Regulation of cap-dependent translation by eIF4E inhibitory proteins

Richter, Joel D.; Sonenberg, Nahum

doi:10.1038/nature03205

Cited by 877 publications

(852 citation statements)

References 39 publications

(37 reference statements)

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“…It should be noted that this eIF4E-binding motif contains a non-consensus charged arginine residue in the last position instead of a hydrophobic one (Figure 5b), which could result in relatively weak binding. This finding may reflect the requirement for an additional specific interaction of DDX3 with mRNA to support the effective DDX3-eIF4E interaction as is the case with several eIF4E-binding proteins (Richter and Sonenberg, 2005). Alternatively, but not exclusively, the weak interaction between eIF4E and the C-terminus of DDX3 characterized here (Figure 5a) may contribute to enhancing this interaction.…”

Section: Ddx3 Interacts With Eif4e and Regulates Translation J-w Shihmentioning

confidence: 66%

“…It has been reported that several eIF4E-binding proteins recognize eIF4E via a consensus YxxxxLF motif (reviewed by Sachs and Varani, 2000;von der Haar et al, 2004;Richter and Sonenberg, 2005). Careful inspection of the eIF4E-binding region within DDX3 identifies a potential eIF4E-binding motif (YIPPHLR) at amino-acid residues 38-44 (Figures 5b and c).…”

Section: Ddx3 Interacts With Eif4e and Regulates Translation J-w Shihmentioning

confidence: 94%

“…The eIF4E inhibitory proteins harboring the eIF4E-binding consensus are mutually exclusive for binding to eIF4E and block translation initiation by competing with eIF4G for eIF4E binding (reviewed in von der Haar et al, 2004;Richter and Sonenberg, 2005). In view of this, we further investigated whether DDX3 disrupts the eIF4E-eIF4G complex by a competition assay.…”

Section: Ddx3 Blocks Eif4e-eif4g Complex Formationmentioning

confidence: 99%

“…eIF4E plays a central role in gene expression control and thereby affects development, cell-cycle progression, metabolism and tumorigenesis (Richter and Sonenberg, 2005). It has been reported that a group of cellular factors, the eIF4E inhibitory proteins, including the 4E-BPs, eIF4E transporter (4E-T), Cup, Maskin and Bicoid, are able to control translation initiation by modulating the eIF4E-eIF4G interaction through the eIF4E-binding motif (for recent reviews, see von der Haar et al, 2004;Richter and Sonenberg, 2005).…”

Section: Ddx3 Interacts With Eif4e and Regulates Translation J-w Shihmentioning

confidence: 99%

“…The interaction between these two motifs is required for translation initiation and therefore its disruption or reinforcement is an important target for translational control. Interestingly, a group of cellular factors generally known as eIF4E inhibitory proteins, including the original three eIF4E-binding proteins (4EBP1, 4EBP2 and 4EBP3) as well as Maskin, Bicoid and Cup, utilize this conserved region to modulate capdependent translation by the prevention of eIF4F complex formation through sequestering the available eIF4E (for current reviews, see Gebauer and Hentze, 2004;von der Haar et al, 2004;Richter and Sonenberg, 2005). These eIF4E inhibitory proteins play fundamental roles in cell cycle progression, metabolism, development, tumor formation and responses to various stimuli (Gebauer and Hentze, 2004;von der Haar et al, 2004;Richter and Sonenberg, 2005).…”

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confidence: 99%

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Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Shih¹,

Tsai²,

Chao³

et al. 2007

Oncogene

163

199

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DDX3 is a human RNA helicase with plethoric functions. Our previous studies have indicated that DDX3 is a transcriptional regulator and functions as a tumor suppressor. In this study, we use a bicistronic reporter to demonstrate that DDX3 specifically represses cap-dependent translation but enhances hepatitis C virus internal ribosome entry site-mediated translation in vivo in a helicase activity-independent manner. To elucidate how DDX3 modulates translation, we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. Point mutations within the consensus eIF4E-binding motif in DDX3 impair its ability to bind eIF4E and result in a loss of DDX3's regulatory effects on translation. All these features together indicate that DDX3 is a new member of the eIF4E inhibitory proteins involved in translation initiation regulation. Most importantly, this DDX3-mediated translation regulation also confers the tumor suppressor function on DDX3. Altogether, this study demonstrates regulatory roles and action mechanisms for DDX3 in translation, cell growth and likely viral replication.

