The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins
The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins
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DOI：
10.1073/pnas.94.6.2156
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发表时间：
1997-03-18
影响因子：
11.1
通讯作者：
Klausner, RD
中科院分区：
文献类型：
--
作者：
Pause, A;Lee, S;Klausner, RD
von Hippel-Lindau（VHL）基因的失活使受影响的个体易患VHL综合征，并且是与散发性肾细胞癌和CNS血管母细胞瘤相关的早期遗传事件。VHL蛋白（pVHL）已显示与延伸蛋白B和延伸蛋白C形成稳定的复合物，这两种因子稳定和激活转录延伸因子延伸蛋白A。在这里，Hs-CUL-2，最近确定的多基因家族，cullin的成员，显示出特异性地与三聚体pVHL-延长蛋白B-C（VBC）复合物在体外和体内。近70%的VHL的天然存在的癌症易感突变破坏了这种相互作用。pVHL-Hs-CUL-2缔合严格依赖于三聚体VBC复合物的完整性。免疫荧光研究显示Hs-CUL-2是可以通过pVHL易位到细胞核的胞质蛋白。最近已经显示酵母Ns-CUL-2同系物Cdc 53，是泛素蛋白连接酶复合物的一部分，其靶向细胞周期蛋白以通过泛素蛋白水解途径降解。在秀丽隐杆线虫中，另一个Hs-cul-2同源物Ce-cul-1的无效突变导致所有组织中的增生，并且是细胞周期退出所必需的。因此，Hs-cul-2可能是VHL功能所必需的，因此，可能是候选的人类肿瘤抑制基因。
The inactivation of the von Hippel-Lindau (VHL) gene predisposes affected individuals to VHL syndrome and is an early genetic event associated with sporadic renal cell carcinoma and CNS hemangioblastomas. The VHL protein (pVHL) has been shown to form a stable complex with elongin B and elongin C, two factors that stabilize and activate the transcription elongation factor elongin A. Here, Hs-CUL-2, a member of the recently identified multigene family, the cullins, is shown to specifically associate with the trimeric pVHL-elongin B-C (VBC) complex in vitro and in vivo. Nearly 70% of naturally occurring cancer-predisposing mutations of VHL disrupt this interaction, The pVHL-Hs-CUL-2 association is strictly dependent on the integrity of the trimeric VBC complex, Immunofluorescence studies show Hs-CUL-2 to be a cytosolic protein that can be translocated to the nucleus by pVHL, Recently it has been shown that a yeast Ns-CUL-2 homolog, Cdc53, is part of a ubiquitin protein ligase complex that targets cell cycle proteins for degradation by the ubiquitin proteolytic pathway. In Caenorhabditis elegans, a null mutation of another Hs-cul-2 homolog, Ce-cul-1, results in hyperplasia in all tissues and is required for cell cycle exit, Hence, Hs-cul-2 may be required for VHL function and, therefore, may be a candidate human tumor-suppressor gene.