Enhancement of IRES-Mediated Translation of the c-myc and BiP mRNAs by the Poly(A) Tail Is Independent of Intact eIF4G and PABP

Thoma, Christian; Bergamini, Giovanna; Galy, Bruno; Hundsdoerfer, Patrick; Hentze, Matthias W.

doi:10.1016/j.molcel.2004.08.021

Cited by 85 publications

(107 citation statements)

References 61 publications

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“…eIF4A may also act as an mRNA-specific translational enhancer. Cap-independent translation of mRNAs containing the c-myc or BiP 5Ј-UTRs was strongly stimulated by increased levels of eIF4A compared with a control m 7 G-capped reporter containing an artificial 56-nucleotide 5Ј-UTR (21). Selective recruitment of multiple molecules of eIF4A to certain 5Ј-UTRs could explain why eIF4A is severalfold more abundant than eIF4E in yeast (37,38).…”

Section: Dedicated Ires or Translational Enhancer?mentioning

confidence: 98%

Alternative Ways to Think about Cellular Internal Ribosome Entry

Gilbert

2010

Journal of Biological Chemistry

108

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Internal ribosome entry sites (IRESs) are specialized mRNA elements that allow recruitment of eukaryotic ribosomes to naturally uncapped mRNAs or to capped mRNAs under conditions in which cap-dependent translation is inhibited. Putative cellular IRESs have been proposed to play crucial roles in stress responses, development, apoptosis, cell cycle control, and neuronal function. However, most of the evidence for cellular IRES activity rests on bicistronic reporter assays, the reliability of which has been questioned. Here, the mechanisms underlying cap-independent translation of cellular mRNAs and the contributions of such translation to cellular protein synthesis are discussed. I suggest that the division of cellular mRNAs into mutually exclusive categories of "cap-dependent" and "IRESdependent" should be reconsidered and that the implications of cellular IRES activity need to be incorporated into our models of cap-dependent initiation.Eukaryotic mRNAs are modified by the addition of an m 7 GpppN cap structure to their 5Ј-ends. The m 7 G cap is thought to stimulate translation of most mRNAs by enhancing binding of a 43 S preinitiation complex (containing 40 S ribosomal subunits, methionine initiator tRNA, and initiation factors eIF2 and eIF3) to 5Ј-UTRs of mRNAs through recognition of the m 7 G cap by a complex of the cap-binding protein, eIF4E; a large scaffold protein, eIF4G; and an ATP-dependent RNA helicase, eIF4A. Subsequent movement of the 43 S complex in a 5Ј-to 3Ј-direction (scanning) locates the initiating AUG through recognition by the anticodon of the initiator tRNA. The discovery that naturally uncapped picornaviral mRNAs can efficiently recruit the host cell translation machinery via internal ribosome entry sites (IRESs) 2 raised the possibility that certain cellular mRNAs might have a similar capability (1, 2).The cellular IRES hypothesis offered an attractive solution to two problems. First, a number of cellular stress responses involve inhibition of one or more general translation initiation factors, yet the adaptive responses to stress require new protein synthesis. Cellular IRES elements could allow mRNAs encoding key regulatory proteins to escape the general inhibition of translation. The observation that some cellular mRNAs continue to be translated in poliovirus-infected cells after the inhibition of cap-dependent initiation (through cleavage of eIF4G by a virally encoded protease) is consistent with this hypothesis (3). Second, the existence of cellular IRESs could explain how mRNAs with very long 5Ј-UTRs or containing numerous predicted stem-loop structures or upstream AUG codons within their 5Ј-UTRs could be translated with reasonable efficiency, despite evidence that such features can significantly reduce translation of model mRNAs (4 -6).Both arguments in favor of the cellular IRES hypothesis rest on certain assumptions about the predominant mechanism of cap-and scanning-dependent initiation that this minireview will re-examine in light of recent publications that (i) demonstrate that l...

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Section: Dedicated Ires or Translational Enhancer?mentioning

confidence: 98%

Alternative Ways to Think about Cellular Internal Ribosome Entry

Gilbert

2010

Journal of Biological Chemistry

108

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“…In several instances, these cellular IRES elements facilitate translation under stress conditions, including hypoxia, when protein synthesis via cap-dependent translation is reduced (111). Specifically, vascular endothelial growth factor (112), HIF-1a (113), and BiP (114,115) have all been reported to have IRES activity, although this is still controversial (116). The availability of eIF4E has been proposed to control a ''switch'' between cap-dependent and IRES-mediated translation (117).…”

