Evi1 is a survival factor which conveys resistance to both TGFb-β and taxol-mediated cell death via PI3K/AKT
Evi1 is a survival factor which conveys resistance to both TGFb-β and taxol-mediated cell death via PI3K/AKT
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DOI：
10.1038/sj.onc.1209403
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发表时间：
2006-06-15
期刊：
影响因子：
8
通讯作者：
Thompson, E. A.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Chen, L.;Thompson, E. A.
在造血细胞中，亲嗜性病毒整合位点1（Evi 1）癌基因的转化潜力被认为依赖于抑制TGF β信号传导的能力。尽管Evi 1最近被认为与某些上皮癌有关，但Evi 1对上皮细胞转化和TGF β信号传导的影响尚未完全了解。在此，我们确定了Evi 1对肠上皮细胞中TGF β信号传导的影响。Evi 1在非转化肠上皮细胞中的稳定表达抑制了一些Smad 3依赖性TGF β靶基因的诱导，如PAI 1。然而，TGF β介导的细胞粘附信号传导成分，如整合素1和桩蛋白的诱导不受Evi 1抑制，也不抑制TGF β介导的上皮间质转化。同样，Evi 1不抑制TGF β介导的细胞周期蛋白D1的下调或阻断TGF β介导的生长抑制。然而，Evi 1确实通过涉及磷酸肌醇-3-激酶（PI 3 K）及其下游效应子AKT的过程抑制TGF β介导的凋亡。Evi 1抑制细胞凋亡的能力不限于TGF β介导的细胞死亡，因为Evi 1还保护肠上皮细胞免受紫杉醇介导的细胞凋亡。Evi 1在一些人结肠癌细胞系中过表达，并且过表达与Evi 1基因的扩增相关。通过siRNA敲低Evi 1抑制HT-29人结肠癌细胞中AKT磷酸化，并增加其对紫杉醇介导的凋亡的敏感性。这些数据表明，Evi 1在肠上皮细胞和结肠癌细胞中作为存活基因发挥作用，激活PI 3 K/AKT并传递对生理和治疗性凋亡刺激的抗性。
In hematopoietic cells the transforming potential of the ecotropic viral integration site 1 (Evi1) oncogene is thought to be dependent upon the ability to inhibit TGF beta signaling. Although Evi1 has recently been implicated in certain epithelial cancers, the effects of Evi1 on transformation and TGF beta signaling in epithelial cells are not completely understood. Herein, we have determined the effects of Evi1 on TGF beta signaling in intestinal epithelial cells. Stable expression of Evi1 in non-transformed intestinal epithelial cells inhibited induction of some Smad3-dependent TGF beta target genes, such as PAI1. However, TGF beta-mediated induction of cellular adhesion signaling components such as integrin1 and paxillin was not inhibited by Evi1; nor did Evi1 inhibit TGF beta-mediated epithelial to mesenchymal transition. Likewise, Evi1 did not inhibit TGF beta-mediated downregulation of cyclin D1 or block TGF beta-mediated growth inhibition. However, Evi1 did inhibit TGF beta-mediated apoptosis by a process that involves phosphoinositide-3-kinase (PI3K) and its downstream effector AKT. The ability of Evi1 to suppress apoptosis is not restricted to TGF beta-mediated cell death, since Evi1 also protects intestinal epithelial cells from taxol-mediated apoptosis. Evi1 is overexpressed in some human colon cancer cell lines, and overexpression is associated with amplification of the Evi1 gene. Knockdown of Evi1 by siRNA inhibited AKT phosphorylation in HT-29 human colon cancer cells and increased their sensitivity to taxol-mediated apoptosis. These data indicate that Evi1 functions as a survival gene in intestinal epithelial cells and colon cancer cells, activating PI3K/AKT and conveying resistance to both physiological and therapeutic apoptotic stimuli.