Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control

Abstract

Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and the dysregulation of translation, which in turn, leads to aberrant protein synthesis. In addition, the machinery that is involved in protein synthesis plays critical roles in stem cell fate determination. In the current review, recent advances in the understanding of translational control, especially translational initiation in cancer development and stem cell fate control, are described. Therapeutic targets of mRNA translation such as eIF4E, 4EBP, and eIF2, for cancer treatment or stem cell fate regulation are reviewed. Upstream signaling pathways that regulate and affect translation initiation were introduced. It is important to regulate the expression of protein for normal cell behavior and development. mRNA translation initiation is a key step to regulate protein synthesis, therefore, identifying and targeting molecules that are critical for protein synthesis is necessary and beneficial to develop cancer therapeutics and stem cells fate regulation.

Keywords: cancer; cell fate; differentiation; proliferation; stem cell; translation.

Figure 1

Cap-dependent translation initiation. When an initiator tRNA binds to guanosine triphosphate (GTP)-bound eukaryotic initiation factor (eIF2), the complex can further recruit eIF1, eIF1A, eIF3, eIF5, and 40S ribosome to form 43S pre-initiation complex (43S PIC). eIF4F, composed of eIF4A, eIF4E, and eIF4G, facilitates the recruitment of mRNA to 43S PIC. Then, eIF4E binds to the 5′-cap of mRNA, and eIF4G recruits poly(A)-binding protein (PABP), which binds to poly(A) on mRNA on the 3′-end, thus circularizing the mRNA to stabilize it for translation. eIF4A functions as a helicase and may facilitate mRNA scanning to find the initiation codon AUG. Once the codon is found by 43S PIC, eIFs are released and the 60S ribosomal subunit joins the assembly to generate protein synthesis-ready 80S ribosome ready for translation elongation.

Figure 2

Signaling pathways that influence protein synthesis. Signals that are activated by growth factors not only affect transcription but also translation. Mitogen-Activated Protein Kinase Interacting Protein Kinases (MNKs) can be phosphorylated by activated extracellular signal-regulated kinases (ERKs) and further phosphorylate eIF4E, which is important for recruiting mRNA for translation initiation. Binding of the growth factors to the receptors activates phosphatidylinositol 3-kinase (PI3K) and AKT. Activated AKT phosphorylates tuberous sclerosis complex 2 (TSC2), which leads to the dissociation of the TSC1/ TSC2 complex that negatively regulates mammalian target of rapamycin complex 1 (mTORC1) and leads to mTORC1 activation. mTORC1 hyper-phosphorylates 4EBP, which results in the release of eIF4E for protein synthesis. Activated mTORC1 also activates S6Ks, which further activate eukaryotic translation elongation factor 2 (eEF2) and facilitate elongation.