Translational control and the cancer cell response to stress

Robichaud, Nathaniel; Sonenberg, Nahum

doi:10.1016/j.ceb.2017.05.007

Cited by 61 publications

(61 citation statements)

References 96 publications

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“…Strikingly, using hESCs, we noted that similarly to VEGF and ATF4 and in contrast to RPLPO, the translation of NANOG, NODAL and SNAIL mRNA was either sustained or increased under hypoxia ( Figure 1m). Stresses such as hypoxia cause adaptive translational reprogramming via modulating mTOR and integrated stress response (ISR) signaling pathways [33][34][35][36] . Using Western blotting, we confirmed that in T47D cells hypoxia reduces mTORC1 activity -as illustrated by reduced 4E-BP1 and ribosomal protein S6 (rpS6) phosphorylation (1% O2; 24 hours) -while inducing ISR as evidenced by eIF2 phosphorylation (Figure 1 n; Supplemental Figure 1j, 1% O2).…”

Section: Hypoxia Alters the Levels Of Nodal Nanog And Snail By Modulmentioning

confidence: 99%

Translational control of breast cancer plasticity

Jewer

Lee²,

Liu³

et al. 2019

Preprint

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Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG, SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5' Untranslated Regions (5'UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. This leads to accumulation of corresponding proteins which induce plasticity and "fate-switching" toward stem-cell like phenotypes. Surprisingly, we observed that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG, SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem cell-like phenotypes. Strikingly, these effects can be overcome with drugs that antagonize translational reprogramming caused by eIF2 phosphorylation (e.g. ISRIB). Collectively, our findings unravel a hitherto unappreciated mechanism of induction of plasticity of breast cancer cells, and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.

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Section: Hypoxia Alters the Levels Of Nodal Nanog And Snail By Modulmentioning

confidence: 99%

Translational control of breast cancer plasticity

Jewer

Lee²,

Liu³

et al. 2019

Preprint

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“…Cancer mutations impact on translation mainly for two reasons. Firstly, many cancer cells are exposed to stresses that cause cap-dependent translation to be inhibited [14,177,178], yet cancer cells require high levels of protein synthesis to grow and proliferate. Hence, the mutations found in cancer cells either boost cap-dependent translation [179] or activate alternate translation modes to bypass the block in cap-dependent translation [77].…”

Section: Translation Dysregulation In Cancermentioning

confidence: 99%

Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

2018

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Recent work has brought to light many different mechanisms of translation initiation that function in cells in parallel to canonical cap-dependent initiation. This has important implications for cancer. Canonical cap-dependent translation initiation is inhibited by many stresses such as hypoxia, nutrient limitation, proteotoxic stress, or genotoxic stress. Since cancer cells are often exposed to these stresses, they rely on alternate modes of translation initiation for protein synthesis and cell growth. Cancer mutations are now being identified in components of the translation machinery and in -regulatory elements of mRNAs, which both control translation of cancer-relevant genes. In this review, we provide an overview on the various modes of non-canonical translation initiation, such as leaky scanning, translation re-initiation, ribosome shunting, IRES-dependent translation, and mA-dependent translation, and then discuss the influence of stress on these different modes of translation. Finally, we present examples of how these modes of translation are dysregulated in cancer cells, allowing them to grow, to proliferate, and to survive, thereby highlighting the importance of translational control in cancer.

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“…Importantly, besides initiation, eIF3 was also shown to i) control translation termination and ribosomal recycling (Beznosková et al, 2013;Beznoskova et al, 2015;Pisarev et al, 2007); and to ii) stimulate reinitiation (REI) on downstream cistrons after translation of short upstream uORFs -due to its ability to remain bound to elongating ribosomes immediately following termination Park et al, 2001;Szamecz et al, 2008). Owing to the manifold functions of eIF3, deregulated eIF3 expression is associated with numerous pathological conditions (reviewed in (Gomes-Duarte et al, 2018;Robichaud and Sonenberg, 2017;Valasek et al, 2017)).…”

Section: Introductionmentioning

confidence: 99%

Selective Translation Complex Profiling Reveals Staged Initiation and Co-translational Assembly of Initiation Factor Complexes

Wagner

Herrmannová

Hronová

et al. 2019

Preprint

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Translational control targeting mainly the initiation phase is central to the regulation of gene expression. Understanding all of its aspects requires substantial technological advancements. Here we modified yeast Translational Complex Profile sequencing (TCP-seq), related to ribosome profiling, and adopted it for mammalian cells. Human TCP-seq, capable of capturing footprints of 40S subunits (40Ses) in addition to 80S ribosomes (80Ses), revealed that mammalian and yeast 40Ses distribute similarly across 5'UTRs indicating considerable evolutionary conservation. We further developed a variation called Selective TCP-seq (Sel-TCP-seq) enabling selection for 40Ses and 80Ses associated with an immuno-targeted factor in yeast and human. Sel-TCP-seq demonstrated that eIF2 and eIF3 travel along 5'UTRs with scanning 40Ses to successively dissociate upon start codon recognition. Manifesting the Sel-TCPseq versatility for gene expression studies, we also identified four initiating 48S conformational intermediates, provided novel insights into ATF4 and GCN4 mRNA translational control, and demonstrated co-translational assembly of initiation factor complexes.

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Translational control and the cancer cell response to stress

Cited by 61 publications

References 96 publications

Translational control of breast cancer plasticity

Translational control of breast cancer plasticity

Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

Selective Translation Complex Profiling Reveals Staged Initiation and Co-translational Assembly of Initiation Factor Complexes

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