Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis
Translation initiation factor 4E blocks endoplasmic reticulum-mediated apoptosis
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DOI：
10.1074/jbc.m312467200
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发表时间：
2004-05-14
影响因子：
4.8
通讯作者：
Bitterman, PB
中科院分区：
文献类型：
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作者：
Li, SN;Perlman, DM;Bitterman, PB
真核翻译起始因子4 E（eIF 4 E）是利用5'帽结构翻译细胞mRNA所需的mRNA帽结合蛋白。eIF 4 E是mRNA募集到核糖体的限速因子，是生长因子、激素和其他细胞外刺激物调节翻译的主要靶点。当过度表达时，eIF 4 E对细胞生长和存活产生深远影响，导致癌基因依赖性细胞凋亡的抑制，导致恶性转化并赋予肿瘤多药耐药性。我们以前发现过表达的eIF 4 E通过选择性地激活Bcl-X-L的表达来阻断生长因子戒断和细胞毒性药物诱导的凋亡途径，从而阻止细胞色素c的线粒体释放。在这项研究中，我们研究了异位eIF 4 E表达对内质网（ER）介导的细胞凋亡的影响。在这里，我们表明，eIF 4 E从ER应激源布雷菲德菌素A，衣霉素，毒胡萝卜素，和Ca 2+离子载体A23187拯救细胞。此外，我们发现从Ca 2+离子载体触发的凋亡中拯救的细胞既不从其ER释放钙，也不将caspase-12从ER转运到细胞质。这些数据有力地支持了eIF 4 E作为细胞活力的多效性调节剂发挥作用的概念，并且细胞凋亡的关键细胞器介导的检查点的整合可以由帽依赖性翻译装置控制。
Eukaryotic translation initiation factor 4E (eIF4E) is the mRNA cap-binding protein required for translation of cellular mRNAs utilizing the 5' cap structure. The rate-limiting factor for mRNA recruitment to ribosomes, eIF4E is a major target for regulation of translation by growth factors, hormones, and other extracellular stimuli. When overexpressed, eIF4E exerts profound effects on cell growth and survival, leading to suppression of oncogene-dependent apoptosis, causing malignant transformation and conferring tumors with multiple drug resistance. We found previously that overexpressed eIF4E interdicts the apoptotic pathway induced by growth factor withdrawal and cytotoxic drugs by selectively activating the expression of Bcl-X-L, thus preventing mitochondrial release of cytochrome c. In this study, we examined the impact of ectopic eIF4E expression on apoptosis mediated by the endoplasmic reticulum (ER). Here we show that eIF4E rescued cells from the ER stressors brefeldin A, tunicamycin, thapsigargin, and the Ca2+ ionophore A23187. In addition, we found that cells rescued from Ca2+ ionophore-triggered apoptosis did not release calcium from their ER nor did they translocate caspase-12 from the ER to the cytoplasm. These data lend strong support to the concept that eIF4E functions as a pleiotropic regulator of cell viability and that integration of critical organelle-mediated checkpoints for apoptosis can be controlled by the cap-dependent translation apparatus.