PDLIM2 regulates transcription factor activity in epithelial-to-mesenchymal transition via the COP9 signalosome.
PDLIM2 regulates transcription factor activity in epithelial-to-mesenchymal transition via the COP9 signalosome.
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DOI：
10.1091/mbc.e13-06-0306
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发表时间：
2014-01
影响因子：
3.3
通讯作者：
O'Connor R
中科院分区：
文献类型：
--
作者：
Bowe RA;Cox OT;Ayllón V;Tresse E;Healy NC;Edmunds SJ;Huigsloot M;O'Connor R
PDLIM 2整合了细胞骨架信号传导与基因表达，使上皮癌细胞能够可逆分化。PDLIM 2与COP 9信号体相关，并控制其核转位和间充质或上皮表型所需的关键转录因子的稳定性。上皮细胞分化和极化迁移与上皮间质转化（EMT）在癌症中需要整合基因表达与细胞骨架动力学。我们发现PDZ-LIM结构域蛋白PDLIM 2（Mystique/SLIM）是一种已知的细胞骨架蛋白，同时也是核因子κB（NFκB）和信号转导和转录激活因子（STAT）降解的启动子，它通过COP 9信号体（CSN）调节转录因子活性和基因表达。尽管在某些癌症中受到抑制，但PDLIM 2在侵袭性癌细胞中高度表达。在这里，我们表明，PDLIM 2抑制导致定向迁移的损失，无法修复细胞骨架，逆转EMT表型。这伴随着几个转录因子家族的活性改变，包括β-连环蛋白、Ap-1、NFκB、干扰素调节因子、STAT、JUN和p53。我们还表明，PDLIM 2协会与CSN 5，细胞与抑制PDLIM 2表现出减少核积累和cSN对cullin-RING泛素连接酶的cullin 1和cullin 3亚基的deneddylation活性。因此，PDLIM 2通过控制关键转录因子的稳定性和CSN活性，将细胞骨架信号传导与上皮分化中的基因表达整合在一起。
PDLIM2 integrates cytoskeletal signaling with gene expression to enable reversible differentiation of epithelial cancer cells. PDLIM2 associates with the COP9 signalosome and controls its nuclear translocation and the stability of key transcription factors necessary for either a mesenchymal or an epithelial phenotype. Epithelial cell differentiation and polarized migration associated with epithelial-to-mesenchymal transition (EMT) in cancer requires integration of gene expression with cytoskeletal dynamics. Here we show that the PDZ-LIM domain protein PDLIM2 (Mystique/SLIM), a known cytoskeletal protein and promoter of nuclear nuclear factor κB (NFκB) and signal transducer and activator of transcription (STAT) degradation, regulates transcription factor activity and gene expression through the COP9 signalosome (CSN). Although repressed in certain cancers, PDLIM2 is highly expressed in invasive cancer cells. Here we show that PDLIM2 suppression causes loss of directional migration, inability to polarize the cytoskeleton, and reversal of the EMT phenotype. This is accompanied by altered activity of several transcription factor families, including β-catenin, Ap-1, NFκB, interferon regulatory factors, STATs, JUN, and p53. We also show that PDLIM2 associates with CSN5, and cells with suppressed PDLIM2 exhibit reduced nuclear accumulation and deneddylation activity of the CSN toward the cullin 1 and cullin 3 subunits of cullin-RING ubiquitin ligases. Thus PDLIM2 integrates cytoskeleton signaling with gene expression in epithelial differentiation by controlling the stability of key transcription factors and CSN activity.