Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets

Sonenberg, Nahum; Hinnebusch, Alan G.

doi:10.1016/j.cell.2009.01.042

Cited by 2,826 publications

(3,267 citation statements)

References 130 publications

Supporting

Mentioning

3,160

Contrasting

Unclassified

Order By: Relevance

“…3). The 5′ UTR plays a critical role in protein translation efficiency as it represents the site of binding for the preinitiation complex initiation of protein translation [15,16]. For example, the eukaryotic initiation factor-4A (eIF4A) binding to the 5′ UTR is important in the unwinding initiation of protein translation [17] and the secondary structure of the 5′ UTR plays a critical role in binding of eIF1A to mRNA [18].…”

Section: Discussionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

View full text Add to dashboard Cite

ABSTRACTmRNA based therapies hold great promise for the treatment of genetic diseases. However, this therapeutic approach suffers from multiple challenges including the short half-life of exogenously administered mRNA and subsequent protein production. Modulation of untranslated regions (UTR) represents one approach to enhance both mRNA stability and translation efficiency. The current studies describe and validate screening methods using a diverse set of 5′UTR and 3′UTR combinations for improved expression of the Arginase 1 (ARG1) protein, a potential therapeutic mRNA target. Data revealed a number of critical aspects which need to be considered when developing a screening approach for engineering mRNA improvements. First, plasmid-based screening methods do not correlate with protein expression driven by exogenously expressed mRNA. Second, improved ARG1 protein production was driven by increased translation and not improved mRNA stability. Finally, the 5′ UTR appears to be the key driver in protein expression for exogenously delivered mRNA. From the testing of the combinatorial library, the 5′UTR for complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1) showed the largest and most consistent increase in protein expression relative to a reference UTR. Collectively, these data provide important information for the development and optimization of therapeutic mRNAs.

show abstract

Section: Discussionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Among the four consecutive stages of translation (initiation, elongation, termination and ribosome recycling), more attention was paid to initiation (Ref. 1). At this stage, the 43S preinitiation ribosome complex is recruited to the 5 ′ terminus of mRNA through translation initiation complex eIF4F (Ref.…”

Section: Introductionmentioning

confidence: 99%

Targeting translation: eIF4E as an emerging anticancer drug target

Makala

et al. 2016

Expert Rev. Mol. Med.

View full text Add to dashboard Cite

The translation initiation factor eIF4E mediates a rate-limiting process that drives selective translation of many oncongenic proteins such as cyclin D1, survivin and VEGF, thereby contributing to tumour growth, metastasis and therapy resistance. As an essential regulatory hub in cancer signalling network, many oncogenic signalling pathways appear to converge on eIF4E. Therefore, targeting eIF4E-mediated cap-dependent translation is considered a promising anticancer strategy. This paper reviews the strategies that can be used to target eIF4E, highlighting agents that target eIF4E activity at each distinct level.

show abstract

“…Although core functions of the ribosome are conserved in all kingdoms of life, eukaryotic ribosomes are at least 40% larger than their bacterial counterparts with a total mass ranging from ,3.3 MDa (yeasts and plants) up to ,4.5 MDa (mammals) [1][2][3] . The additional complexity of the eukaryotic ribosome structure is reflected in differences in terms of functions and aspects of translation and its regulation 4 .…”

mentioning

confidence: 99%