Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1.
Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1.
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DOI：
10.1038/onc.2011.151
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发表时间：
2011-10-20
期刊：
影响因子：
8
通讯作者：
O'Malley, B. W.
中科院分区：
文献类型：
--
作者：
Li, C.;Ao, J.;Fu, J.;Lee, D-F;Xu, J.;Lonard, D.;O'Malley, B. W.
类固醇受体辅激活因子-3（SRC-3/AIB 1）是一种在许多人类癌症中扩增和过表达的癌基因。然而，在肿瘤发生过程中调节“活化SRC-3癌蛋白”周转的分子机制仍有待阐明。SPOP是一种以cullin 3为基础的泛素连接酶，参与SRC-3的泛素化和蛋白水解。SPOP以磷酸化依赖性方式与SRC-3磷酸降解决定子直接相互作用。酪蛋白激酶Iε磷酸化该降解决定子中的S102，并促进SRC-3的SPOP依赖性周转。shRNA敲低和过表达实验证实SPOP/CUL 3/Rbx 1泛素连接酶复合物促进SRC-3周转。对SPOP基因组位点的系统分析显示，在乳腺癌中该位点发生高百分比的基因组丢失或洛缺失。此外，我们证明SPOP表达的恢复抑制SRC-3介导的致癌信号传导和肿瘤发生，从而将SPOP定位为肿瘤抑制因子。
Steroid receptor coactivator-3 (SRC-3/AIB1) is an oncogene that is amplified and overexpressed in many human cancers. However, the molecular mechanisms that regulate ‘activated SRC-3 oncoprotein’ turnover during tumorigenesis remain to be elucidated. Here we report thatspeckle-type POZ protein (SPOP), a cullin 3 (CUL3)-based ubiquitin ligase, is responsible for SRC-3 ubiquitination and proteolysis. SPOP interacts directly with an SRC-3 phospho-degron in a phosphorylation dependent manner. Casein kinase Iε phosphorylates the S102 in this degron and promotes SPOP-dependent turnover of SRC-3. shRNA knockdown and overexpression experiments substantiated that the SPOP/CUL3/Rbx1 ubiquitin ligase complex promotes SRC-3 turnover. A systematic analysis of the SPOP genomic locus revealed that a high percentage of genomic loss or LOH occurs at this locus in breast cancers. Furthermore, we demonstrate that restoration of SPOP expression inhibited SRC-3-mediated oncogenic signaling and tumorigenesis, thus positioning SPOP as a tumor suppressor.
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