Kamura T, Sato S, Haque D, Liu L, Kaelin W G, Conaway R C, Conaway J W
Howard Hughes Medical Institute (HHMI), Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 USA.
Genes Dev. 1998 Dec 15;12(24):3872-81. doi: 10.1101/gad.12.24.3872.
The Elongin BC complex was identified initially as a positive regulator of RNA polymerase II (Pol II) elongation factor Elongin A and subsequently as a component of the multiprotein von Hippel-Lindau (VHL) tumor suppressor complex, in which it participates in both tumor suppression and negative regulation of hypoxia-inducible genes. Elongin B is a ubiquitin-like protein, and Elongin C is a Skp1-like protein that binds to a BC-box motif that is present in both Elongin A and VHL and is distinct from the conserved F-box motif recognized by Skp1. In this report, we demonstrate that the Elongin BC complex also binds to a functional BC box present in the SOCS box, a sequence motif identified recently in the suppressor of cytokine signaling-1 (SOCS-1) protein, as well as in a collection of additional proteins belonging to the SOCS, ras, WD-40 repeat, SPRY domain, and ankyrin repeat families. In addition, we present evidence (1) that the Elongin BC complex is a component of a multiprotein SOCS-1 complex that attenuates Jak/STAT signaling by binding to Jak2 and inhibiting Jak2 kinase, and (2) that by interacting with the SOCS box, the Elongin BC complex can increase expression of the SOCS-1 protein by inhibiting its degradation. These results suggest that Elongin BC is a multifunctional regulatory complex capable of controlling multiple pathways in the cell through interaction with a short degenerate sequence motif found in many different proteins.
延伸蛋白BC复合物最初被鉴定为RNA聚合酶II（Pol II）延伸因子延伸蛋白A的正向调节因子，随后被鉴定为多蛋白冯·希佩尔-林道（VHL）肿瘤抑制复合物的一个组成部分，它在该复合物中参与肿瘤抑制和缺氧诱导基因的负调控。延伸蛋白B是一种类泛素蛋白，延伸蛋白C是一种类Skp1蛋白，它与存在于延伸蛋白A和VHL中的BC盒基序结合，该基序不同于Skp1识别的保守F盒基序。在本报告中，我们证明延伸蛋白BC复合物还与存在于SOCS盒中的功能性BC盒结合，SOCS盒是最近在细胞因子信号抑制因子-1（SOCS-1）蛋白以及属于SOCS、ras、WD-40重复、SPRY结构域和锚蛋白重复家族的其他一些蛋白中鉴定出的序列基序。此外，我们提供的证据表明：（1）延伸蛋白BC复合物是多蛋白SOCS-1复合物的一个组成部分，该复合物通过与Jak2结合并抑制Jak2激酶来减弱Jak/STAT信号传导；（2）通过与SOCS盒相互作用，延伸蛋白BC复合物可以通过抑制SOCS-1蛋白的降解来增加其表达。这些结果表明，延伸蛋白BC是一种多功能调节复合物，能够通过与许多不同蛋白中发现的短简并序列基序相互作用来控制细胞中的多种途径。
