Kaelin W G
Howard Hughes Medical Institute, Dana-Farber and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cold Spring Harb Symp Quant Biol. 2005;70:159-66. doi: 10.1101/sqb.2005.70.001.
Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a common event in hereditary (von Hippel- Lindau disease) and sporadic hemangioblastomas and clear-cell renal carcinomas. Germ-line VHL mutations are also linked to some hereditary pheochromocytoma families. The VHL gene product, pVHL, interacts with a number of cellular proteins and is implicated in the control of angiogenesis, extracellular matrix formation, cell metabolism, and mitogenesis. The best understood function of pVHL relates to its role as the substrate recognition unit of an E3 ligase that targets the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction in the presence of oxygen. Down-regulation of HIF appears to be both necessary and sufficient for renal tumor suppression by pVHL, and HIF is strongly suspected of contributing to hemangioblastoma development as well. Recent work suggests that pVHL's role in pheochromocytoma is not related to HIF but rather to the ability of pVHL to regulate neuronal apoptosis, which is mediated by c-Jun, when growth factors such as NGF become limiting. Loss of pVHL leads to up-regulation of JunB, which antagonizes c-Jun and blunts apoptosis.
冯·希佩尔-林道（VHL）肿瘤抑制基因的双等位基因失活在遗传性（冯·希佩尔-林道病）以及散发性血管母细胞瘤和透明细胞肾细胞癌中是常见事件。种系VHL突变也与一些遗传性嗜铬细胞瘤家族相关。VHL基因产物pVHL与多种细胞蛋白相互作用，并参与血管生成、细胞外基质形成、细胞代谢和有丝分裂的调控。pVHL最被了解的功能与其作为E3连接酶的底物识别单元的作用有关，该E3连接酶在有氧存在时靶向异二聚体转录因子HIF（缺氧诱导因子）进行降解。HIF的下调似乎对于pVHL抑制肾肿瘤既是必要的也是充分的，并且强烈怀疑HIF也促成血管母细胞瘤的发展。最近的研究表明，pVHL在嗜铬细胞瘤中的作用与HIF无关，而是与pVHL在诸如NGF等生长因子变得有限时调节由c-Jun介导的神经元凋亡的能力有关。pVHL的缺失导致JunB上调，后者拮抗c-Jun并减弱细胞凋亡。
