Transcriptional induction of 4E-BP3 prolongs translation repression.
Transcriptional induction of 4E-BP3 prolongs translation repression.
复制标题
4E-BP3 的转录诱导延长了翻译抑制。
DOI：
10.1080/15384101.2016.1224786
复制
发表时间：
2016
期刊：
影响因子：
4.3
通讯作者：
Alain T.
中科院分区：
文献类型：
--
作者：
Tsukumo Y;Sonenberg N;Alain T.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种多方面的丝氨酸/苏氨酸激酶，涉及大量的生理过程和病理状态，包括癌症。1 mTOR形成2种不同的复合物，mTOR复合物1（mTORC 1）和2（mTORC 2），它们在组成、下游靶点、调节和对mTOR变构抑制剂雷帕霉素的敏感性方面不同。由于癌基因和肿瘤抑制因子（例如PI 3 K、TSC 2、PTEN）的异常上游突变，mTORC 1在癌症中经常过度活化。这种信号通路的过度激活是癌细胞增殖和存活的核心，因此，对开发用药理学抑制剂靶向mTORC 1的治疗策略有相当大的兴趣。1 mTORC 1的一个关键作用是调节翻译，部分通过磷酸化（失活）真核翻译起始因子4 E（eIF 4 E）结合蛋白（4 E-BP）。在哺乳动物中存在3种4 E-BP（注释为4 E-BP 1、4 E-BP 2和4 E-BP 3），每种都作为翻译阻遏物发挥作用。2，3在营养不良或药物抑制mTORC 1的条件下，4 E-BP变得低磷酸化（活化）并以高亲和力结合5-帽结合蛋白eIF 4 E。4 E-BP与eIF 4 E的结合阻止eIF 4G结合和eIF 4F复合物组装，从而限制帽依赖性翻译的起始。在营养素、胰岛素或生长因子刺激mTORC 1后，4 E-BP然后被过度磷酸化，导致它们从eIF 4 E释放并有利于帽依赖性翻译。1虽然这些蛋白质具有明显相同的分子功能，但4 E-BP具有约60%的蛋白质同一性，并且据报道具有不同的组织分布和表达，出版物显示4 E-BP 1高度存在于骨骼肌、胰腺和脂肪组织中，4 E-BP 2普遍表达但主要存在于脑和淋巴细胞中，4 E-BP 3表达水平较低，但发现存在于大多数组织中。2-5 4 E-BP 1和4 E-BP 2也经常在各种肿瘤中过表达和过度磷酸化，特别是，4 E-BP 1表达和磷酸化被用作替代标志物来预测几种癌症中的患者结果。1也许是由于市售试剂的可用性，迄今为止的大多数研究都集中在4 E-BP 1和4 E-BP 2的调节机制和功能上，而不是4 E-BP 3。我们先前发现，由于编码促增殖蛋白的eIF 4 E敏感性mRNA的持续翻译，4 E-BP 1和2的耗尽使细胞对mTOR抑制剂的抗肿瘤作用具有抗性。6，7虽然这些研究是在转化的小鼠胚胎成纤维细胞中进行的，其中4 E-BP 3的蛋白表达有限或没有7，但我们最新的研究2表明，在几种人癌细胞系中，在延长的mTORC 1抑制后，4 E-BP 3可以在转录和蛋白水平上被强烈诱导。除了这些体外实验，我们发现，4 E-BP 3在用mTOR靶向药物长期治疗的化学诱导的肝癌小鼠模型的肿瘤中转录增加，重要的是，人乳腺癌患者中的4 E-BP 3 mRNA表达与mTORC 1通路的激活呈负相关。这些结果表明，4 E-BP 3通常在细胞中以低水平表达，但在长期mTORC 1抑制后显著增加。这与4 E-BP 1和4 E-BP 2蛋白形成鲜明对比，已经发现4 E-BP 1和4 E-BP 2蛋白在长时间的mTOR抑制性药物治疗期间表达降低或降解。2，6我们最近的研究表明...
The mammalian target of rapamycin (mTOR) is a multifaceted serine/threonine kinase implicated in a large number of physiological processes and pathological states including cancer. 1 mTOR forms 2 distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in their composition, downstream targets, regulation, and sensitivity to the mTOR allosteric inhibitor rapamycin. mTORC1 is frequently hyperactivated in cancers due to aberrant upstream mutations in oncogenes and tumor suppressors (eg PI3K, TSC2, PTEN). Hyperactivation of this signaling pathway is central to cancer cell proliferation and survival, thus there is considerable interest in the development of therapeutic strategies targeting mTORC1 with pharmacological inhibitors. 1 One critical role of mTORC1 is to regulate translation, in part, by phosphorylating (inactivating) the eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). In mammals 3 4E-BPs exist (annotated as 4E-BP1, 4E-BP2, and 4E-BP3), each functioning as a translational repressor. 2, 3 Under conditions of poor nutrition or pharmacological inhibition of mTORC1, 4E-BPs become hypophosphorylated (activated) and bind to the 5 0-cap-binding protein eIF4E with high affinity. The binding of 4E-BPs to eIF4E prevents eIF4G association and eIF4F complex assembly, thereby limiting initiation of cap-dependent translation. Upon stimulation of mTORC1 by nutrients, insulin or growth factors, 4E-BPs are then hyperphosphorylated, resulting in their release from eIF4E and favoring of capdependent translation. 1 While these proteins have apparent identical molecular functions, 4E-BPs share approximately 60%-protein identity and have been reported to have different tissue distributions and expression, with publications showing 4E-BP1 highly present in skeletal muscle, pancreas, and adipose tissues, 4E-BP2 ubiquitously expressed but predominant in the brain and in lymphocyte cells, and 4E-BP3 expressed at lower levels but found to be present in most tissues. 2-5 4E-BP1 and 4E-BP2 are also frequently overexpressed and hyperphosphorylated in various tumors, and in particular, 4E-BP1 expression and phosphorylation are used as surrogate markers to predict patient outcome in several cancers. 1Perhaps due to the availability of commercially available reagents, most studies to date have focused on the regulatory mechanisms and functions of 4E-BP1 and 4E-BP2 rather than 4E-BP3. We previously found that depletion of 4E-BP1 and 2 renders cells resistant to anti-tumor effects of mTOR inhibitors, due to sustained translation of eIF4E-sensitive mRNAs encoding pro-proliferative proteins. 6, 7 While these studies were performed in transformed mouse embryonic fibroblasts with limited to no protein expression of 4E-BP3 7, our latest study 2 demonstrates that in several human cancer cell lines, 4E-BP3 can become strongly induced both transcriptionally and at protein levels upon prolonged mTORC1 inhibition. In addition to these in vitro experiments, we found that 4E-BP3 is transcriptionally increased in tumors of a chemically-induced liver cancer mouse model chronically treated with mTOR-targeting agents, and importantly, that 4E-BP3 mRNA expression in human breast cancer patients inversely correlates with activation of the mTORC1 pathway. These results indicate that 4E-BP3 is normally expressed at low levels in cells but is considerably increased after long-term mTORC1 inhibition. This is in sharp contrast to 4E-BP1 and 4E-BP2 proteins, which have been found to decrease in expression or be degraded during prolonged mTOR-inhibitory drug treatments. 2, 6 Our recent studies show that …