Department of Pharmacology and Cancer Biology, Duke University Medical Center, DUMC-3813, Durham, NC 27710, USA.
Mol Cancer Res. 2010 Feb;8(2):223-31. doi: 10.1158/1541-7786.MCR-09-0189. Epub 2010 Feb 9.
The genes encoding the Ras family of small GTPases are mutated to yield constitutively active GTP-bound oncogenic proteins in one third of all human cancers. Oncogenic Ras binds to and activates a number of proteins that promote tumorigenic phenotypes, including the family of Ral guanine nucleotide exchange factors (RalGEF). Activated RalGEFs convert the Ral family of small GTPases, composed of RalA and RalB, from an inactive GDP-bound state to an active GTP-bound state. As both RalA and RalB have been implicated in a variety of tumorigenic phenotypes, we sought to determine which proteins downstream of Rals promote transformation and tumorigenesis. Here, we report that shRNA-mediated knockdown of the Ral effector proteins Sec5 and Exo84, but less so in the case of RalBP1, reduced oncogenic RalGEF-mediated transformation and oncogenic Ras-driven tumorigenic growth of human cells. These results suggest that Rals promote oncogenic Ras-mediated tumorigenesis through, at least in part, Sec5 and Exo84.
编码 Ras 家族小 GTPases 的基因发生突变，导致三分之一的人类癌症中产生持续激活的 GTP 结合致癌蛋白。致癌 Ras 与许多促进肿瘤发生表型的蛋白质结合并激活它们，包括 Ral 鸟嘌呤核苷酸交换因子（RalGEF）家族。激活的 RalGEFs 将由 RalA 和 RalB 组成的 Ral 家族小 GTPases 从无活性的 GDP 结合状态转换为活性的 GTP 结合状态。由于 RalA 和 RalB 都与多种肿瘤发生表型有关，我们试图确定 Ral 下游的哪些蛋白质促进转化和肿瘤发生。在这里，我们报告说，shRNA 介导的 Ral 效应蛋白 Sec5 和 Exo84 的敲低，而 RalBP1 的情况则较少，降低了致癌 RalGEF 介导的人类细胞转化和致癌 Ras 驱动的肿瘤发生性生长。这些结果表明，Ral 通过至少部分通过 Sec5 和 Exo84 促进致癌 Ras 介导的肿瘤发生。
