在肾透明细胞癌中的临床活性有关，并为在这种疾病中检测抑制HIF或HIF应答基因产物的其他药物奠定了基础。
Germ line VHL tumor suppressor gene loss-of-function mutations cause von Hippel-Lindau disease, which is associated with an increased risk of central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas. Somatic VHL mutations are also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitylation, and hence, proteasomal degradation, when oxygen is available. pVHL-defective clear cell renal carcinomas overproduce a variety of mRNAs that are under the control of HIF, including the mRNAs that encode vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor alpha. In preclinical models, down-regulation of HIF-alpha, especially HIF-2 alpha, is both necessary and sufficient for renal tumor suppression by pVHL. These observations are probably relevant to the demonstrated clinical activity of vascular endothelial growth factor antagonists in clear cell renal carcinoma and form a foundation for the testing of additional agents that inhibit HIF, or HIF-responsive gene products, in this disease.