Assessing IRES activity in the HIF-1α and other cellular 5′ UTRs

Bert, Andrew G.; Grépin, Renaud; Vadas, Mathew A.; Goodall, Gregory J.

doi:10.1261/rna.2320506

Cited by 115 publications

(120 citation statements)

References 34 publications

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“…Our data also revealed that arsenite stress induced RBM4 binding to cellular mRNAs encoding Bcl-2 and c-Myc. Although whether translation of these two mRNAs is mediated by authentic IRES is still being debated (23,32), RBM4 may activate their expression either through IRES or via a not-yet-known mechanism but also involving eIF4A in response to cell stresses.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Hypoxia induces the expression of a subset of genes directly regulated by the transcription factor HIF-1α (hypoxia-inducible factor-1α). The translation of the HIF-1α mRNA is cap-dependent (26), and may be fine-tuned by Mnk1/2-mediated phosphorylation of eIF4E (27). In addition, HIF-1α mRNA contains an internal ribosomal entry site (IRES) in its 5′ untranslated region.…”

Section: Mnk1/mnk2 Double Deficiency Does Not Affect Cellular Responsmentioning

confidence: 99%

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Ueda

Sato

Elia

et al. 2010

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

189

196

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MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) are proteinserine/threonine kinases that are activated by ERK or p38 and phosphorylate eIF4E, which is involved in cap-dependent translation initiation. However, Mnk1/2 double knockout (Mnk-DKO) mice show normal cell growth and development despite an absence of eIF4E phosphorylation. Here we show that the tumorigenesis occurring in the Lck-Pten mouse model (referred to here as tPten −/− mice) can be suppressed by the loss of Mnk1/2. Phosphorylation of eIF4E was greatly enhanced in lymphomas of parental tPten −/− mice compared with lymphoid tissues of wild-type mice, but was totally absent in lymphomas of tPten −/− ; Mnk-DKO mice. Notably, stable knockdown of Mnk1 in the human glioma cell line U87MG resulted in dramatically decreased tumor formation when these cells were injected into athymic nude mice. Our data demonstrate an oncogenic role for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer drug targets that could be inactivated with minimal side effects.

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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

210

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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Assessing IRES activity in the HIF-1α and other cellular 5′ UTRs

Cited by 115 publications

References 34 publications

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

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

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

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

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