Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms.
Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms.
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DOI：
10.1038/onc.2011.442
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发表时间：
2012-05-03
期刊：
影响因子：
8
通讯作者：
Hsu, T.
中科院分区：
文献类型：
--
作者：
Hsu, T.
von Hippel-Lindau 肿瘤抑制基因 (VHL) 引起了人们的广泛兴趣，不仅因为它的突变使携带者容易患上毁灭性肿瘤，还因为它参与生理条件下的氧感应。 VHL 功能丧失突变会导致器官特异性肿瘤，例如中枢神经系统的血管母细胞瘤和肾细胞癌，这两种肿瘤都无法用常规化疗治疗。 VHL 蛋白最出名的是一种 E3 泛素连接酶，它针对缺氧诱导因子 α (HIF-α)，但许多不同的非典型细胞功能也被分配给 VHL，这主要是基于细胞培养系统的研究。因此，尽管 VHL 的 HIF 依赖性作用至关重要，但 VHL 的全部病理生理功能仍未得到解决。这种理解需要与生理相关的实验模型仔细交叉参考。对模型系统（如秀丽隐杆线虫、果蝇、斑马鱼和小鼠）的研究为 VHL-HIF 通路提供了关键的体内确认，并验证了潜在的重要细胞功能，包括微管稳定和上皮形态发生。最近，动物模型还表明 VHL 在造血、代谢稳态和炎症中的系统作用。在本次综述中，将总结在模型生物体中进行的研究，并将其与现有的临床和体外数据结合起来。
The von Hippel–Lindau tumor suppressor gene (VHL) has attracted intensive interest not only because its mutations predispose carriers to devastating tumors, but also because it is involved in oxygen sensing under physiological conditions. VHL loss-of-function mutations result in organ-specific tumors, such as hemangioblastoma of the central nervous system and renal cell carcinoma, both untreatable with conventional chemotherapies. The VHL protein is best known as an E3 ubiquitin ligase that targets hypoxia-inducible factor-α (HIF-α), but many diverse, non-canonical cellular functions have also been assigned to VHL, mainly based on studies in cell culture systems. As such, although the HIF-dependent role of VHL is critical, the full spectrum of pathophysiological functions of VHL is still unresolved. Such understanding requires careful cross-referencing with physiologically relevant experimental models. Studies in model systems, such as Caenorhabditis elegans, Drosophila, zebrafish and mouse have provided critical in vivo confirmation of the VHL–HIF pathway, and verification of potentially important cellular functions including microtubule stabilization and epithelial morphogenesis. More recently, animal models have also suggested systemic roles of VHL in hematopoiesis, metabolic homeostasis and inflammation. In this review, the studies performed in model organisms will be summarized and placed in context with existing clinical and in vitro data.
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