Section: Selective Gene Expression Mediated By Eif4f Regulation Durinmentioning

confidence: 99%

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

Koumenis

Wouters

2006

Molecular Cancer Research

209

170

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Poor oxygenation (hypoxia) is present in the majority of human tumors and is associated with poor prognosis due to the protection it affords to radiotherapy and chemotherapy. Hypoxia also elicits multiple cellular response pathways that alter gene expression and affect tumor progression, including two recently identified separate pathways that strongly suppress the rates of mRNA translation during hypoxia. The first pathway is activated extremely rapidly and is mediated by phosphorylation and inhibition of the eukaryotic initiation factor 2A. Phosphorylation of this factor occurs as part of a coordinated endoplasmic reticulum stress response program known as the unfolded protein response and activation of this program is required for hypoxic cell survival and tumor growth. Translation during hypoxia is also inhibited through the inactivation of a second eukaryotic initiation complex, eukaryotic initiation factor 4F. At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2 -dependent inhibition of the mammalian target of rapamycin kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia-induced proteins. Consequently, both arms of translational control during hypoxia influence gene expression and phenotype. These hypoxic response pathways show differential activation requirements that are dependent on the level of oxygenation and duration of hypoxia and are themselves highly dynamic. Thus, the severity and duration of hypoxia can lead to different biological and therapeutic consequences. (Mol Cancer Res 2006;4(7):423 -36)

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“…4A). Translation initiation factor eIF4A is essential but limiting for the EMCV IRES-mediated translation (20). Therefore, when eIF4A was overexpressed, the activity of Renilla luciferase was elevated by Ϸ4-fold (Fig.…”

Section: Rbm4 Suppresses Cap-dependent Translationmentioning

confidence: 99%

Cell stress modulates the function of splicing regulatory protein RBM4 in translation control

Lin

Hsu

Tarn

2007

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

117

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RNA-binding motif protein 4 (RBM4) plays a regulatory role in alternative splicing of precursor mRNA. We show here that cell stress such as arsenite exposure induces phosphorylation of RBM4 at serine 309 and also drives its cytoplasmic accumulation and targeting to stress granule via the MKK 3/6-p38 signaling pathway. Accordingly, RBM4 suppresses cap-dependent translation in a cis-element-dependent manner. However, RBM4 concomitantly activates internal ribosome entry site (IRES)-mediated translation likely by promoting the association of translation initiation factor eIF4A with IRES-containing mRNAs. Overexpression of RBM4 therefore mimics the effect of cell stress-induced signaling on translation initiation control. Whereas arsenite treatment promotes RBM4 loading onto IRES mRNAs and enhances RBM4 -eIF4A interactions, a nonphosphorylatable mutant of RBM4 was unresponsive to arsenite stress and failed to activate IRES-mediated translation. Thus, our results uncover a previously unrecognized paradigm for the RNA-binding protein RBM4 in its phosphorylation-modulated dual action as a suppressor of cap-dependent and enhancer of IRES-mediated translation in response to stress signals.cell stress ͉ eIF4A ͉ internal ribosome entry site ͉ phosphorylation ͉ splicing factor P osttranscriptional control of eukaryotic gene expression comprises several levels of regulation such as processing, export, turnover, localization, and translation of mRNAs (1). Each regulation step involves various combinations of RNAbinding proteins that form dynamic messenger ribonucleoproteins with the transcript. These messenger ribonucleoproteins may individually play specific roles in mRNA metabolism by forming distinct regulatory complexes (2). Some of them continuously shuttle between the nucleus and cytoplasm and may thus participate in multiple steps of mRNA metabolism in different subcellular compartments. For example, nuclear precursor mRNA splicing factors serine/arginine-rich (SR) proteins were recently implicated in several postsplicing activities including mRNA export, quality control, and translation (1, 3-5).Cellular signaling pathways may relocate messenger ribonucleoproteins and thereby modulate their function. For example, environmental stimuli such as osmotic shock induce phosphorylation and cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein (hnRNP) A1 via the MAPK pathway and hence alter its activity in splicing regulation (6, 7). Activation of the ERK signaling pathway can drive cytoplasmic accumulation of hnRNP K; blockade of this pathway attenuates the ability of hnRNP K to inhibit translation (8).The cellular response to environmental stress immediately leads to global repression of protein synthesis and aggregation of stalled translation complexes in cytoplasmic foci termed stress granules (SGs) (9, 10). However, stress-induced attenuation of global translation is also accompanied by selective translation of mRNAs that possess internal ribosome entry sites (IRES) (11,12). In particular, IRES-mediated tran...

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Enhancement of IRES-Mediated Translation of the c-myc and BiP mRNAs by the Poly(A) Tail Is Independent of Intact eIF4G and PABP

Cited by 85 publications

References 61 publications

Alternative Ways to Think about Cellular Internal Ribosome Entry

Alternative Ways to Think about Cellular Internal Ribosome Entry

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

Cell stress modulates the function of splicing regulatory protein RBM4 in translation control

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