TGF-β signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer:: Role of the β-spectrin, ELF
TGF-β signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer:: Role of the β-spectrin, ELF
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DOI：
10.1016/j.bbrc.2006.03.236
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发表时间：
2006-06-16
影响因子：
3.1
通讯作者：
Mishra, Lopa
中科院分区：
文献类型：
--
作者：
Kim, Sang Soo;Shetty, Kirti;Mishra, Lopa
我们已经表明，ELF，一种干细胞衔接蛋白的缺失，通过Smad 3和Smad 4定位破坏TGF-β信号传导。值得注意的是elf（+/-）/smad 4（+/-）小鼠发生胃癌，这是分析胃癌发生中分子事件的重要模型。为了进一步了解ELF在胃癌抑制中的功能作用，我们对导致胃肿瘤发生的细胞周期事件进行了详细的表征。elf（-/-）细胞和elf（+/-）/smad 4（+/-）小鼠表现出细胞周期调节因子如Cdk 4、K-Ras和p21的显著改变。Cdk 4的水平与正常对照相比增加，表明ELF的丧失导致细胞周期调节的功能异常。我们进一步证明elf（-/-）MEFs显示G（1）/S细胞周期转换的中断和衰老的显著减少。因此，在ELF缺乏的反应中，G（1）/S检查点和衰老的异常有助于其恶性转化的易感性增加。(c)2006年由Elsevier Inc.出版
We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-beta signaling through Smad3 and Smad4 localization. Notably elf(+/-)/smad4(+/-) mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf(-/-) cells and elf(+/-)/smad4(+/-) mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf(-/-) MEFs show a disruption of G(1)/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G(1)/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation. (c) 2006 Published by Elsevier Inc.