Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression

Hiraishi, Hiroyuki; Oatman, Jamie; Haller, Sherry L.; Blunk, Logan; McGivern, Benton; Morris, Jacob; Papadopoulos, Evangelos; Gutierrez, Wade R.; Gordon, Michelle; Bokhari, Wahaj; Ikeda, Yuka; Miles, D. Howard; Fellers, John P.; Asano, Masayo; Wagner, Gerhard; Tazi, Loubna; Rothenburg, Stefan; Brown, Susan J.; Asano, Katsura

doi:10.1093/nar/gku670

Cited by 27 publications

(41 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The affinity of eIF5 to other components of the 43S may also be regulated by post-translational modifications of its partners or the factor itself (see below). Finally, the presence of eIF5 in the 43S may be abolished by competitors like eIF5-mimic proteins BZW2/5MP1 and BZW1/5MP2 ( 57 , 58 ).…”

Section: Discussionmentioning

confidence: 99%

Sliding of a 43S ribosomal complex from the recognized AUG codon triggered by a delay in eIF2-bound GTP hydrolysis

et al. 2015

View full text Add to dashboard Cite

During eukaryotic translation initiation, 43S ribosomal complex scans mRNA leader unless an AUG codon in an appropriate context is found. Establishing the stable codon–anticodon base-pairing traps the ribosome on the initiator codon and triggers structural rearrangements, which lead to Pi release from the eIF2-bound GTP. It is generally accepted that AUG recognition by the scanning 43S complex sets the final point in the process of start codon selection, while latter stages do not contribute to this process. Here we use translation reconstitution approach and kinetic toe-printing assay to show that after the 48S complex is formed on an AUG codon, in case GTP hydrolysis is impaired, the ribosomal subunit is capable to resume scanning and slides downstream to the next AUG. In contrast to leaky scanning, this sliding is not limited to AUGs in poor nucleotide contexts and occurs after a relatively long pause at the recognized AUG. Thus, recognition of an AUG per se does not inevitably lead to this codon being selected for initiation of protein synthesis. Instead, it is eIF5-induced GTP hydrolysis and Pi release that irreversibly trap the 48S complex, and this complex is further stabilized by eIF5B and 60S joining.

show abstract

Section: Discussionmentioning

confidence: 99%

Sliding of a 43S ribosomal complex from the recognized AUG codon triggered by a delay in eIF2-bound GTP hydrolysis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Furthermore, in vitro, eIF2 demonstrated mutually exclusive interactions with eIF5 and 5MP1, suggesting 5MP1 as a competitive inhibitor of eIF5 [168]. 5MP promotes expression of GADD34 (a downstream target of ATF4) in Tribolium castaneum [169]. Further, 5MP binds eIF2 to inhibit general translation and when overexpressed, it promotes ATF4 expression in fibrosarcoma [166,169].…”

Section: Eif4fmentioning

confidence: 97%

“…5MP promotes expression of GADD34 (a downstream target of ATF4) in Tribolium castaneum [169]. Further, 5MP binds eIF2 to inhibit general translation and when overexpressed, it promotes ATF4 expression in fibrosarcoma [166,169]. ATF4 is expressed in hypoxic-and nutrientdeprived tumor regions, with functions in development, promoting metabolic homeostasis, and cancer cell proliferation [170].…”

Section: Eif4fmentioning

confidence: 99%

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Sharma

Bressler

Patel

et al. 2016

Journal of Nucleic Acids

View full text Add to dashboard Cite

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.

show abstract

“…5MP does not carry the GTPase activating function displayed by eIF5 ( 10 ), but possesses a W2-type CTD for eIF2 and eIF3 binding, similar to eIF5 ( 5 ). All eukaryotes except most protozoans, yeasts and nematodes contain 5MP ( 11 ). The two human copies, 5MP1 and 5MP2, are 70% identical to each other and expressed in cultured mammalian cells at a level stoichiometric to initiation factors (∼50–80% of eIF2 levels) ( 12 ).…”

mentioning

confidence: 99%

“…Although the interaction between 5MP and eIF2 and the competition between 5MP and eIF5 for eIF2 have been demonstrated in vitro ( 5 , 11 ), the interaction between 5MP and eIF2 has not been demonstrated or even compared to the interaction between eIF5 and eIF2 in human cells. Curiously, the current proteomics databases do not list any interaction between 5MP and eIF2 or between 5MP and any other translation initiation factor.…”

mentioning

confidence: 99%

Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and inducesATF4translation through delayed re-initiation

et al. 2016

Self Cite

View full text Add to dashboard Cite

ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila. The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions.

show abstract

Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression

Cited by 27 publications

References 38 publications

Sliding of a 43S ribosomal complex from the recognized AUG codon triggered by a delay in eIF2-bound GTP hydrolysis

Sliding of a 43S ribosomal complex from the recognized AUG codon triggered by a delay in eIF2-bound GTP hydrolysis

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and inducesATF4translation through delayed re-initiation

Contact Info

Product

Resources

About