Loss of E-Cadherin-mediated Cell-Cell Contacts Activates a Novel Mechanism for Up-Regulation of the Proto-Oncogene c-Jun
Loss of E-Cadherin-mediated Cell-Cell Contacts Activates a Novel Mechanism for Up-Regulation of the Proto-Oncogene c-Jun
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DOI：
10.1091/mbc.e08-12-1196
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发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Vardimon, Lily
中科院分区：
文献类型：
--
作者：
Knirsh, Revital;Ben-Dror, Iris;Vardimon, Lily
e -钙粘蛋白介导的细胞-细胞接触的丧失可以引发信号通路，导致获得侵袭性表型。在这里，我们发现在这条通路的接收端是原癌基因c-Jun，它是激活蛋白-1转录因子家族的成员，在刺激细胞增殖和促进肿瘤中起关键作用。细胞分离或取消e -钙粘蛋白介导的细胞-细胞接触都会导致c-Jun蛋白积累的急剧增加。与生长因子通过激活c-Jun基因的转录来增强c-Jun的表达不同，细胞接触依赖性的c-Jun积累的增加并不伴随着c-Jun mRNA或c-Jun蛋白稳定性的相应增加，而是伴随着c-Jun转录物的可翻译性的增加。一致地，c-Jun积累的增加不依赖于有丝分裂原激活的蛋白激酶或β -连环蛋白途径的激活，而是由重组的细胞骨架触发的信号介导。细胞骨架的解聚可以模拟细胞分离的效果，导致c-Jun积累的急剧增加，而紫杉醇则抑制细胞接触依赖性的增加。这种新的c-Jun调控机制似乎是结肠癌患者肿瘤细胞中c-Jun过度表达的基础。
Loss of E-cadherin-mediated cell-cell contacts can elicit a signaling pathway that leads to acquisition of an invasive phenotype. Here, we show that at the receiving end of this pathway is the proto-oncogene c-Jun, a member of the activator protein-1 family of transcription factors that play a key role in stimulation of cell proliferation and tumor promotion. Cell separation or abrogation of E-cadherin-mediated cell-cell contacts both cause a dramatic increase in accumulation of the c-Jun protein. Unlike growth factors that enhance the expression of c-Jun by activating the transcription of the c-jun gene, the cell contact-dependent increase in c-Jun accumulation is not accompanied by a corresponding increase in c-Jun mRNA or c-Jun protein stability but rather in the translatability of the c-Jun transcript. Consistently, the increase in c-Jun accumulation is not dependent on activation of the mitogen-activated protein kinase or beta-catenin pathways but is mediated by signals triggered by the restructured cytoskeleton. Depolymerization of the cytoskeleton can mimic the effect of cell separation and cause a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase. This novel mechanism of c-Jun regulation seems to underlie the robust overexpression of c-Jun in tumor cells of patients with colon carcinoma.