Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products
Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products
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DOI：
10.1073/pnas.97.15.8507
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发表时间：
2000-07-18
影响因子：
11.1
通讯作者：
Burk, RD
中科院分区：
文献类型：
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作者：
Schoenfeld, AR;Davidowitz, EJ;Burk, RD
Von Hippel-Lindau(VHL)抑癌基因失活导致家族性癌症综合征。VHL病，其特征是易患肾细胞癌和其他类型的肿瘤。在大多数散发性肾癌中也发现VHL基因功能丧失。在VHL病中检测到的大多数肿瘤处理的遗传性错义突变位于VHL的细长蛋白结合域内。这一区域介导了含有细长蛋白B、细长蛋白C.Cul-2的多蛋白VHL复合体的形成。和Rbx1。这种VHL复合体被认为是一种E3泛素连接酶。在这里，我们报告了含有突变的VHL蛋白，这些突变破坏了细长蛋白结合，是不稳定的，并被蛋白酶体迅速降解。相反，野生型VHL蛋白通过与细长蛋白B和C结合而直接稳定。此外，细长蛋白B和C通过相互作用和VHL而稳定。因此，整个VHL/细长蛋白复合体都能抵抗蛋白酶体的降解。由于VHL的延伸素结合域在癌症中经常发生突变，这些结果表明延伸素结合的丢失通过损害VHL蛋白的稳定性和/或潜在的VHL泛素化功能而导致肿瘤的发生。
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the familial cancer syndrome. VHL disease, characterized by a predisposition to renal cell carcinoma and other tumor types. Loss of VHL gene function also is found in a majority of sporadic renal carcinomas. A preponderance of the tumor-disposing inherited missense mutations detected in VHL disease are within the elongin-binding domain of VHL. This region mediates the formation of a multiprotein VHL complex containing elongin B. elongin C. cul-2. and Rbx1. This VHL complex is thought to function as an E3 ubiquitin ligase. Here, we report that VHL proteins harboring mutations which disrupt elongin binding are unstable and rapidly degraded by the proteasome. In contrast, wild-type VHL proteins are directly stabilized by associating with both elongins B and C. In addition, elongins B and C are stabilized through their interactions with each other and VHL. Thus, the entire VHL/elongin complex is resistant to proteasomal degradation. Because the elongin-binding domain of VHL is frequently mutated in cancers, these results suggest that loss of elongin binding causes tumorigenesis by compromising VHL protein stability and/or potential VHL ubiquitination functions.