scholarly journals The regulation of protein translation and its implications for cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ping Song ◽  
Fan Yang ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Mrna Translation ◽  
Protein Translation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Precision Therapy ◽  
Novel Approaches

AbstractIn addition to the deregulation of gene transcriptions and post-translational protein modifications, the aberrant translation from mRNAs to proteins plays an important role in the pathogenesis of various cancers. Targeting mRNA translation are expected to become potential approaches for anticancer treatments. Protein translation is affected by many factors including translation initiation factors and RNA-binding proteins. Recently, modifications of mRNAs mainly N6-methyladenine (m6A) modification and noncoding RNAs, such as microRNAs and long noncoding RNAs are involved. In this review, we generally summarized the recent advances on the regulation of protein translation by the interplay between mRNA modifications and ncRNAs. By doing so, we hope this review could offer some hints for the development of novel approaches in precision therapy of human cancers.

scholarly journals Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity

2021 ◽  
Vol 118 (6) ◽  
pp. e2021719118 ◽  
Author(s):  
Aravinth Kumar Jayabalan ◽  
Srivathsan Adivarahan ◽  
Aakash Koppula ◽  
Rachy Abraham ◽  
Mona Batish ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Early Stage ◽  
Nonstructural Protein ◽  
Granule Formation ◽  
Adp Ribosylation ◽  
Initiation Factors ◽  
Translation Initiation Factors

While biomolecular condensates have emerged as an important biological phenomenon, mechanisms regulating their composition and the ways that viruses hijack these mechanisms remain unclear. The mosquito-borne alphaviruses cause a range of diseases from rashes and arthritis to encephalitis, and no licensed drugs are available for treatment or vaccines for prevention. The alphavirus virulence factor nonstructural protein 3 (nsP3) suppresses the formation of stress granules (SGs)—a class of cytoplasmic condensates enriched with translation initiation factors and formed during the early stage of infection. nsP3 has a conserved N-terminal macrodomain that hydrolyzes ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds the essential SG component G3BP1. Here, we show that macrodomain hydrolase activity reduces the ADP-ribosylation of G3BP1, disassembles virus-induced SGs, and suppresses SG formation. Expression of nsP3 results in the formation of a distinct class of condensates that lack translation initiation factors but contain G3BP1 and other SG-associated RNA-binding proteins. Expression of ADP-ribosylhydrolase–deficient nsP3 results in condensates that retain translation initiation factors as well as RNA-binding proteins, similar to SGs. Therefore, our data reveal that ADP-ribosylation controls the composition of biomolecular condensates, specifically the localization of translation initiation factors, during alphavirus infection.

scholarly journals Long noncoding RNAs as tumorigenic factors and therapeutic targets for renal cell carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haiyan Shen ◽  
Guomin Luo ◽  
Qingjuan Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Protein Translation ◽  
Long Noncoding Rnas ◽  
In Vivo Studies

AbstractApproximately 338,000 patients are diagnosed with kidney cancer worldwide each year, and renal cell carcinoma (RCC), which is derived from renal epithelium, accounts for more than ninety percent of the malignancy. Next generation RNA sequencing has enabled the identification of novel long noncoding RNAs (lncRNAs) in the past 10 years. Recent studies have provided extensive evidence that lncRNAs bind to chromatin modification proteins, transcription factors, RNA-binding proteins and microRNAs, and thereby modulate gene expression through regulating chromatin status, gene transcription, pre-mRNA splicing, mRNA decay and stability, protein translation and stability. In vitro and in vivo studies have demonstrated that over-expression of oncogenic lncRNAs and silencing of tumor suppressive lncRNAs are a common feature of human RCC, and that aberrant lncRNA expression is a marker for poor patient prognosis, and is essential for the initiation and progression of RCC. Because lncRNAs, compared with mRNAs, are expressed in a tissue-specific manner, aberrantly expressed lncRNAs can be better targeted for the treatment of RCC through screening small molecule compounds which block the interaction between lncRNAs and their binding proteins or microRNAs.

