Pseudohypoxic pathways in renal cell carcinoma
Pseudohypoxic pathways in renal cell carcinoma
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DOI：
10.1158/1078-0432.ccr-06-2510
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发表时间：
2007-08-15
影响因子：
11.5
通讯作者：
Linehan, W. Marston
中科院分区：
文献类型：
--
作者：
Bratslavsky, Gennady;Sudarshan, Sunil;Linehan, W. Marston
von Hippel-Lindau（VHL）或富马酸水合酶（FH）基因的突变导致形态学上不同的肾细胞癌，具有不同的临床病程和结局。VHL蛋白是泛素连接酶复合物的一部分，其靶向蛋白质以进行蛋白质体降解。FH是Kreb循环的线粒体酶之一。尽管有两种不同的功能和细胞位置，但VHL或FH产物的缺失已显示出改变缺氧诱导因子（HIF-1 α和HIF-2 α）及其下游靶点的表达水平。HIF蛋白是氧稳态的关键调节因子。HIF的严格调节允许细胞在缺氧应激时存活和生长。HIF通过血管内皮生长因子、血小板衍生生长因子、内皮生长因子受体、葡萄糖转运蛋白1、促红细胞生成素和转化生长因子-α的转录调节发挥作用。VHL或FH的丧失被认为导致假性缺氧状态，使得尽管在正常的氧条件下，由HIF介导的细胞反应途径被激活。除了为靶向治疗方法提供理论基础之外，对这些假性缺氧途径的理解还提供了对致癌的分子机制的更好理解。
Mutations of the von Hippel-Lindau (VHL) or fumarate hydratase (FH) genes lead to morphologically different renal cell carcinomas with distinct clinical courses and outcomes. The VHL protein is a part of an ubiquitin ligase complex that targets proteins for proteosomal degradation. FH is one of the mitochondrial enzymes of the Kreb's cycle. Despite two different functionalities and cellular locations, loss of either VHL or FH products has been shown to alter expression levels of hypoxia-inducible factors (HIF-1 alpha and HIF-2 alpha) and their downstream targets. HIF proteins are key regulators of oxygen homeostasis. Tight regulation of HIF allows for cell survival and growth at the time of hypoxic stress. HIF acts via transcriptional regulation of vascular endothelial growth factor, platelet derived growth factor, endothelial growth factor receptor, glucose transporter protein 1, erythropoietin, and transforming growth factor-a. Loss of VHL or FH is thought to result in a pseudohypoxic state so that cellular response pathways mediated by HIF are activated despite normal oxygen conditions, Understanding of these pseudohypoxic pathways has provided a better appreciation of the molecular mechanisms of carcinogenesis in addition to providing a rationale for targeted therapeutic approaches.