Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
Oncogene. 2022 Apr;41(17):2431-2443. doi: 10.1038/s41388-022-02262-5. Epub 2022 Mar 12.
eIF3a (eukaryotic translation initiation factor 3a), a subunit of the eIF3 complex, has been suggested to play a regulatory role in protein synthesis and in cellular response to DNA-damaging treatments. S6K1 is an effector and a mediator of mTOR complex 1 (mTORC1) in regulating protein synthesis and integrating diverse signals into control of cell growth and response to stress. Here, we show that eIF3a regulates S6K1 activity by inhibiting mTORC1 kinase via regulating Raptor synthesis. The regulation of Raptor synthesis is via eIF3a interaction with HuR (human antigen R) and binding of the eIF3a-HuR complex to the 5'-UTR of Raptor mRNA. Furthermore, mTORC1 may mediate eIF3a function in cellular response to cisplatin by regulating synthesis of NER proteins and NER activity. Taken together, we conclude that the mTOR signaling pathway may also be regulated by translational control and mediate eIF3a regulation of cancer cell response to cisplatin by regulating NER protein synthesis.
eIF3a（真核翻译起始因子 3a）是 eIF3 复合物的一个亚基，据推测它在蛋白质合成和细胞对 DNA 损伤处理的反应中发挥调节作用。S6K1 是 mTOR 复合物 1（mTORC1）的效应物和介导物，在调节蛋白质合成和整合多种信号以控制细胞生长和对压力的反应中起作用。在这里，我们表明 eIF3a 通过调节 Raptor 合成来抑制 mTORC1 激酶，从而调节 S6K1 活性。Raptor 合成的调节是通过 eIF3a 与 HuR（人类抗原 R）相互作用以及 eIF3a-HuR 复合物与 Raptor mRNA 5'-UTR 的结合实现的。此外，mTORC1 可能通过调节 NER 蛋白的合成和 NER 活性来介导 eIF3a 在细胞对顺铂反应中的功能。总之，我们得出结论，mTOR 信号通路也可能受到翻译调控的调节，并通过调节 NER 蛋白合成来介导 eIF3a 对顺铂的癌细胞反应的调节。