Control of protein translation by phosphorylation of the mRNA 5′-cap-binding complex

2007 ◽  
Vol 35 (6) ◽  
pp. 1634-1637 ◽  
Author(s):  
O.A. Pierrat ◽  
V. Mikitova ◽  
M.S. Bush ◽  
K.S. Browning ◽  
J.H. Doonan
Keyword(s):  
Environmental Changes ◽  
Mrna Translation ◽  
Cost Effective ◽  
Protein Translation ◽  
Mrna Levels ◽  
Control Of Gene Expression ◽  
Initiation Factors ◽  
Protein Levels ◽  
Translation Initiation Factors ◽  
Cap Binding Complex

Initiation of mRNA translation is a key regulatory step in the control of gene expression. Microarray analysis indicates that total mRNA levels do not always reflect protein levels, since mRNA association with polyribosomes is necessary for protein synthesis. Phosphorylation of translation initiation factors offers a cost-effective and rapid way to adapt to physiological and environmental changes, and there is increasing evidence that many of these factors are subject to multiple regulatory phosphorylation events. The present article focuses on the nature of reversible phosphorylation and the function of the 5′-cap-binding complex in plants.

scholarly journals Translation initiation mediated by RNA looping

2015 ◽  
Vol 112 (4) ◽  
pp. 1041-1046 ◽  
Author(s):  
Ki Young Paek ◽  
Ka Young Hong ◽  
Incheol Ryu ◽  
Sung Mi Park ◽  
Sun Ju Keum ◽  
...  
Keyword(s):  
Reporter Gene ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Encephalomyocarditis Virus ◽  
Initiation Codon ◽  
Translation Efficiency ◽  
Upstream Gene ◽  
Translational Initiation ◽  
Initiation Factors ◽  
Translation Initiation Factors

Eukaryotic translation initiation commences at the initiation codon near the 5′ end of mRNA by a 40S ribosomal subunit, and the recruitment of a 40S ribosome to an mRNA is facilitated by translation initiation factors interacting with the m7G cap and/or poly(A) tail. The 40S ribosome recruited to an mRNA is then transferred to the AUG initiation codon with the help of translation initiation factors. To understand the mechanism by which the ribosome finds an initiation codon, we investigated the role of eIF4G in finding the translational initiation codon. An artificial polypeptide eIF4G fused with MS2 was localized downstream of the reporter gene through MS2-binding sites inserted in the 3′ UTR of the mRNA. Translation of the reporter was greatly enhanced by the eIF4G-MS2 fusion protein regardless of the presence of a cap structure. Moreover, eIF4G-MS2 tethered at the 3′ UTR enhanced translation of the second cistron of a dicistronic mRNA. The encephalomyocarditis virus internal ribosome entry site, a natural translational-enhancing element facilitating translation through an interaction with eIF4G, positioned downstream of a reporter gene, also enhanced translation of the upstream gene in a cap-independent manner. Finally, we mathematically modeled the effect of distance between the cap structure and initiation codon on the translation efficiency of mRNAs. The most plausible explanation for translational enhancement by the translational-enhancing sites is recognition of the initiation codon by the ribosome bound to the ribosome-recruiting sites through “RNA looping.” The RNA looping hypothesis provides a logical explanation for augmentation of translation by enhancing elements located upstream and/or downstream of a protein-coding region.

scholarly journals Uncoupling Stress Granule Assembly and Translation Initiation Inhibition

2009 ◽  
Vol 20 (11) ◽  
pp. 2673-2683 ◽  
Author(s):  
Sophie Mokas ◽  
John R. Mills ◽  
Cristina Garreau ◽  
Marie-Josée Fournier ◽  
Francis Robert ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Binding Protein ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Ribosomal Subunits ◽  
Initiation Factors ◽  
Eif2α Phosphorylation ◽  
Translation Initiation Factors ◽  
Dependent Pathway ◽  
Regulatory Sites

