Translational control of cell fate: Availability of phosphorylation sites on translational repressor 4E-BP1 governs its proapoptotic potency
Translational control of cell fate: Availability of phosphorylation sites on translational repressor 4E-BP1 governs its proapoptotic potency
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DOI：
10.1128/mcb.22.8.2853-2861.2002
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发表时间：
2002-04-01
影响因子：
5.3
通讯作者：
Bitterman, PB
中科院分区：
文献类型：
--
作者：
Li, SN;Sonenberg, N;Bitterman, PB
最近，翻译控制已被添加到公认的基因组、转录和翻译后调控细胞凋亡的机制中。我们先前发现，过表达的真核细胞起始因子4E(EIF4E)可以挽救细胞的凋亡，而野生型eIF4E结合蛋白1(4E-BP1)的异位表达则激活了细胞的凋亡--但仅在转化的细胞中。为了测试未转化细胞比转化细胞需要更少的帽依赖翻译来抑制细胞凋亡的可能性，我们加强了未转化成纤维细胞的翻译抑制水平。在这里，我们证明了雷帕霉素抑制4E-BP1的磷酸化引发了异位表达野生型4E-BP1的细胞的凋亡，而4E-BP1磷酸化位点突变体的表达以磷酸化位点特异性的方式有效地激活了细胞的凋亡。总体而言，促凋亡的效力与抑制帽子依赖的翻译是平行的。然而，这种关系并不是简单的单调。随着对帽依赖翻译的抑制增强，细胞凋亡增加到最大值。进一步的抑制导致较少的细胞凋亡--一种与通过内部核糖体进入位点激活翻译有关的状态。这些发现表明：4E-BP1的促凋亡活性由磷酸化事件控制，4E-BP1在正常和转化的成纤维细胞中都是促凋亡的，恶性转化与对帽依赖翻译的更高要求有关，以抑制细胞凋亡。我们的结果表明，4E-BP1介导的凋亡控制是通过蛋白质合成的质的而不是量的变化发生的，这种变化是由帽依赖和帽非依赖性过程之间的动态相互作用所介导的。
Translational control has been recently added to well-recognized genomic, transcriptional, and posttranslational mechanisms regulating apoptosis. We previously found that overexpressed eukaryotic initiation factor 4E (eIF4E) rescues cells from apoptosis, while ectopic expression of wild-type eIF4E-binding protein 1 (4E-BP1), the most abundant member of the 4E-BP family of eIF4E repressor proteins, activates apoptosis - but only in transformed cells. To test the possibility that nontransformed cells require less cap-dependent translation to suppress apoptosis than do their transformed counterparts, we intensified the level of translational repression in nontransformed fibroblasts. Here, we show that inhibition of 4E-BP1 phosphorylation by rapamycin triggers apoptosis in cells ectopically expressing wild-type 4E-BP1 and that expression of 4E-BP1 phosphorylation site mutants potently activates apoptosis in a phosphorylation site-specific manner. In general, proapoptotic potency paralleled repression of cap-dependent translation. However, this relationship was not a simple monotone. As repression of cap-dependent translation intensified, apoptosis increased to a maximum value. Further repression resulted in less apoptosis-a state associated with activation of translation through internal ribosomal entry sites. These findings show: that phosphorylation events govern the proapoptotic potency of 4E-BP1, that 4E-BP1 is proapoptotic in normal as well as transformed fibroblasts, and that malignant transformation is associated with a higher requirement for cap-dependent translation to inhibit apoptosis. Our results suggest that 4E-BP1-mediated control of apoptosis occurs through qualitative rather than quantitative changes in protein synthesis, mediated by a dynamic interplay between cap-dependent and cap-independent processes.