Ras transformation of RIE-1 cells activates cap-independent translation of ornithine decarboxylase: regulation by the Raf/MEK/ERK and phosphatidylinositol 3-kinase pathways.
Ras transformation of RIE-1 cells activates cap-independent translation of ornithine decarboxylase: regulation by the Raf/MEK/ERK and phosphatidylinositol 3-kinase pathways.
复制标题
RIE-1 细胞的 Ras 转化激活鸟氨酸脱羧酶的帽独立翻译：受 Raf/MEK/ERK 和磷脂酰肌醇 3-激酶途径调节。
DOI：
10.1158/0008-5472.can-06-4627
复制
发表时间：
2007
期刊：
影响因子：
11.2
通讯作者：
Shantz,LisaM
中科院分区：
文献类型：
--
作者：
Origanti,Sofia;Shantz,LisaM
鸟氨酸脱羧酶（ODC）是多胺生物合成的第一个限速酶。ODC的失调对肿瘤的生长至关重要，ODC是Ras的靶点。这些实验研究了RIE-1细胞中ODC的翻译调控，将未转化的细胞与活化的Ras 12 V突变体转化的细胞进行比较。对ODC 5′非翻译区（5′UTR）的分析显示了4个剪接变异体，其中有2个内含子序列存在或缺失。在两种细胞系中均发现了所有四种5′UTR;然而，含有内含子序列的变体在Ras转化细胞中更丰富。所有剪接变体支持内部核糖体进入位点（IRES）介导的翻译，IRES活性在Ras转化的细胞中显著升高。Ras效应靶点的抑制表明ODC IRES元件受翻译因子eIF 4 E的磷酸化状态调节。通过抑制促分裂原活化蛋白/细胞外信号调节激酶（ERK）激酶（MEK）或eIF 4 E激酶Mnk 1/2使eIF 4 E去磷酸化，可增加两种细胞系中ODC IRES活性。当Raf/MEK/ERK和磷脂酰肌醇3-激酶/哺乳动物雷帕霉素靶点通路在正常细胞中被抑制时，ODC IRES活性非常低，细胞停滞在G1期。当这些途径在Ras转化细胞中被抑制时，细胞周期停滞不会发生，ODC IRES活性增加，有助于维持高ODC活性。[Cancer Res 2007;67（10）：4834-42]
Ornithine decarboxylase (ODC) is the first and generally rate-limiting enzyme in polyamine biosynthesis. Deregulation of ODC is critical for oncogenic growth, and ODC is a target ofRas. These experiments examine translational regulation of ODC in RIE-1 cells, comparing untransformed cells with those transformed by an activated Ras12V mutant. Analysis of the ODC 5′ untranslated region (5′UTR) revealed four splice variants with the presence or absence of two intronic sequences. All four 5′UTR species were found in both cell lines; however, variants containing intronic sequences were more abundant in Ras-transformed cells. All splice variants support internal ribosome entry site (IRES)–mediated translation, and IRES activity is markedly elevated in cells transformed by Ras. Inhibition of Ras effector targets indicated that the ODC IRES element is regulated by the phosphorylation status of the translation factor eIF4E. Dephosphorylation of eIF4E by inhibition of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) or the eIF4E kinase Mnk1/2 increases ODC IRES activity in both cell lines. When both the Raf/MEK/ERK and phosphatidylinositol 3-kinase/mammalian target of rapamycin pathways are inhibited in normal cells, ODC IRES activity is very low and cells arrest in G1. When these pathways are inhibited in Ras-transformed cells, cell cycle arrest does not occur and ODC IRES activity increases, helping to maintain high ODC activity. [Cancer Res 2007;67(10):4834–42]