Unique translation initiation of mRNAs-containing TISU element

Elfakess, Rofa; Sinvani, Hadar; Haimov, Ora; Svitkin, Yuri V.; Sonenberg, Nahum; Dikstein, Rivka

doi:10.1093/nar/gkr484

Cited by 94 publications

(123 citation statements)

References 31 publications

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“…Silvestrol inhibited cap‐dependent translation of Renilla luciferase, but the translation driven by the TISU sequence was only marginally inhibited (Fig 4A) as expected (Elfakess et al , 2011). In contrast, silvestrol stimulated HCV IRES‐driven translation of an F‐Luc reporter, which was included as a transfection control (Fig EV3H).…”

Section: Resultssupporting

confidence: 84%

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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AbstractmiRNAs associate with Argonaute (AGO) proteins to silence the expression of mRNA targets by inhibiting translation and promoting deadenylation, decapping, and mRNA degradation. A current model for silencing suggests that AGOs mediate these effects through the sequential recruitment of GW182 proteins, the CCR4–NOT deadenylase complex and the translational repressor and decapping activator DDX6. An alternative model posits that AGOs repress translation by interfering with eIF4A function during 43S ribosomal scanning and that this mechanism is independent of GW182 and the CCR4–NOT complex in Drosophila melanogaster. Here, we show that miRNAs, AGOs, GW182, the CCR4–NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning‐independent mechanisms in both human and Dm cells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not require eIF4A function during ribosomal scanning.

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Section: Resultssupporting

confidence: 84%

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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“…mRNAs with short 5 ′ UTRs, encoding proteins with mitochondrial function, were enriched (4.7-fold enrichment, P = 0.03) for translation initiator of short 5 ′ UTR (TISU) elements ( Fig. 3D,E; Elfakess et al 2011). Thus, in addition to TOP mRNAs, MTOR-sensitive mRNAs include non-TOP mRNAs with long 5 ′ UTRs, which encode proliferation-and survival-promoting proteins, and a subset of mRNAs with short (<30 nt) 5 ′ UTRs that were enriched with TISU elements (Fig.…”

Section: Low Sensitivity Limits the Catalog Of Mtor-sensitive Mrnas Imentioning

confidence: 99%

“…Expression of proteins encoded by a subset of MTOR-sensitive mRNAs harboring short 5 ′ UTRs requires EIF4E but is largely unaffected by EIF4A1 TISU elements render mRNA translation sensitive to MTOR but not to EIF4A inhibition (Elfakess et al 2011). We therefore depleted EIF4E or EIF4A1 in MCF7 and HEK293E cells and monitored expression of proteins encoded by MTOR-sensitive mRNAs with either long (CCND3, MCL1, BIRC5, and BCL2) or short (ATP5O, ATP5G1, NDUFS6, and UQCC2) 5 ′ UTRs.…”

Section: Low Sensitivity Limits the Catalog Of Mtor-sensitive Mrnas Imentioning

confidence: 99%

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

et al. 2016

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The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine motif) and TOP-like mRNAs, polysome-profiling indicated that MTOR also modulates translation of mRNAs without the 5′ TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5′ TOP motif but that 5′ UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5′ UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5′ UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1-sensitive. Selective inhibition of translation of mRNAs harboring long 5′ UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5′ UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5′ UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells.

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“…mechanism under an inhibited translation state, as induced by nutrient starvation (28)(29)(30). However, target of rapamycin complex 1 (TORC1) has been shown to be the main regulator of TOP mRNA translation through the phosphorylation of 4E-BP and S6K proteins under nutrient availability conditions (31).…”

Section: Translation Efficiency Is Regulated During the Diurnal Cyclementioning

confidence: 99%

“…One interesting finding consisted of the rhythmic regulation of TISU genes (28,29). Recently, it was shown that these genes are protected from AMPK-induced translation inhibition (30), and the rhythmic activation of the AMPK pathway thus provides an explanation for their rhythmic translation activation (12,60).…”

Section: Translation Efficiency Is Regulated During the Diurnal Cyclementioning

confidence: 99%

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

Atger

Gobet

Marquis

et al. 2015

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

215

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Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5′-Terminal Oligo Pyrimidine tract (5′-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5′-UTR (TISU) motif. The increased translation efficiency of 5′-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.circadian rhythms | ribosome profiling | mRNA translation | 5′-TOP sequences | TISU motifs L iving organisms on Earth are subjected to light-dark cycles caused by rotation of the Earth around the sun. To anticipate these changes, virtually all organisms have acquired a circadian timing system during evolution that allows a better adaptation to their environment. As a consequence, most aspects of their physiology are orchestrated in a rhythmic way by the circadian clock (from the Latin circa diem, meaning "about a day"), an endogenous and autonomous oscillator with a period of around 24 h (1, 2). Not surprisingly, perturbations of this clock in mammals lead to pathologies including psychiatric, metabolic, and vascular disorders (1,3,4). At the organismal scale, the oscillatory clockwork is organized in a hierarchal manner. Within the suprachiasmatic nuclei (SCN) of the hypothalamus, the "master clock" receives light input via the retina and communicates timing signals to "enslave" oscillators in peripheral organs (1, 2). The molecular oscillator consists of interconnected transcriptional and translational feedback loops, in which multiple layers of control, including temporal posttranscriptional and posttranslational regulation, play important roles (5). These additional layers of regulation are largely coordinated by systemic cues originating from circadian clock and/or feeding-coordinated rhythmic metabolism, allowing the adjustment of the molecular clo...

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Unique translation initiation of mRNAs-containing TISU element

Cited by 94 publications

References 31 publications

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

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