Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer.
Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer.
复制标题
DOI：
10.1172/jci162480
复制
发表时间：
2022-09-15
影响因子：
15.9
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Kaelin, William G., Jr.
VHL肿瘤抑制基因的种系功能丧失突变可导致von Hippel-Lindau病，该疾病与血管母细胞瘤、透明细胞肾细胞癌（ccRCCs）和副神经节瘤的风险增加相关。本文综述了VHL基因产物在氧感应、蛋白质降解和肿瘤发展中的作用机制，以及目前针对这些机制的治疗策略。VHL基因产物是泛素连接酶的底物识别亚基，该酶靶向异二聚体缺氧诱导因子（HIF）转录因子的α亚基，在氧气存在时进行蛋白酶体降解。这种氧依赖性源于EglN（也称为PHD）脯氨酸羟化酶家族成员要求HIFα在两个保守的脯氨酸残基中的一个（或两个）上被脯氨酸羟化。解除对HIF，特别是HIF2的管制，推动了vhl缺陷ccrcc的增长。抑制hif反应性基因产物VEGF的药物现在是ccRCC治疗的主要药物。最近，一种变抗HIF2抑制剂被批准用于治疗VHL疾病中出现的ccrcc，并且基于有希望的I/II期数据，已推进到散发性ccrcc的III期试验。口服EglN抑制剂用于治疗贫血和缺血的试验正在进行中。其中五种药物已在世界各国被批准用于治疗慢性肾脏疾病的贫血。
Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.