Downregulation of Rap1GAP contributes to ras transformation
Downregulation of Rap1GAP contributes to ras transformation
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DOI：
10.1128/mcb.00155-07
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Meinkoth, Judy L.
中科院分区：
文献类型：
--
作者：
Tsygankova, Oxana A.;Prendergast, Gregory V.;Meinkoth, Judy L.
尽管Rap 1GAP在分化良好的大鼠甲状腺细胞中大量表达，但在人甲状腺肿瘤衍生细胞系的一个亚群中Rap 1GAP表达消失。有趣的是，Rap 1GAP在获得间充质形态的肿瘤细胞系中选择性下调。恢复Rap 1GAP表达这些细胞抑制细胞迁移和侵袭，与Rap 1和Rac 1活性的抑制相关的影响。Rap 1 GAP的重新表达也抑制了DNA合成和非贴壁依赖性增殖。相反，消除大鼠甲状腺细胞中Rap 1 GAP的表达会诱导细胞数量的短暂增加。引人注目的是，Rap 1GAP的表达被Ras转化废除。Ras下调Rap 1GAP需要激活Raf/MEK/细胞外信号调节激酶级联反应，并与间充质形态和迁移行为的诱导相关。值得注意的是，致癌Ras的急性表达足以下调大鼠甲状腺细胞中Rap 1GAP的表达，从而确定Rap 1GAP是致癌Ras的新靶点。总的来说，这些数据暗示Rap 1GAP是甲状腺中假定的肿瘤/侵袭抑制因子。为了支持这一观点，Rap 1GAP在正常人甲状腺细胞中高度表达，在原发性甲状腺肿瘤中下调。
Although abundant in well-differentiated rat thyroid cells, Rap1GAP expression was extinguished in a subset of human thyroid tumor-derived cell lines. Intriguingly, Rap1GAP was downregulated selectively in tumor cell lines that had acquired a mesenchymal morphology. Restoring Rap1GAP expression to these cells inhibited cell migration and invasion, effects that were correlated with the inhibition of Rap1 and Rac1 activity. The reexpression of Rap1GAP also inhibited DNA synthesis and anchorage-independent proliferation. Conversely, eliminating Rap1GAP expression in rat thyroid cells induced a transient increase in cell number. Strikingly, Rap1GAP expression was abolished by Ras transformation. The downregulation of Rap1GAP by Ras required the activation of the Raf/MEK/extracellular signal-regulated kinase cascade and was correlated with the induction of mesenchymal morphology and migratory behavior. Remarkably, the acute expression of oncogenic Ras was sufficient to downregulate Rap1GAP expression in rat thyroid cells, identifying Rap1GAP as a novel target of oncogenic Ras. Collectively, these data implicate Rap1GAP as a putative tumor/invasion suppressor in the thyroid. In support of that notion, Rap1GAP was highly expressed in normal human thyroid cells and downregulated in primary thyroid tumors.