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mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
In addition, TORC1 enhances the translation of a different set of RNAs by phosphorylating 4E-BP1 (2,6). eIF4E is a component of a helicase complex that binds to the 7-methylguanine cap at the 5′ end of mRNAs and enhances the ability of ribosome-eIF complexes to scan the mRNA for initiation sites. 4E-BP1, in its unphosphorylated state, binds to eIF4E and inhibits the eIF4E-containing helicase complex. Activation of TORC1 signaling causes hyperphosphorylation of 4E-BP1, diminishing the stability of the 4E-BP1/eIF4E complex, and causing its dissociation. Free eIF4E then binds to the scaffold protein eIF4G and the RNA helicase eIF4A, forming an active helicase that facilitates translation of mRNAs containing long, highly folded 5′ untranslated regions. Included in this class of transcripts are messages encoding cyclin D1, c-Myc, hypoxia inducible factor-lα (HIF-lα), vascular endothelial growth factor and fibroblast growth factor as well as ribosomal proteins themselves (2,3,6). These molecules are not only critical for cell survival and proliferation, but also have the potential to be used to monitor therapy. Because HIF-lα regulates the glycolytic pathway and fluorodeoxyglucose positron emission tomography (FDG-PET) detects tumors by their elevated rates of glycolysis, FDG-PET can potentially be used to assess inhibition of this pathway after treatment with mTOR inhibitors (2,3).
Protein and amino acids
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
The EAAs play a role in regulating MPS by enhancing the efficiency of translation (34) due to a stimulation of peptide chain initiation relative to elongation (40). Peptide-chain initiation involves dissociation of the 80S ribosome into 40S and 60S ribosomal subunits, formation of the 43S preinitiation complex with binding of initiator methionyl-tRNA to the 40S subunit, binding of mRNA to the 43S preinitiation complex and association of the 60S ribosomal subunit to form an active 80S ribosome (74). First, peptide chain initiation is controlled by the binding of initiator methionyl tRNA to the 40S ribosomal subunit to form the 43S preinitiation complex, a reaction mediated by eukaryotic initiation factor 2 (eIF2) and regulated by eIF2B. Second is the binding of mRNA to the 43S preinitiation complex, which is mediated by eIF4F (73). During translation initiation, the eIF4E·mRNA complex binds to eIF4G and eIF4A to form the active eIF4F complex (63). The binding of eIF4E to eIF4G is controlled by 4E-binding protein 1 (4E-BP1), a repressor of translation. Binding of 4E-BP1 to eIF4E limits eIF4E availability for formation of active eIF4E·eIF4G complex and is regulated by phosphorylation of 4E-BP1 (73).
Transport of mRNA into the Cytoplasm
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Werner E. G. Müller, Paul S. Agutter, Heinz C. Schröder
Our studies revealed no identity of the NE RNA helicase with the nuclear protein p68 described by Ford et al.28 The latter protein represents a RNA-dependent ATPase,29 which, as shown by Hirling et al.30 also possesses a helicase activity. P68 is a member of the “DEAD family” of RNA helicase-like proteins,31 among which is also the initiation factor eIF4A.32 Sequence analyses of a number of splicing factors in yeast suggest that a number of RNA-dependent ATPases are involved in the assembly of spliceosomes.33 Notably, an ATP-dependent RNA helicase seems to be involved in the release of spliced mRNA from the spliceosomes in yeast.34
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
Messenger RNA untranslated regions (UTR), including the 5ʹUTR and 3ʹUTR, contain multiple regulatory elements to control the stability and translation of mRNA. The 5ʹUTR plays an important role in controlling protein translation efficiency because it represents the binding site for the preinitiation complex initiation of protein translation [65–67]. The binding of eukaryotic initiation factor-4A (eIF4A) to the 5ʹUTR is crucial to unwind the secondary structure of mRNA before protein translation can occur [65]. The secondary structure of the 5ʹUTR also affects the binding of eIF1A to mRNA [68]. On the other hand, most eukaryotic mRNAs contain mRNA degradation signals in their 3ʹUTR, which regulate mRNA stability. AU-rich sequences in mRNA 3ʹUTR are known to participate in the removal of the poly(A) tail during mRNA degradation [69]. Therefore, half-life of the labile mRNAs could be increased when their AU-rich sequences are replaced with 3ʹUTR sequences from more stable mRNA [70]. Another important mRNA stability-regulating sequence within the 3ʹUTR is called the iron-responsive elements (IREs) [71]. IREs have also been reported to regulate mRNA translation [71].
The MAP kinase-interacting kinases (MNKs) as targets in oncology
Published in Expert Opinion on Therapeutic Targets, 2019
Jianling Xie, James E. Merrett, Kirk B. Jensen, Christopher G. Proud
The availability of eukaryotic initiation factor 4E (eIF4E) regulates the initiation of mRNA translation in eukaryotic cells and thus the rate of protein synthesis. eIF4E binds directly the 5ʹ-cap structure found on all cytoplasmic mRNAs in eukaryotes and is essential for the translation of these mRNAs. In turn, eIF4E binds to other initiation factors including eIF4G and eIF4A to recruit ribosomes to initiate mRNA translation. Over-expression or dysregulation of eIF4E is associated with cell transformation and tumorigenesis [1]. The phosphorylation of eIF4E at Ser209, an event that in-vivo is only catalysed by the mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs; [2]), promotes oncogenic transformation (see, e.g. [3,4]). MNKs are activated by the p38/ERK MAPKs. Aberrant phospho-eIF4E levels are observed in many human cancers, correlated with disease severity, and is associated with metastasis and poor survival ([4,5], reviewed [1]). Given the key role of eIF4E in mRNA translation, the eIF4E-Mnk axis has been suggested as a target in oncology. Here we evaluate the role of the MNKs in human cancers and the properties that make them suitable targets in cancer. The review introduces the signalling pathways that regulate the MNKs and their substrate eIF4E, the experimental approaches that have been used to study the MNKs, and summarises the studies implicating MNK activity in human cancers. It also discusses the current MNK therapeutic landscape and the potential for future MNK-targeting therapies.
Noradrenergic gating of long-lasting synaptic potentiation in the hippocampus: from neurobiology to translational biomedicine
Published in Journal of Neurogenetics, 2018
Peter V. Nguyen, Jennifer N. Gelinas
One important process where various signals and transmitters can act to regulate protein synthesis is at the level of translation initiation, a rate-limiting step in translation of many species of mRNA. Here, different protein kinases act to phosphorylate eukaryotic initiation factors (eIFs) involved in the assembly of translation initiation complexes that promote mRNA binding to ribosomal proteins (Costa-Mattioli et al., 2009). For example, two key protein kinases, extracellular signal-regulated protein kinase (ERK) and mammalian target of rapamycin (mTOR), play an important role in formation of the eukaryotic initiation factor 4F (eIF4F) complex (Gelinas et al., 2007; Kelleher, Govindarajan, & Tonegawa, 2004; Klann, Antion, Banko, & Hou, 2004; Tsokas, Ma, Iyengar, Landau, & Blitzer, 2007). The eIF4F initiation complex is assembled from the initiation factors eIF4A, 4E, and 4 G (Figure 1). In the basal state, formation of eIF4F is restrained by binding of eIF4E to the inhibitory protein, 4E-binding protein (4E-BP) (Banko et al., 2005). Phosphorylation of 4E-BP by mTOR triggers the release of eIF4E, which can then associate with eIF4G and form the eIF4F complex (Figure 1). In addition, ERK phosphorylates and activates the protein kinase, Mnk1 (MAPK signal-integrating kinase-1), which in turn phosphorylates 4E to further enhance translation.