Cytoplasmic stress granules (SGs) are specialized regulatory sites of mRNA translation that form under different stress conditions known to inhibit translation initiation. The formation of SG occurs via two pathways; the eukaryotic initiation factor (eIF) 2α phosphorylation-dependent pathway mediated by stress and the eIF2α phosphorylation-independent pathway mediated by inactivation of the translation initiation factors eIF4A and eIF4G. In this study, we investigated the effects of targeting different translation initiation factors and steps in SG formation in HeLa cells. By depleting eIF2α, we demonstrate that reduced levels of the eIF2.GTP.Met-tRNAiMet ternary translation initiation complexes is sufficient to induce SGs. Likewise, reduced levels of eIF4B, eIF4H, or polyA-binding protein, also trigger SG formation. In contrast, depletion of the cap-binding protein eIF4E or preventing its assembly into eIF4F results in modest SG formation. Intriguingly, interfering with the last step of translation initiation by blocking the recruitment of 60S ribosome either with 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamideis or through depletion of the large ribosomal subunits protein L28 does not induce SG assembly. Our study identifies translation initiation steps and factors involved in SG formation as well as those that can be targeted without induction of SGs.

scholarly journals Translational specialization in pluripotency by RBPMS poises future lineage-decisions

2021 ◽  
Author(s):  
Deniz Bartsch ◽  
Kaustubh Kalamkar ◽  
Gaurav Ahuja ◽  
Hisham Bazzi ◽  
Argyris Papantonis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Translation Initiation ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Lineage Commitment ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Selective Translation

SUMMARYIn mammals, translation is uniquely regulated at the exit of pluripotency to rapidly reprogram the proteome to enable lineage commitment. Yet, the developmental mediators of translational control and their mode-of-action remain elusive. Using human embryonic stem cells, we identified RBPMS as a vital translation specialization factor that allows selective translation of developmental regulators. RBPMS-driven translational control balances the abundance of cell-fate regulators to enable accurate lineage decisions upon receiving differentiation cues. RBPMS loss, without affecting pluripotency, specifically and severely impedes mesoderm specification and subsequent cardiogenesis. Mechanistically, the direct binding of RBPMS to 3’UTR allows selective translation of transcripts encoding developmental regulators including integral components of central morphogen signaling networks specifying mesoderm. RBPMS-loss results in aberrant retention of key translation initiation factors on ribosomal complexes. Our data unveil how emerging lineage choices from pluripotency are controlled by translational specialization via ribosomal platforms acting as a regulatory nexus for developmental cell fate decisions.IN BRIEFFuture lineage choices from pluripotency are controlled by translational specialization. The RNA binding protein RBPMS is a vital translational specialization factor that unlocks the mesoderm commitment potential of pluripotent stem cells by enabling selective translation of cell-fate regulators instructing lineage decisions.HIGHLIGHTSLineage choices emerging from pluripotency are selectively controlled by translational specializationThe RNA-binding protein RBPMS is a translation specialization factor dedicated to mesoderm commitmentRBPMS-driven translational specialization enables accurate lineage commitment via balancing the availability of key morphogen signaling componentsRBPMS loss selectively impairs mesoderm commitment and subsequently impedes cardiogenesisRBPMS binds the 3’UTRs of target mRNAs to allow their selective translation; its depletion leads to aberrant retention of key translation initiation factors on ribosomal complexes

scholarly journals Positive mRNA Translational Control in Germ Cells by Initiation Factor Selectivity

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Andrew J. Friday ◽  
Brett D. Keiper
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Translation Initiation ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Positive Function ◽  
Initiation Factor ◽  
C Elegans ◽  
Initiation Factors

Ultimately, the production of new proteins in undetermined cells pushes them to new fates. Other proteins hold a stem cell in a mode of self-renewal. In germ cells, these decision-making proteins are produced largely from translational control of preexisting mRNAs. To date, all of the regulation has been attributed to RNA binding proteins (RBPs) that repress mRNAs in many models of germ cell development (Drosophila, mouse,C. elegans, andXenopus). In this review, we focus on the selective, positive function of translation initiation factors eIF4E and eIF4G, which recruit mRNAs to ribosomes upon derepression. Evidence now shows that the two events are not separate but rather are coordinated through composite complexes of repressors and germ cell isoforms of eIF4 factors. Strikingly, the initiation factor isoforms are themselves mRNA selective. The mRNP complexes of translation factors and RBPs are built on specific populations of mRNAs to prime them for subsequent translation initiation. Simple rearrangement of the partners causes a dormant mRNP to become synthetically active in germ cells when and where they are required to support gametogenesis.

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