scholarly journals Targeting translation: eIF4E as an emerging anticancer drug target

2016 ◽  
Vol 18 ◽  
Author(s):  
Chunwan Lu ◽  
Levi Makala ◽  
Daqing Wu ◽  
Yafei Cai
Keyword(s):  
Drug Target ◽  
Therapy Resistance ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Signalling Pathways ◽  
Signalling Network ◽  
Distinct Level ◽  
Selective Translation ◽  
Rate Limiting ◽  
Oncogenic Signalling

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.

scholarly journals Cap-Dependent Translation Initiation Factor eIF4E: An Emerging Anticancer Drug Target

2012 ◽  
Vol 32 (4) ◽  
pp. 786-814 ◽  
Author(s):  
Yan Jia ◽  
Vitaly Polunovsky ◽  
Peter B. Bitterman ◽  
Carston R. Wagner
Keyword(s):  
Anticancer Drug ◽  
Translation Initiation ◽  
Drug Target ◽  
Translation Initiation Factor ◽  
Initiation Factor

scholarly journals Molecular mechanisms relating to amino acid regulation of protein synthesis

2019 ◽  
Vol 32 (2) ◽  
pp. 183-191 ◽  
Author(s):  
Yangchun Cao ◽  
Shimin Liu ◽  
Kai Liu ◽  
Imtiaz Hussain Raja Abbasi ◽  
Chuanjiang Cai ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Translation Initiation ◽  
Molecular Mechanisms ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Signalling Pathways ◽  
Control Of Gene Expression ◽  
Ribosomal Protein S6 ◽  
New Findings

AbstractSome amino acids (AA) act through several signalling pathways and mechanisms to mediate the control of gene expression at the translation level, and the regulation occurs, specifically, on the initiation and the signalling pathways for translation. The translation of mRNA to protein synthesis proceeds through the steps of initiation and elongation, and AA act as important feed-forward activators that are involved in many pathways, such as the sensing and the transportation of AA by cells, in these steps in many tissues of mammals. For the translation, phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a critical molecule that controls the translation initiation and its functions can be regulated by some AA. Another control point in the mRNA binding step in the translation initiation is at the regulation by mammalian target of rapamycin, which requires a change of phosphorylation status of ribosomal protein S6. In fact, the change of phosphorylation status of ribosomal protein S6 might be involved in global protein synthesis. The present review summarises recent work on the molecular mechanisms of the regulation of protein synthesis by AA and highlights new findings.

scholarly journals Signalling to eIF4E in cancer

2015 ◽  
Vol 43 (5) ◽  
pp. 763-772 ◽  
Author(s):  
Nadeem Siddiqui ◽  
Nahum Sonenberg
Keyword(s):  
Protein Kinase ◽  
Translational Control ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Mammalian Target Of Rapamycin ◽  
Ribosomal Subunit ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Signalling Pathways

Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen-activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy.

scholarly journals Weakening the IF2-fMet-tRNA Interaction Suppresses the Lethal Phenotype Caused by GTPase Inactivation

2021 ◽  
Vol 22 (24) ◽  
pp. 13238
Author(s):  
Jerneja Tomsic ◽  
Enrico Caserta ◽  
Cynthia L. Pon ◽  
Claudio O. Gualerzi
Keyword(s):  
Conformational Changes ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Gtp Hydrolysis ◽  
Lethal Phenotype ◽  
Dominant Lethal ◽  
Thermally Driven ◽  
Rate Limiting ◽  
Late Stages

Substitution of the conserved Histidine 448 present in one of the three consensus elements characterizing the guanosine nucleotide binding domain (IF2 G2) of Escherichia coli translation initiation factor IF2 resulted in impaired ribosome-dependent GTPase activity which prevented IF2 dissociation from the ribosome, caused a severe protein synthesis inhibition, and yielded a dominant lethal phenotype. A reduced IF2 affinity for the ribosome was previously shown to suppress this lethality. Here, we demonstrate that also a reduced IF2 affinity for fMet-tRNA can suppress this dominant lethal phenotype and allows IF2 to support faithful translation in the complete absence of GTP hydrolysis. These results strengthen the premise that the conformational changes of ribosome, IF2, and fMet-tRNA occurring during the late stages of translation initiation are thermally driven and that the energy generated by IF2-dependent GTP hydrolysis is not required for successful translation initiation and that the dissociation of the interaction between IF2 C2 and the acceptor end of fMet-tRNA, which represents the last tie anchoring the factor to the ribosome before the formation of an elongation-competent 70S complex, is rate limiting for both the adjustment of fMet-tRNA in a productive P site and the IF2 release from the ribosome.

