La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)

Fonseca, Bruno D.; Zakaria, Chadi; Jia, Jian Jun; Graber, Tyson E.; Svitkin, Yuri V.; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, James C.; Diao, Ilo T.; Lussier, Alexandre A.; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta‐Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M.; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, José L.; Hernández, Greco; Alain, Tommy; Damgaard, Christian Kroun

doi:10.1074/jbc.m114.621730

Cited by 214 publications

(419 citation statements)

References 100 publications

(100 reference statements)

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“…However, LARP1 activity by itself seems insufficient to explain 5′TOP-mediated translation, as a recent study found that LARP1 interacts with a broad class of approximately 3,000 mRNAs that include most but not all 5′TOP-containing transcripts 131 . Moreover, there is evidence that LARP1 binding to the 5′TOP may actually repress translation rather than activate it 132 . Further studies using unbiased approaches, such as comprehensive identification of RBPs by MS (CHIRP-MS) to identify physiologically relevant RBPs and in vivo click-SHAPE (icSHAPE) to identify RNA structure, are needed to fully elucidate the underlying mechanisms of this and other translational elements and to move towards a comprehensive understanding of how mRNA structure and sequence synergize to write the translational code.…”

Section: Sequence-specific Rna Elementsmentioning

confidence: 99%

New frontiers in translational control of the cancer genome

Truitt¹,

Ruggero²

2016

Nat Rev Cancer

316

321

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The past several years have seen dramatic leaps in our understanding of how gene expression is rewired at the translation level during tumorigenesis to support the transformed phenotype. This work has been driven by an explosion in technological advances and is revealing previously unimagined regulatory mechanisms that dictate functional expression of the cancer genome. In this Review we discuss emerging trends and exciting new discoveries that reveal how this translational circuitry contributes to specific aspects of tumorigenesis and cancer cell function, with a particular focus on recent insights into the role of translational control in the adaptive response to oncogenic stress conditions.

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Section: Sequence-specific Rna Elementsmentioning

confidence: 99%

New frontiers in translational control of the cancer genome

Truitt¹,

Ruggero²

2016

Nat Rev Cancer

316

321

View full text Add to dashboard Cite

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“…In contrast, a more recent study proposed that active mTORC1 interacts with LARP1 and inhibits LARP1’s function to suppress translation initiation of LARP1-interacting 5’TOP mRNAs (Fonseca et al, 2015). Thus, the functional importance of LARP1-mTORC1 interaction and the role of LARP1 in the regulation of translation of LARP1-interacting mRNAs remain unclear.…”

Section: Resultsmentioning

confidence: 99%

LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs

Hong

Freeberg

Han

et al. 2017

eLife

163

236

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The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5’ and 3’UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3’UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis.DOI: http://dx.doi.org/10.7554/eLife.25237.001

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“…This suggests that the length of the 5 ′ UTR, rather than the presence of a TISU, is the primary factor that determines EIF4E-versus EIF4A1-sensitivity. mTORC1 modulates translation of TOP mRNAs via LARP1 (Tcherkezian et al 2014;Fonseca et al 2015), whereas synthesis of mitochondrial, proliferation-and survival-promoting proteins is controlled by the EIF4EBP/EIF4E pathway (Larsson et al 2012;Morita et al 2013). Notably, 5…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this view, the effects of serum deprivation on TOP mRNA translation also appeared to be EIF4E-independent (Shama et al 1995). In turn, LARP1 and TIA1/TIAL1 (also known as TIAR) were reported to mediate effects of mTORC1 on TOP mRNAs (Damgaard and Lykke-Andersen 2011;Tcherkezian et al 2014;Fonseca et al 2015). Polysome-profiling showed that the mTORC1/EIF4EBP axis also regulates translation of non-TOP mRNAs, including those encoding mitochondrial and survivaland proliferation-promoting proteins (Larsson et al 2012;Morita et al 2013).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

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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La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)

Cited by 214 publications

References 100 publications

New frontiers in translational control of the cancer genome

New frontiers in translational control of the cancer genome

LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs

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

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