Targeting the eIF4F Translation Initiation Complex: A Critical Nexus for Cancer Development

Pelletier, Jerry; Graff, Jeremy R.; Ruggero, Davide; Sonenberg, Nahum

doi:10.1158/0008-5472.can-14-2789

Cited by 306 publications

(546 citation statements)

References 213 publications

(263 reference statements)

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“…To obtain a fuller appreciation of where eIF4F fits into the grand scheme of things, the reader may find one or more of the closing references to reviews useful (72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85) …”

Section: Other Complicationsmentioning

confidence: 99%

eIF4F: A Retrospective

Merrick

2015

Journal of Biological Chemistry

148

156

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The original purification of the heterotrimeric eIF4F was published over 30 years ago (Grifo, J. A., Tahara, S. M., Morgan, M. A., Shatkin, A. J., and Merrick, W. C. (1983) J. Biol. Chem. 258, 5804 -5810). Since that time, numerous studies have been performed with the three proteins specifically required for the translation initiation of natural mRNAs, eIF4A, eIF4B, and eIF4F. These have involved enzymatic and structural studies of the proteins and a number of site-directed mutagenesis studies. The regulation of translation exhibited through the mammalian target of rapamycin (mTOR) pathway is predominately seen as the phosphorylation of 4E-BP, an inhibitor of protein synthesis that functions by binding to the cap binding subunit of eIF4F (eIF4E). A hypothesis that requires the disassembly of eIF4F during translation initiation to yield free subunits (eIF4A, eIF4E, and eIF4G) is presented. The Biology of eIF4FThe initial findings in the study of natural mRNA translation reflected the newly discovered m 7 G cap at the 5Ј end of eukaryotic mRNAs (2). mRNAs lacking this structure were translated with less efficiency than mRNAs that contained this structure (3). This unique structure allowed for specific assays or purifications, many established in the laboratory of Dr. Aaron Shatkin with assists from his colleagues. Two of note were the use of m 7 G-Sepharose for affinity purification (4, 5) and the crosslinking of periodate-oxidized mRNAs to proteins (6).The initial application of these methodologies identified two different molecular weight species (about 25,000 and at least 200,000), although the high molecular weight protein contained the small molecular weight component, now known as eIF4E (7). Given the size of several other known translation factors, the question was whether these contained the small molecular weight subunit (notably eIF3 and eIF4B) (8 -11). Ultimate purification of eIF4F indicated that neither of these were correct but that eIF4F would form stable complexes with either, thus being consistent with the eIF4E component tracking with them. At the same time, it was recognized that the 46,000 molecular weight subunit of eIF4F was eIF4A. By physical analysis, eIF4F was a heterotrimeric complex of eIF4A, eIF4E, and eIF4G (1).The next studies were to attempt to identify the functions of the various proteins required specifically for natural mRNA translation (eIF4A, eIF4B, and eIF4F). The characteristics of these three proteins were very different. In the absence of ATP, binding to RNA could only be well demonstrated with eIF4F (Table 1). eIF4A and eIF4F could hydrolyze ATP in the presence of single-stranded RNA, and eIF4B would enhance both of these activities (12). In terms of mechanism, the coupling of the binding of ATP and RNA was realized in recognizing that eIF4A or eIF4F had the ability to unwind duplex RNA. As noted in Table 1, the "strength" of the helicase activity was greater with eIF4F (14).As the ability to determine amino acid sequence from RNA sequence advanced, it was found that there...

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Section: Other Complicationsmentioning

confidence: 99%

eIF4F: A Retrospective

Merrick

2015

Journal of Biological Chemistry

148

156

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“…Control of translation is exerted mainly by two key protein complexes: eIF4F (eIF4E-eIF4G-eIF4A) and the ternary complex (eIF2-GTP-Met-tRNA Met i ) (7). The mammalian target of rapamycin complex 1 (mTORC1) controls the assembly of eIF4F through the phosphorylation of eIF4E-binding proteins (4E-BPs) (8,9). The 4E-BPs consist of a family of small molecular weight (15-20 kDa) translational inhibitors (4E-BP1, -2, and -3 in mammals), that, when dephosphorylated, avidly bind eIF4E and block its association with eIF4G to form the eIF4F complex.…”

mentioning

confidence: 99%

“…4E-BPs inhibit cap-dependent translation in embryonic and somatic stem cells (3,4,13,14). Although eIF4E promotes cap-dependent translation of all cellular mRNAs, the translation of a subset of mRNAs, which generally contain a long and highly structured 5′-UTR, is strongly dependent on eIF4E (9,15). These mRNAs are known as "eIF4E-sensitive" and Significance Embryonic stem cells (ESCs) maintain a low translation rate; therefore control of mRNA translation is critical for preserving their stemness.…”

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confidence: 99%

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Tahmasebi

Jafarnejad

Tam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tractbinding protein 1 (PTBP1) promotes the retention of an intron in the 5′-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.mRNA translation | 4E-BPs | PTBP | embryonic stem cell | YY2

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“…[44][45][46][47] mTOR complex 1 (mTORC1) kinase activity phosphorylates eIF4E-binding proteins (eIF4EBPs or 4EBPs). 44,48 Phosphorylated 4EBP dissociates from eIF4E, allowing eIF4E-eIF4G interaction and eIF4F complex formation.…”

Section: Canonical Translation Mechanismmentioning

confidence: 99%

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

Bukhari

Vasudevan

2017

RNA Biology

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Eukaryotic protein synthesis is a multifaceted process that requires coordination of a set of translation factors in a particular cellular state. During normal growth and proliferation, cells generally make their proteome via conventional translation that utilizes canonical translation factors. When faced with environmental stress such as growth factor deprivation, or in response to biological cues such as developmental signals, cells can reduce canonical translation. In this situation, cells adapt alternative modes of translation to make specific proteins necessary for required biological functions under these distinct conditions. To date, a number of alternative translation mechanisms have been reported, which include non-canonical, cap dependent translation and cap independent translation such as IRES mediated translation. Here, we discuss one of the alternative modes of translation mediated by a specialized microRNA complex, FXR1a-microRNP that promotes non-canonical, cap dependent translation in quiescent conditions, where canonical translation is reduced due to low mTOR activity.

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Targeting the eIF4F Translation Initiation Complex: A Critical Nexus for Cancer Development

Cited by 306 publications

References 213 publications

eIF4F: A Retrospective

eIF4F: A Retrospective

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

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