scholarly journals Eukaryotic Translation Initiation Factor 3 (eIF3) and eIF2 Can Promote mRNA Binding to 40S Subunits Independently of eIF4G in Yeast

2006 ◽  
Vol 26 (4) ◽  
pp. 1355-1372 ◽  
Author(s):  
Antonina V. Jivotovskaya ◽  
Leoš Valášek ◽  
Alan G. Hinnebusch ◽  
Klaus H. Nielsen
Keyword(s):  
Ternary Complex ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eukaryotic Translation Initiation ◽  
Mrna Binding ◽  
Rate Limiting

ABSTRACT Recruitment of the eukaryotic translation initiation factor 2 (eIF2)-GTP-Met-tRNAi Met ternary complex to the 40S ribosome is stimulated by multiple initiation factors in vitro, including eIF3, eIF1, eIF5, and eIF1A. Recruitment of mRNA is thought to require the functions of eIF4F and eIF3, with the latter serving as an adaptor between the ribosome and the 4G subunit of eIF4F. To define the factor requirements for these reactions in vivo, we examined the effects of depleting eIF2, eIF3, eIF5, or eIF4G in Saccharomyces cerevisiae cells on binding of the ternary complex, other initiation factors, and RPL41A mRNA to native 43S and 48S preinitiation complexes. Depleting eIF2, eIF3, or eIF5 reduced 40S binding of all constituents of the multifactor complex (MFC), comprised of these three factors and eIF1, supporting a mechanism of coupled 40S binding by MFC components. 40S-bound mRNA strongly accumulated in eIF5-depleted cells, even though MFC binding to 40S subunits was reduced by eIF5 depletion. Hence, stimulation of the GTPase activity of the ternary complex, a prerequisite for 60S subunit joining in vitro, is likely the rate-limiting function of eIF5 in vivo. Depleting eIF2 or eIF3 impaired mRNA binding to free 40S subunits, but depleting eIF4G led unexpectedly to accumulation of mRNA on 40S subunits. Thus, it appears that eIF3 and eIF2 are more critically required than eIF4G for stable binding of at least some mRNAs to native preinitiation complexes and that eIF4G has a rate-limiting function at a step downstream of 48S complex assembly in vivo.

Expression of Translation Initiation Factors eIF-4E and eIF-2α and a Potential Physiologic Role of Continuous Protein Synthesis in Human Platelets

2001 ◽  
Vol 85 (01) ◽  
pp. 142-151 ◽  
Author(s):  
Anping Han ◽  
Linrong Lu ◽  
German Pihan ◽  
Bruce Woda ◽  
Jane-Jane Chen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Human Platelets ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Synthesis Inhibitors ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Rate Limiting

SummaryIt is generally believed that platelets do not have a functionally significant protein synthetic machinery. However, our analysis demonstrated that normal bone marrow megakaryocytes express high levels of translation initiation factors eIF-4E and eIF-2α and the expression of these protein synthesis initiation factors is continued in platelets (as determined by immunohistochemistry and Western blot analysis). Both eIF-4E and eIF-2α are key regulators of protein synthesis. The eIF-4E is a rate-limiting part of a multisubunit complex, eIF-4F, that binds to the 5’ cap structure present in virtually all eukaryotic mRNAs, and carries out transfer of mRNAs to ribosomes for translation. Translation initiation factor eIF-2α is also a rate-limiting protein which associates with two other proteins to form an eIF-2 initiation factor complex responsible for the transfer of initiator methionyl-tRNA to the 40S ribosomal subunit. We confirm that expression of eIF-4E and eIF-2α is biologically relevant in that platelets continue protein synthesis, albeit at a 16 times lower rate than WBC (as determined by 35S-labeled amino acid incorporation, SDS-PAGE and scintillation counting). Finally, we determined that protein synthesis inhibitors (puromycin and emetine) attenuate the platelet aggregation response to a combination of ADP and epinephrine, but potentiate the response to collagen. Our data are consistent with the existence of different signal transducing pathways mediating the response to ADP/epinephrine and collagen. We suggest that the ADP/epinephrine response is positively affected by continuously synthesized proteins, while the response to collagen is modulated by continuously produced inhibitory proteins. Taken together, our results suggest that continuous protein synthesis is important for platelet function and its role in platelet physiology and pathophysiology deserves further study.

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