Li Xiaotao, Lonard David M, Jung Sung Yun, Malovannaya Anna, Feng Qin, Qin Jun, Tsai Sophia Y, Tsai Ming-Jer, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Cell. 2006 Jan 27;124(2):381-92. doi: 10.1016/j.cell.2005.11.037.
Steroid receptor coactivator-3 (SRC-3/AIB1) is an oncogene frequently amplified and overexpressed in breast cancers. Here we report that SRC-3 interacts with REGgamma, a proteasome activator known to stimulate the trypsin-like activity of the 20S proteasome. RNAi knockdown and gain-of-function experiments suggest that REGgamma promotes SRC-3 protein degradation. Cellular levels of REGgamma expression affect estrogen-receptor target-gene expression and cell growth as a result of its ability to promote degradation of the SRC-3 protein. In vitro proteasome proteolysis assays using purified REGgamma, SRC-3, and the 20S proteasome reinforce these conclusions and demonstrate that REGgamma promotes the degradation of SRC-3 in a ubiquitin- and ATP-independent manner. This work demonstrates the first example of a physiologically relevant endogenous cellular target for the REGgamma-proteasome complex. It also highlights the fact that an alternative mode of proteasome-mediated protein degradation, independent of the 19S proteasome regulatory cap, targets the SRC-3 protein for degradation.
类固醇受体辅激活因子-3（SRC-3/AIB1）是一种在乳腺癌中经常扩增和过表达的癌基因。在此我们报告，SRC-3与REGγ相互作用，REGγ是一种已知能刺激20S蛋白酶体胰蛋白酶样活性的蛋白酶体激活剂。RNA干扰敲低和功能获得实验表明，REGγ促进SRC-3蛋白降解。由于REGγ促进SRC-3蛋白降解的能力，其细胞表达水平影响雌激素受体靶基因表达和细胞生长。使用纯化的REGγ、SRC-3和20S蛋白酶体进行的体外蛋白酶体蛋白水解分析强化了这些结论，并证明REGγ以不依赖泛素和ATP的方式促进SRC-3的降解。这项工作展示了REGγ-蛋白酶体复合物在生理上相关的内源性细胞靶点的首个实例。它还突出了这样一个事实，即蛋白酶体介导的蛋白质降解的一种替代模式，独立于19S蛋白酶体调节帽，靶向SRC-3蛋白进行降解。
