The adaptor SASH1 acts through NOTCH1 and its inhibitor DLK1 in a 3D model of lumenogenesis involving CEACAM1.
The adaptor SASH1 acts through NOTCH1 and its inhibitor DLK1 in a 3D model of lumenogenesis involving CEACAM1.
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DOI：
10.1016/j.yexcr.2017.08.022
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发表时间：
2017-10-15
影响因子：
3.7
通讯作者：
Shively JE
中科院分区：
文献类型：
--
作者：
Stubblefield K;Chean J;Nguyen T;Chen CJ;Shively JE
CEACAM 1转染乳腺癌细胞在3D培养模型中恢复管腔形成。在与管腔形成恢复相关的最高上调基因中，鉴定了接头蛋白SASH 1。此外，SASH 1被证明是至关重要的管腔形成的RNAi抑制。在分析来自用SASH 1 RNAi处理的CEACAM 1/MCF 7细胞的基因阵列时，发现NOTCH 1信号传导的抑制剂DLK 1被下调至与SASH 1相同的程度。随后用针对DLK 1的RNAi处理CEACAM 1/MCF 7细胞也抑制了管腔形成，支持其与SASH 1的关联。与DLK 1作为NOTCH 1抑制剂的作用一致，NOTCH 1及其调控基因HES 1和HEY 1在CEACAM 1/MCF 7细胞中通过DLK 1 RNAi的作用被下调，而通过SASH 1 RNAi被上调。当用已知抑制NOTCH信号传导的γ-分泌酶抑制剂处理CEACAM 1/MCF 7细胞时，管腔形成被抑制。我们的结论是，CEACAM 1通过衔接蛋白SASH 1和NOTCH 1抑制剂DLK 1调节NOTCH 1信号通路的管腔形成的恢复。这些数据表明，NOTCH 1作为乳腺癌中的肿瘤促进基因的假定参与可能取决于其在癌症中缺乏调节，而其参与正常管腔形成需要激活其表达，随后抑制其信号传导。
CEACAM1 transfection into breast cancer cells restores lumen formation in a 3D culture model. Among the top up-regulated genes that were associated with restoration of lumen formation, the adaptor protein SASH1 was identified. Furthermore, SASH1 was shown to be critical for lumen formation by RNAi inhibition. Upon analyzing the gene array from CEACAM1/MCF7 cells treated with SASH1 RNAi, DLK1, an inhibitor of NOTCH1 signaling, was found to be down-regulated to the same extent as SASH1. Subsequent treatment of CEACAM1/MCF7 cells with RNAi to DLK1 also inhibited lumen formation, supporting its association with SASH1. In agreement with the role of DLK1 as a NOTCH1 inhibitor, NOTCH1, as well as its regulated genes HES1 and HEY1, were down-regulated in CEACAM1/MCF7 cells by the action of DLK1 RNAi, and up-regulated by SASH1 RNAi. When CEACAM1/MCF7 cells were treated with a γ-secretase inhibitor known to inhibit NOTCH signaling, lumen formation was inhibited. We conclude that restoration of lumen formation by CEACAM1 regulates the NOTCH1 signaling pathway via the adaptor protein SASH1 and the NOTCH1 inhibitor DLK1. These data suggest that the putative involvement of NOTCH1 as a tumor-promoting gene in breast cancer may depend on its lack of regulation in cancer, whereas its involvement in normal lumen formation requires activation of its expression, and subsequently, inhibition of its signaling.
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影响因子：
3.7
作者：
Chen CJ;Nguyen T;Shively JE
通讯作者：
Shively JE
DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
caspase-3对SASH1的激活和切割介导了凋亡反应。
影响因子：
9
作者：
Burgess JT;Bolderson E;Adams MN;Baird AM;Zhang SD;Gately KA;Umezawa K;O'Byrne KJ;Richard DJ
通讯作者：
Richard DJ
影响因子：
4.8
作者：
Chen, Charng-Jui;Kirshner, Julia;Shively, John E.
通讯作者：
Shively, John E.
影响因子：
8
作者：
Curry, CL;Reed, LL;Foreman, KE
通讯作者：
Foreman, KE