A New Paradigm for Translational Control: Inhibition via 5′-3′ mRNA Tethering by Bicoid and the eIF4E Cognate 4EHP

Cho, Park F.; Poulin, Francis; Cho-Park, Yoon Andrew; Cho-Park, Ian B.; Chicoine, Jarred; Lasko, Paul; Sonenberg, Nahum

doi:10.1016/j.cell.2005.02.024

Cited by 243 publications

(245 citation statements)

References 41 publications

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“…4), which resembles the cap-to-tail closed-loop mRNA conformation (37). A similar mechanism of translational inhibition had been described in Drosophila embryos wherein an interaction between 4EHP and Bicoid bridges the 5′ and 3′ ends of caudal mRNA (23). Thus, 4EHP-mediated mRNA looping appears as a general repressive mechanism implicated in various posttranscriptional regulatory pathways.…”

Section: Discussionmentioning

confidence: 90%

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Cap-binding protein 4EHP effects translation silencing by microRNAs

Chapat

Jafarnejad

Matta‐Camacho

et al. 2017

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

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111

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MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4-NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precise mechanism is unknown. Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4-NOT complex. Our results show that 4EHP competes with eIF4E for binding to 4E-T, and this interaction increases the affinity of 4EHP for the cap. We propose a model wherein the 4E-T/4EHP interaction engenders a closed-loop mRNA conformation that blocks translational initiation of miRNA targets.M icroRNAs (miRNAs) are short, ∼22-nucleotide noncoding RNAs that affect gene expression in most eukaryotes. miRNAs mediate posttranscriptional silencing by guiding the miRNA-induced silencing complex (miRISC), an assembly of Argonautes and GW182/TNRC6 proteins, to target mRNAs. Target recognition initiates a succession of events: mRNA translational repression, deadenylation, and mRNA decay (1). miRNAs impair the function of eIF4F, a three-subunit complex composed of eIF4E, the m 7 GTP (cap)-interacting factor; eIF4G, a scaffolding protein; and eIF4A, a DEAD-box RNA helicase (2-5). The silencing activity of miRISC is mediated by the CCR4-NOT deadenylase complex through the scaffolding subunit, CNOT1 (6-8). CNOT1 recruits the DDX6 and 4E-T (eIF4E transporter, also known as EIF4ENIF1) proteins, which are important for miRNA-mediated silencing (9-16). The 4E-T protein is a conserved eIF4E-binding protein, which directly binds to the dorsal surface of eIF4E through its canonical eIF4E-binding YX 4 LL (Y 30 TKEELL) motif and impairs the eIF4E/eIF4G interaction and translation initiation (17). The 4E-T protein also facilitates the decay of CCR4-NOT-targeted mRNAs by linking the 3′-terminal mRNA decay machinery to the cap via its interaction with eIF4E (13).In mammals, eIF4E is the best-studied member of a family of proteins composed of eIF4E (eIF4E1), 4EHP (4E-homologous protein; eIF4E2), and eIF4E3. The 4EHP and eIF4E proteins share 28% sequence identity (18,19). The 4EHP protein is ubiquitously expressed, and it is 5-10 times less abundant than eIF4E in a number of mammalian cell lines (18)(19)(20). Like eIF4E, 4EHP binds to 4E-T, but in sharp contrast to eIF4E, it does not associate with eIF4G (18, 21). The 4EHP protein has a 30-to 100-fold weaker affinity for the cap than eIF4E due to a twoamino acid substitution in its cap-binding pocket (22).The 4EHP protein has primarily been documented as a translation repressor. In the Drosophila embryo, 4EHP associates with the RNA binding protein Bicoid to repress caudal mRNA translation (23). Similarly, 4EHP also represses the hunchback mRNA by binding to the nanos repressive element complex, which consists of nanos...

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Section: Discussionmentioning

confidence: 90%

“…In the Drosophila embryo, 4EHP associates with the RNA binding protein Bicoid to repress caudal mRNA translation (23). Similarly, 4EHP also represses the hunchback mRNA by binding to the nanos repressive element complex, which consists of nanos, pumilio, and brain tumor proteins (24).…”

mentioning

confidence: 99%

Cap-binding protein 4EHP effects translation silencing by microRNAs

Chapat

Jafarnejad

Matta‐Camacho

et al. 2017

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

Self Cite

111

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“…Perhaps Pum2 inhibits ePAB activity, which, as Collier et al (2005) point out, could impact eIF4G, eIF4B, or poly(A)-interacting protein (PAIP), which binds the helicase eIF4A. On the other hand, Pum2 might block the interaction of eIF4E with eIF4G like Maskin (Stebbins-Boaz et al 1999;Cao and Richter 2002), or of eIF4E with the cap like 4EHP (Cho et al 2005), among other possibilities. Irrespective of the mechanism of Pum2-mediated repression, its dissociation from RINGO/Spy RNA, and from ePAB and DAZL, during maturation is almost certainly necessary for translation.…”

Section: Discussionmentioning

confidence: 99%

Regulated Pumilio-2 binding controls RINGO/Spy mRNA translation and CPEB activation

Padmanabhan¹,

Richter²

2006

Genes Dev.

127

174

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CPEB is a sequence-specific RNA-binding protein that controls the polyadenylation-induced translation of mos and cyclin B1 mRNAs in maturing Xenopus oocytes. CPEB activity requires not only the phosphorylation of S174, but also the synthesis of a heretofore-unknown upstream effector molecule. We show that the synthesis of RINGO/Spy, an atypical activator of cyclin-dependent kinases (cdks), is necessary for CPEB-directed polyadenylation. Deletion analysis and mRNA reporter assays show that a cis element in the RINGO/Spy 3 UTR is necessary for translational repression in immature (G2-arrested) oocytes. The repression is mediated by 3 UTR Pumilio-Binding Elements (PBEs), and by its binding protein Pumilio 2 (Pum2). Pum2 also interacts with the Xenopus homolog of human Deleted for Azoospermia-like (DAZL) and the embryonic poly(A)-binding protein (ePAB). Following the induction of maturation, Pum2 dissociates not only from RINGO/Spy mRNA, but from XDAZL and ePAB as well; as a consequence, RINGO/Spy mRNA is translated. These results demonstrate that a reversible Pum2 interaction controls RINGO/Spy mRNA translation and, as a result, CPEB-mediated cytoplasmic polyadenylation.

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“…In contrast, most homeobox proteins and other transcription factors are localized in the nucleus, where they bind DNA and modulate transcription. Only in exceptional cases are transcription factors retained in the cytoplasm or exported from the nucleus to the cytoplasm, where they are either sequestered from regulating transcription or confer different activities in the cytoplasm, such as modulating translation (40)(41)(42). RHOXF1 and RHOXF2 differ in their subcellular localization.…”

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confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility.

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A New Paradigm for Translational Control: Inhibition via 5′-3′ mRNA Tethering by Bicoid and the eIF4E Cognate 4EHP

Cited by 243 publications

References 41 publications

Cap-binding protein 4EHP effects translation silencing by microRNAs

Cap-binding protein 4EHP effects translation silencing by microRNAs

Regulated Pumilio-2 binding controls RINGO/Spy mRNA translation and CPEB activation

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

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