The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion
The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion
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DOI：
10.4161/cam.4.3.11407
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发表时间：
2010-07-01
影响因子：
3.2
通讯作者：
Nepveul, Alain
中科院分区：
文献类型：
--
作者：
Kedinger, Valerie;Nepveul, Alain
切割的同源异型盒基因1(CUX1)编码几种同源结构域蛋白，这些蛋白具有不同的DNA结合和转录特性。以前发现一些CUX1亚型可以刺激细胞进入S期。最近，siRNA介导的CUX1基因敲除被证明导致细胞迁移和侵袭减少。相反，在组织培养中异位表达p110或p75CUX1可刺激细胞迁移和侵袭。此外，在p75CUX1转基因小鼠的乳腺肿瘤形成后，少数病例观察到肺转移。染色质免疫沉淀(CHIP)和启动子阵列杂交(CHIP-CHIP)鉴定了20多个受CUX1直接调控的基因，这些基因编码与细胞骨架重塑、细胞-细胞和细胞-基质黏附、上皮到间充质转化和转录调控有关的蛋白质。CUX1的许多靶点都是Rho GTP酶的调节者，Rho GTP酶既在细胞周期进程中发挥作用，又在细胞运动中发挥作用。有趣的是，一些促进细胞运动的基因被CUX1激活，而一些抑制细胞运动的基因则被CUX1抑制。CUX1作为激活物和抑制物的双重功能最好的例证是调控级联反应，通过CUX1激活Snail和Slug转录因子的表达，然后与它们合作抑制E-钙粘素和阻滞素基因，从而导致细胞-细胞连接的严重解体。综上所述，这些研究表明，CUX1通过调节参与各种分子功能的大量基因来刺激细胞运动。
The Cut homeobox gene 1 (CUX1) codes for several homeodomain proteins that display distinct DNA binding and transcriptional properties. Some CUX1 isoforms were previously shown to stimulate entry into S phase. More recently, siRNA-mediated knockdown of CUX1 was shown to cause a decrease in cell migration and invasion. In contrast, ectopic expression of p110 or p75 CUX1 stimulated cell migration and invasion in tissue culture. Moreover, metastasis to the lung was observed in a few cases following development of mammary tumors in p75 CUX1 transgenic mice. Chromatin immunoprecipitation (ChIP) assays followed by hybridization on promoter arrays (ChIP-chip) led to the identification of more than 20 genes that are directly regulated by CUX1 and code for proteins involved in cytoskeleton remodeling, cell-cell and cell-matrix adhesion, epithelial to mesenchymal transition and transcriptional regulation. Many targets of CUX1 are regulators of Rho GTPases that play a role both in cell cycle progression and cell motility. Interestingly, some genes that promote cell motility are activated by CUX1, while some genes that inhibit cell motility are repressed by CUX1. The dual function of CUX1 as an activator and repressor is best exemplified by the regulatory cascade whereby CUX1 activates expression of the Snail and Slug transcription factors and then cooperates with them to repress the E-cadherin and occludin genes, thereby causing a severe disorganization of cell-cell junctions. Together, these studies indicate that CUX1 stimulates cell motility by regulating a large number of genes involved in various molecular functions.