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eIF3a regulation of mTOR signaling and translational control via HuR in cellular response to DNA damage

Oncogene volumeย 41,ย pages 2431โ€“2443 (2022)Cite this article

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Abstract

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 5สน-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.

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Fig. 1: eIF3a knockdown increases mTORC1 activity.
Fig. 2: eIF3a regulates expression of other mTORC1 subunits.
Fig. 3: Raptor mediates eIF3a regulation of mTORC1 activity.
Fig. 4: eIF3a regulates the 5สน-UTR activity of Raptor mRNA.
Fig. 5: HuR binds to the 5สน-UTR sequence of Raptor mRNA.
Fig. 6: eIF3a regulates Akt-mediated PRAS40 phosphorylation.
Fig. 7: mTORC1 mediates eIF3a regulation of cellular response to cisplatin.
Fig. 8: mTORC1 mediates eIF3a regulation of NER gene expression.

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Acknowledgements

This work was supported in part by the NIH grant R01 CA211904.

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  1. Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Shijie Ma,ย Zizheng Dongย &ย Jian-Ting Zhang

  2. Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Yanfei Huangย &ย Jing-Yuan Liu

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SM, ZD and JTZ: designed research; SM: performed research; SM, YH and JL: analyzed data; SM and JTZ: wrote the paper.

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Correspondence to Jian-Ting Zhang.

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Ma, S., Dong, Z., Huang, Y. et al. eIF3a regulation of mTOR signaling and translational control via HuR in cellular response to DNA damage. Oncogene 41, 2431โ€“2443 (2022). https://doi.org/10.1038/s41388-022-02262-5

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