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Section: Ddx3 Interacts With Eif4e and Regulates Translation J-w Shihmentioning

confidence: 66%

Section: Ddx3 Interacts With Eif4e and Regulates Translation J-w Shihmentioning

confidence: 94%

Section: Ddx3 Blocks Eif4e-eif4g Complex Formationmentioning

confidence: 99%

Section: Ddx3 Interacts With Eif4e and Regulates Translation J-w Shihmentioning

confidence: 99%

mentioning

confidence: 99%

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Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Shih¹,

Tsai²,

Chao³

et al. 2007

Oncogene

163

199

View full text Add to dashboard Cite

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mTOR referees memory and disease through mRNA repression and competition

Raab‐Graham

Niere

2017

FEBS Letters

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Mammalian target of rapamycin (mTOR) activity is required for memory and is dysregulated in disease. Activation of mTOR promotes protein synthesis; however, new studies are demonstrating that mTOR activity also represses the translation of mRNAs. Almost three decades ago, Kandel and colleagues hypothesised that memory was due to the induction of positive regulators and removal of negative constraints. Are these negative constraints repressed mRNAs that code for proteins that block memory formation? Herein, we will discuss the mRNAs coded by putative memory suppressors, how activation/inactivation of mTOR repress protein expression at the synapse, how mTOR activity regulates RNA binding proteins, mRNA stability, and translation, and what the possible implications of mRNA repression are to memory and neurodegenerative disorders.

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Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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Phosphorylation of translational repressor eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) controls the initiation of capdependent translation, a type of protein synthesis that is frequently upregulated in human diseases such as cancer. Because of its critical cellular function, it is not surprising that multiple kinases can post-translationally modify 4E-BP1 to drive aberrant cap-dependent translation. We recently reported a site-selective chemoproteomic method for uncovering kinase-substrate interactions, and using this approach, we discovered the cyclin-dependent kinase (CDK)4 as a new 4E-BP1 kinase. Herein, we describe our extension of this work and reveal the role of CDK4 in modulating 4E-BP1 activity in the transition from mitosis to G1, thereby demonstrating a novel role for this kinase in cell cycle regulation.Cap-dependent translation is an important cellular process that controls the translation of select mRNAs typically encoding for growth factors and oncogenes [1][2][3][4]. The initiation of cap-dependent mRNA translation is governed by the availability of eIF4E, the m 7 GpppX-cap-binding translation initiation factor [5,6]. This protein is highly regulated, primarily through the work of the 4E-BPs, which sequester eIF4E from eIF4G and the eIF4F translation initiation complex [7][8][9][10][11][12][13]. The activity of 4E-binding protein 1 (4E-BP1) is in turn regulated by phosphorylation, where hypophosphorylated 4E-BP1 binds strongly to eIF4E to inhibit translation, while hyperphosphorylated 4E-BP1 releases eIF4E to initiate capdependent translation [13][14][15][16]. For many years, the only validated kinase known to affect 4E-BP1 phosphorylation has been mechanistic target of rapamycin complex 1 (mTORC1), which was shown to hierarchically phosphorylate 4E-BP1 at T37 and T46 followed by T70 and S65 [14,15,17,18]. However, several findings have called into question the exclusivity of mTORC1 for each of these phosphorylation sites [19], namely reports demonstrating that other unknown kinases can also phosphorylate 4E-BP1 to stimulate cap-dependent translation [20][21][22], particularly in cases of mTOR inhibitor drug resistance [23][24][25][26].Recently, our laboratory has developed a chemoproteomic pipeline by which to identify site-specific kinase-substrate interactions, Phosphosite-Accurate kinase-substrate cross(X)linking Assay or PhAXA [27]. Using this methodology, we discovered that cyclin-dependent kinase 4 (CDK4), which is primarily responsible for controlling the cell cycle checkpoint at the G 1 /S transition through phosphorylation of the retinoblastoma tumor suppressor protein (Rb) Abbreviations 4E-BP1, 4E-binding protein 1; CDK, cyclin-dependent kinase; FDR, false discovery rate; mTORC1, mechanistic target of rapamycin complex 1; PSMs, peptide-spectrum matches; WT, wild-type.

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Regulation of cap-dependent translation by eIF4E inhibitory proteins

Cited by 877 publications

References 39 publications

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

mTOR referees memory and disease through mRNA repression and competition

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

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