scholarly journals Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

2016 ◽  
Vol 2016 ◽  
pp. 1-19 ◽  
Author(s):  
Divya Khandige Sharma ◽  
Kamiko Bressler ◽  
Harshil Patel ◽  
Nirujah Balasingam ◽  
Nehal Thakor
Keyword(s):  
Protein Synthesis ◽  
Cancer Progression ◽  
Translation Initiation ◽  
Tumor Development ◽  
Mrna Translation ◽  
Translation Control ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Rate Limiting Step ◽  
Precise Understanding

Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

scholarly journals Structural differences in translation initiation between pathogenic trypanosomatids and their mammalian hosts

2019 ◽  
Author(s):  
Anthony Bochler ◽  
Jailson Brito Querido ◽  
Terezie Prilepskaja ◽  
Heddy Soufari ◽  
Angelita Simonetti ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Trypanosoma Cruzi ◽  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Mass Spectrometry Data ◽  
Initiation Complex ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Structural Differences

SUMMARYCanonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires the binding of several eukaryotic initiation factors (eIF 1, 1A, 2, 3 and 5), Met-tRNAiMet and the small ribosomal subunit (40S). Compared to their mammalian hosts, trypanosomatids present significant structural differences in their 40S suggesting substantial variability in translation initiation. Here we determined the structure of the 43S PIC from Trypanosoma cruzi, the parasite causing the Chagas disease. Our structure shows numerous specific features, such as the variant eIF3 structure and its unique interactions with the large rRNA ESs 9S, 7S and 6S, and the association of a kinetoplastid-specific ~245 kDa DDX60-like helicase. It also revealed the so-far-elusive 40S-binding site of the eIF5 C-terminal domain and the structures of key terminal tails of several conserved eIFs underlying their activities within the PIC. Our results are corroborated by GST-pulldown assays in both human and T. cruzi and mass-spectrometry data.

scholarly journals Amino acid-induced stimulation of translation initiation in rat skeletal muscle

1999 ◽  
Vol 277 (6) ◽  
pp. E1077-E1086 ◽  
Author(s):  
Thomas C. Vary ◽  
Leonard S. Jefferson ◽  
Scot R. Kimball
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Translation Initiation ◽  
Amino Acid Supplementation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Amino Acid Concentrations ◽  
Stimulation Of

Amino acids stimulate protein synthesis in skeletal muscle by accelerating translation initiation. In the two studies described herein, we examined mechanisms by which amino acids regulate translation initiation in perfused skeletal muscle hindlimb preparation of rats. In the first study, the effects of supraphysiological amino acid concentrations on eukaryotic initiation factors (eIF) 2B and 4E were compared with physiological concentrations of amino acids. Amino acid supplementation stimulated protein synthesis twofold. No changes were observed in eIF2B activity, in the amount of eIF4E associated with the eIF4E-binding protein (4E-BP1), or in the phosphorylation of 4E-BP1. The abundance of eIF4E bound to eIF4G and the extent of phosphorylation of eIF4E were increased by 800 and 20%, respectively. In the second study, we examined the effect of removing leucine on translation initiation when all other amino acids were maintained at supraphysiological concentrations. Removal of leucine from the perfusate decreased the rate of protein synthesis by 40%. The inhibition of protein synthesis was associated with a 40% decrease in eIF2B activity and an 80% fall in the abundance of eIF4E ⋅ eIF4G complex. The fall in eIF4G binding to eIF4E was associated with increased 4E-BP1 bound to eIF4E and a reduced phosphorylation of 4E-BP1. In contrast, the extent of phosphorylation of eIF4E was unaffected. We conclude that formation of the active eIF4E ⋅ eIF4G complex controls protein synthesis in skeletal muscle when the amino acid concentration is above the physiological range, whereas removal of leucine reduces protein synthesis through changes in both eIF2B and eIF4E.

Translation initiation in the crenarchaeon Sulfolobus solfataricus: eukaryotic features but bacterial route

2013 ◽  
Vol 41 (1) ◽  
pp. 350-355 ◽  
Author(s):  
Anna La Teana ◽  
Dario Benelli ◽  
Paola Londei ◽  
Udo Bläsi
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Current Knowledge ◽  
Sulfolobus Solfataricus ◽  
Initiation Complex ◽  
Initiation Factors ◽  
Sequence Of Events ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

The formation of the translation initiation complex represents the rate-limiting step in protein synthesis. Translation initiation in the crenarchaeon Sulfolobus solfataricus depends on several translation IFs (initiation factors), some of which have eukaryal but no bacterial counterparts. In the present paper, we review the current knowledge of the structure, function and evolution of the IFs in S. solfataricus in the context of eukaryotic and bacterial orthologues. Despite similarities between eukaryotic and S. solfataricus IFs, the sequence of events in translation initiation in S. solfataricus follows the bacterial mode.

scholarly journals The Jigsaw Puzzle of mRNA Translation Initiation in Eukaryotes: A Decade of Structures Unraveling the Mechanics of the Process

2018 ◽  
Vol 47 (1) ◽  
pp. 125-151 ◽  
Author(s):  
Yaser Hashem ◽  
Joachim Frank
Keyword(s):  
Structural Biology ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Start Codon ◽  
Jigsaw Puzzle ◽  
Reading Frame ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Initiation Process

Translation initiation in eukaryotes is a highly regulated and rate-limiting process. It results in the assembly and disassembly of numerous transient and intermediate complexes involving over a dozen eukaryotic initiation factors (eIFs). This process culminates in the accommodation of a start codon marking the beginning of an open reading frame at the appropriate ribosomal site. Although this process has been extensively studied by hundreds of groups for nearly half a century, it has been only recently, especially during the last decade, that we have gained deeper insight into the mechanics of the eukaryotic translation initiation process. This advance in knowledge is due in part to the contributions of structural biology, which have shed light on the molecular mechanics underlying the different functions of various eukaryotic initiation factors. In this review, we focus exclusively on the contribution of structural biology to the understanding of the eukaryotic initiation process, a long-standing jigsaw puzzle that is just starting to yield the bigger picture.

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

scholarly journals Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?

2020 ◽  
Vol 21 (18) ◽  
pp. 6650
Author(s):  
Usha Kabilan ◽  
Tyson E. Graber ◽  
Tommy Alain ◽  
Dmitry Klokov
Keyword(s):  
Protein Synthesis ◽  
Ionizing Radiation ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mrna Translation ◽  
Cellular Responses ◽  
Translation Control ◽  
Cis Acting ◽  
Radiation Hormesis ◽  
Downstream Signaling

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control.

Subcellular localization of mRNA and factors involved in translation initiation

2008 ◽  
Vol 36 (4) ◽  
pp. 648-652 ◽  
Author(s):  
Nathaniel P. Hoyle ◽  
Mark P. Ashe
Keyword(s):  
Protein Synthesis ◽  
Subcellular Localization ◽  
Translation Initiation ◽  
Potential Functions ◽  
Present Review ◽  
Cellular Activity ◽  
Initiation Factors ◽  
Translation Initiation Factors

Both the process and synthesis of factors required for protein synthesis (or translation) account for a large proportion of cellular activity. In eukaryotes, the most complex and highly regulated phase of protein synthesis is that of initiation. For instance, across eukaryotes, at least 12 factors containing 22 or more proteins are involved, and there are several regulated steps. Recently, the localization of mRNA and factors involved in translation has received increased attention. The present review provides a general background to the subcellular localization of mRNA and translation initiation factors, and focuses on the potential functions of localized translation initiation factors. That is, as genuine sites for translation initiation, as repositories for factors and mRNA, and as sites of regulation.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

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