Controlling Gene Expression through RNA Regulons: The Role of the Eukaryotic Translation Initiation Factor eIF4E

Čuljković, Biljana; Topisirović, Ivan; Borden, Katherine L. B.

doi:10.4161/cc.6.1.3688

Cited by 137 publications

(165 citation statements)

References 37 publications

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“…PML is a key cellular regulator of the oncogenic activities of eIF4E and understanding how it regulates eIF4E at the atomic level is of great interest. PML's ability to inhibit eIF4E function is closely tied to its ability to impair cap binding and thus the mRNA export activity of eIF4E (1,2,17,18). Additionally in vitro, PML (a small percentage being cytoplasmic) and Z impair eIF4E-dependent translation through their RING domains (16).…”

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confidence: 99%

“…eIF4E expression levels are highly elevated in several human cancers, including breast, prostate, and some leukemias, and elevated levels of eIF4E are a marker of poor prognosis in patients (5,6). Notably, both the mRNA export and translation functions of eIF4E are dysregulated in cancer (2). Targeting eIF4E-m 7 G cap-binding activity in a phase II trial in leukemia patients led to clinical benefit (7), which further underscores the importance of understanding the regulation of this eIF4E activity at the molecular level.…”

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confidence: 99%

“…eIF4E coordinately and combinatorially modulates the expression of genes involved in proliferation and survival (1,2). eIF4E acts at two levels of gene expression: cap dependent translation and mRNA export (3,4).…”

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Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E

Volpon

Osborne

Capul

et al. 2010

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

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The eukaryotic translation initiation factor eIF4E, a potent oncogene, is highly regulated. One class of eIF4E regulators, including eIF4G and the 4E-binding proteins (4E-BPs), interact with eIF4E using a conserved YXXXXLΦ-binding site. The structural basis of this interaction and its regulation are well established. Really Interesting New Gene (RING) domain containing proteins, such as the promyelocytic leukemia protein PML and the arenaviral protein Z, represent a second class of eIF4E regulators that inhibit eIF4E function by decreasing eIF4E's affinity for its m 7 G cap ligand. To elucidate the structural basis of this inhibition, we determined the structure of Z and studied the Z-eIF4E complex using NMR methods. We show that Z interacts with eIF4E via a novel binding site, which has no homology with that of eIF4G or the 4E-BPs, and is different from the RING recognition site used in the ubiquitin system. Z and eIF4G interact with distinct parts of eIF4E and differentially alter the conformation of the m 7 G cap-binding site. Our results provide a molecular basis for how PML and Z RINGs reduce the affinity of eIF4E for the m 7 G cap and thereby act as key inhibitors of eIF4E function. Furthermore, our findings provide unique insights into RING protein interactions.Lassa Fever Virus-Z | NMR | promyelocytic leukemia protein

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Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E

Volpon

Osborne

Capul

et al. 2010

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

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“…For instance through its cap-binding activity and subsequent effects on gene expression, eIF4E plays an important role in proliferation and survival (1,3). Indeed, eIF4E is overexpressed in about 30% of human cancers and its overexpression is oncogenic in cell culture and animal models (2,11).…”

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confidence: 99%

“…M etabolism of mRNA is a complex and highly regulated process dependent on the association of the methyl-7-guanosine (m 7 G) cap structure on the 5′ end of transcripts with appropriate proteins (1)(2)(3). In mammalian cells, the two major cap-binding proteins are the nuclear cap-binding complex (CBC) (4) and eukaryotic translation initiation factor 4E (eIF4E) (3).…”

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eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

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

103

143

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Recognition of the methyl-7-guanosine (m 7 G) cap structure on mRNA is an essential feature of mRNA metabolism and thus gene expression. Eukaryotic translation initiation factor 4E (eIF4E) promotes translation, mRNA export, proliferation, and oncogenic transformation dependent on this cap-binding activity. eIF4E-cap recognition is mediated via complementary charge interactions of the positively charged m 7 G cap between the negative π-electron clouds from two aromatic residues. Here, we demonstrate that a variant subfamily, eIF4E3, specifically binds the m 7 G cap in the absence of an aromatic sandwich, using instead a different spatial arrangement of residues to provide the necessary electrostatic and van der Waals contacts. Contacts are much more extensive between eIF4E3-cap than other family members. Structural analyses of other cap-binding proteins indicate this recognition mode is atypical. We demonstrate that eIF4E3 relies on this cap-binding activity to act as a tumor suppressor, competing with the growthpromoting functions of eIF4E. In fact, reduced eIF4E3 in high eIF4E cancers suggests that eIF4E3 underlies a clinically relevant inhibitory mechanism that is lost in some malignancies. Taken together, there is more structural plasticity in cap recognition than previously thought, and this is physiologically relevant.M etabolism of mRNA is a complex and highly regulated process dependent on the association of the methyl-7-guanosine (m 7 G) cap structure on the 5′ end of transcripts with appropriate proteins (1-3). In mammalian cells, the two major cap-binding proteins are the nuclear cap-binding complex (CBC) (4) and eukaryotic translation initiation factor 4E (eIF4E) (3). Specific cap recognition is key for the fate of transcripts and impacts processes such as mRNA processing and bulk mRNA export via the CBC or the nuclear export of specific transcripts as well as bulk translation by eIF4E (5). NMR and crystallographic studies reveal that m 7 G cap is specifically recognized by both the CBC and eIF4E via intercalation of the m 7 G cap moiety with the side chains of two aromatic residues, i.e., an aromatic sandwich (4, 6-9). This is an electrostatically driven process relying on the partial positive charge of the m 7 G cap and the negative π-electron clouds of the aromatic residues. The aromatic residues are completely conserved in these cap-binding proteins. This recognition motif is used almost exclusively by proteins that specifically bind the m 7 G cap including eIF4E, CBC, and vaccinia virus protein VP39 (4, 10).Dysregulation of cap-binding proteins can have striking physiological consequences. For instance through its cap-binding activity and subsequent effects on gene expression, eIF4E plays an important role in proliferation and survival (1, 3). Indeed, eIF4E is overexpressed in about 30% of human cancers and its overexpression is oncogenic in cell culture and animal models (2, 11). Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transform...

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The eukaryotic translation initiation factor eIF4E unexpectedly acts in splicing thereby coupling mRNA processing with translation

Borden

2023

BioEssays

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Recent findings position the eukaryotic translation initiation factor eIF4E as a novel modulator of mRNA splicing, a process that impacts the form and function of resultant proteins. eIF4E physically interacts with the spliceosome and with some intron‐containing transcripts implying a direct role in some splicing events. Moreover, eIF4E drives the production of key components of the splicing machinery underpinning larger scale impacts on splicing. These drive eIF4E‐dependent reprogramming of the splicing signature. This work completes a series of studies demonstrating eIF4E acts in all the major mRNA maturation steps whereby eIF4E drives production of the RNA processing machinery and escorts some transcripts through various maturation steps. In this way, eIF4E couples the mRNA processing‐export‐translation axis linking nuclear mRNA processing to cytoplasmic translation. eIF4E elevation is linked to worse outcomes in acute myeloid leukemia patients where these activities are dysregulated. Understanding these effects provides new insight into post‐transcriptional control and eIF4E‐driven cancers.

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Controlling Gene Expression through RNA Regulons: The Role of the Eukaryotic Translation Initiation Factor eIF4E

Cited by 137 publications

References 37 publications

Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E

Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

The eukaryotic translation initiation factor eIF4E unexpectedly acts in splicing thereby coupling mRNA processing with translation

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