Oncogenic Ras-mediated downregulation of Gadd153/CHOP is required for Ras-induced cellular transformation
Oncogenic Ras-mediated downregulation of Gadd153/CHOP is required for Ras-induced cellular transformation
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DOI：
10.1038/sj.onc.1208660
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发表时间：
2005-07-14
期刊：
影响因子：
8
通讯作者：
Huang, Y
中科院分区：
文献类型：
--
作者：
Rong, R;Montalbano, J;Huang, Y
致癌RAS蛋白通过对细胞增殖和存活至关重要的多个下游信号级联途径转化细胞。Gadd153，也被称为CHOP，是一种生长抑制和促凋亡蛋白，它的表达被许多诱导凋亡的药物上调。在这里，我们报告了我们的新发现，即致癌RAS下调Gadd153在蛋白质和mRNA水平的表达，并且这种下调至少部分是通过降低GADD153 mRNA的稳定性而发生的。Gadd153下调是针对致癌RAS的，因为另一个致癌家族成员R-Ras2/TC21不下调Gadd153。我们进一步证明外源Gadd153的表达干扰了RAS诱导的致癌转化，这表明Gadd153的下调似乎是致癌RAS促进细胞转化的一个重要机制。因此，致癌的RAS介导的细胞转化还包括下调重要的分子，如负向调节细胞生长和存活的Gadd153。
Oncogenic Ras proteins transform cells via multiple downstream signaling cascades that are important for cell proliferation and survival. Gadd153, also known as CHOP, is a growth inhibitory and proapoptotic protein and its expression is upregulated by many agents that induce apoptosis. Here, we report our novel findings that oncogenic Ras downregulates Gadd153 expression at both protein and mRNA levels and that such downregulation occurs, at least in part, via decreases in GADD153 mRNA stability. Gadd153 downregulation is specific to oncogenic Ras since another oncogenic family member R-Ras2/TC21 does not downregulate Gadd153. W e further demonstrate that the expression of exogenous Gadd153 interferes with Ras-induced oncogenic transformation, which suggests that downregulation of Gadd153 appears to be an important mechanism by which oncogenic Ras promotes cellular transformation. Thus, oncogenic Ras-mediated cellular transformation also involves down-modulation of important molecules such as Gadd153 that negatively regulate cell growth and survival.