Estrogen receptor α promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f)
Estrogen receptor α promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f)
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DOI：
10.1074/jbc.ra118.004383
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发表时间：
2019-02-15
影响因子：
4.8
通讯作者：
Holz, Marina K.
中科院分区：
文献类型：
--
作者：
Cuesta, Rafael;Berman, Adi Y.;Holz, Marina K.
大约三分之二的乳腺癌病例是雌激素受体（ER）阳性。这种乳腺癌亚型的治疗与内分泌疗法是有效的辅助和复发设置。然而，它们的有效性因内在或后天抗性的出现而受到损害。因此，新的分子靶点的鉴定可以显著地有助于新的治疗策略的开发。近年来，许多研究表明，翻译起始因子的异常水平与癌症的病因有关，并提供了证据，证明这些因子是有希望的治疗靶点。因此，我们观察到与ER阴性细胞相比，ER阳性乳腺癌细胞中eIF 3亚基eIF 3f的水平降低，并确定低eIF 3f水平是ER阳性MCF 7细胞适当增殖和存活所需的。eIF 3f的表达在转录（基因组途径）和翻译（非基因组途径）水平上受到ER α的严格控制。具体而言，雌激素结合的ER α抑制EIF 3F基因的转录，同时促进eIF 3f mRNA的翻译。为了调节翻译，雌激素激活mTORC 1途径，这增强了eIF 3与eIF 4F复合物的结合，从而增强了48 S前起始复合物的组装和蛋白质合成。我们观察到具有高度结构化的5 '-UTR的mRNA的优先翻译，所述5 '-UTR通常编码参与细胞增殖和存活的因子（例如，细胞周期蛋白D1和存活素）。我们的研究结果强调了雌激素-ER α介导的eIF 3f表达控制对ER阳性乳腺癌细胞增殖和存活的重要性。这些发现可能为开发治疗ER阳性乳腺癌的新疗法提供理论基础。
Approximately two thirds of all breast cancer cases are estrogen receptor (ER)-positive. The treatment of this breast cancer subtype with endocrine therapies is effective in the adjuvant and recurrent settings. However, their effectiveness is compromised by the emergence of intrinsic or acquired resistance. Thus, identification of new molecular targets can significantly contribute to the development of novel therapeutic strategies. In recent years, many studies have implicated aberrant levels of translation initiation factors in cancer etiology and provided evidence that identifies these factors as promising therapeutic targets. Accordingly, we observed reduced levels of the eIF3 subunit eIF3f in ER-positive breast cancer cells compared with ER-negative cells, and determined that low eIF3f levels are required for proper proliferation and survival of ER-positive MCF7 cells. The expression of eIF3f is tightly controlled by ER alpha at the transcriptional (genomic pathway) and translational (nongenomic pathway) level. Specifically, estrogen-bound ER alpha represses transcription of the EIF3F gene, while promoting eIF3f mRNA translation. To regulate translation, estrogen activates the mTORC1 pathway, which enhances the binding of eIF3 to the eIF4F complex and, consequently, the assembly of the 48S preinitiation complexes and protein synthesis. We observed preferential translation of mRNAs with highly structured 5 '-UTRs that usually encode factors involved in cell proliferation and survival (e.g. cyclin D1 and survivin). Our results underscore the importance of estrogen-ER alpha-mediated control of eIF3f expression for the proliferation and survival of ER-positive breast cancer cells. These findings may provide rationale for the development of new therapies to treat ER-positive breast cancer.