Phosphorylation of Eukaryotic Translation Initiation Factor 2α Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress

DuRose, Jenny B.; Scheuner, Donalyn; Kaufman, Randal J.; Rothblum, Lawrence I.; Niwa, Maho

doi:10.1128/mcb.00260-09

Cited by 96 publications

(74 citation statements)

References 61 publications

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“…S1A in the supplemental material). This modest effect on protein translation contrasts with the effects of chemical inhibitors of protein translation, e.g., cycloheximide, and is similar to effects seen previously by other investigators (9,38). In addition, several NMD-targeted transcripts increased their association with polysomes upon treatments that inhibit NMD, also consistent with previous reports (18) (Fig.…”

Section: (D) Perksupporting

confidence: 91%

Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis

Wang

Zavadil

Martin

et al. 2011

Molecular and Cellular Biology

134

209

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While nonsense-mediated RNA decay (NMD) is an established mechanism to rapidly degrade select transcripts, the physiological regulation and biological significance of NMD are not well characterized. We previously demonstrated that NMD is inhibited in hypoxic cells. Here we show that the phosphorylation of the ␣ subunit of eukaryotic initiation factor 2 (eIF2␣) translation initiation factor by a variety of cellular stresses leads to the inhibition of NMD and that eIF2␣ phosphorylation and NMD inhibition occur in tumors. To explore the significance of this NMD regulation, we used an unbiased approach to identify approximately 750 NMD-targeted mRNAs and found that these mRNAs are overrepresented in stress response and tumorpromoting pathways. Consistent with these findings, the inhibition of NMD promotes cellular resistance to endoplasmic reticulum stress and encourages tumor formation. The transcriptional and translational regulations of gene expression by the microenvironment are established mechanisms by which tumor cells adapt to stress. These data indicate that NMD inhibition by the tumor microenvironment is also an important mechanism to dynamically regulate genes critical for the response to cellular stress and tumorigenesis.During tumorigenesis, a disorganized vasculature leads to amino acid and glucose deprivation, cellular hypoxia, the accumulation of reactive oxygen species (ROS), and various other stresses (5, 12). Cellular adaptation to the hostile tumor microenvironment requires the regulation of stress-induced genes (reviewed in reference 16). For example, the transcription factor ATF-4, upregulated in human tumors due to the stress-induced phosphorylation of the ␣ subunit of eukaryotic translation initiation factor 2 (eIF2␣), transactivates genes involved in amino acid metabolism, angiogenesis, and ROS attenuation (2,3,33). Cells that cannot phosphorylate eIF2␣ or that are deficient in ATF-4 and other stress-induced transcription factors do not form tumors in vivo (2, 13, 40), and therefore, a major goal in cancer biology has been to better understand and potentially target these adaptive mechanisms. However, while the translational and transcriptional responses that promote adaptation to the tumor microenvironment are well established, the role of mRNA stabilization in the cellular stress response has not been as thoroughly studied.Nonsense-mediated RNA decay (NMD) degrades up to 30% of all mutated protein-coding mRNAs, including those responsible for many genetic disorders, such as thalassemia, cystic fibrosis, and muscular dystrophy (11). During the processing of mammalian pre-mRNA, introns are excised and marked by an exon junction complex, which contains core NMD components. Newly synthesized mRNAs are thought to undergo a pioneering round of translation by a complex that includes eIF2␣ (6). When this translation complex pauses at a premature termination codon (PTC) upstream of an exon junction complex, the RNA helicase UPF1/Rent1, an essential component of the NMD process, is recruited and the...

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Section: (D) Perksupporting

confidence: 91%

Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis

Wang

Zavadil

Martin

et al. 2011

Molecular and Cellular Biology

134

209

View full text Add to dashboard Cite

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“…A sustained increase in phosphorylated eIF2␣ can cause C/EBP homologous protein (CHOP) mediated apoptosis (Harding et al, 2000;Scheuner et al, 2001;Galehdar et al, 2010). Previous reports described eIF2␣ in the nucleus, which may function to regulate transcriptional and translational processes (Goldstein et al, 1999;DuRose et al, 2009;Tejada et al, 2009). We found that nicotine exposure significantly inhibited nuclear eIF2␣ phosphorylation in ␣4␤2-overexpressing neurons, without affecting total eIF2␣ expression (Fig.…”

Section: Discussionmentioning

confidence: 56%

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Srinivasan

Richards²,

Xia³

et al. 2012

Mol Pharmacol

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We report the first observation that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) can decrease when a central nervous system drug acts as an intracellular pharmacological chaperone for its classic receptor. Transient expression of ␣4␤2 nicotinic receptors (nAChRs) in Neuro-2a cells induced the nuclear translocation of activating transcription factor 6 (ATF6), which is part of the UPR. Cells were exposed for 48 h to the full agonist nicotine, the partial agonist cytisine, or the competitive antagonist dihydro-␤-erythroidine; we also tested mutant nAChRs that readily exit the ER. Each of these four manipulations increased Sec24D-enhanced green fluorescent protein fluorescence of condensed ER exit sites and attenuated translocation of ATF6-enhanced green fluorescent protein to the nucleus. However, we found no correlation among the manipulations regarding other tested parameters [i.e., changes in nAChR stoichiometry (␣4 2 ␤2 3 versus ␣4 3 ␤2 2 ), changes in ER and trans-Golgi structures, or the degree of nAChR up-regulation at the plasma membrane]. The four manipulations activated 0 to 0.4% of nAChRs, which shows that activation of the nAChR channel did not underlie the reduced ER stress. Nicotine also attenuated endogenously expressed ATF6 translocation and phosphorylation of eukaryotic initiation factor 2␣ in mouse cortical neurons transfected with ␣4␤2 nAChRs. We conclude that, when nicotine accelerates ER export of ␣4␤2 nAChRs, this suppresses ER stress and the UPR. Suppression of a sustained UPR may explain the apparent neuroprotective effect that causes the inverse correlation between a person's history of tobacco use and susceptibility to developing Parkinson's disease. This suggests a novel mechanism for neuroprotection by nicotine.

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“…In parallel, ribosomal biogenesis is rapidly repressed by PERK (DuRose et al, 2009) and subsequent binding of free ribosomal proteins to the E3 ligase MDM2 appears to stabilise p53 and cause G1 arrest (Zhang et al, 2006). However, PERK-dependent activation of the GSK3 during ER stress has been shown to destabilise p53 (Baltzis et al, 2007; …”

Section: Discussionmentioning

confidence: 99%

Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response

Malzer

Daly

Moloney

et al. 2010

Journal of Cell Science

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SummaryThe integrated stress response (ISR) protects cells from numerous forms of stress and is involved in the growth of solid tumours; however, it is unclear how the ISR acts on cellular proliferation. We have developed a model of ISR signalling with which to study its effects on tissue growth. Overexpression of the ISR kinase PERK resulted in a striking atrophic eye phenotype in Drosophila melanogaster that could be rescued by co-expressing the eIF2 phosphatase GADD34. A genetic screen of 3000 transposon insertions identified grapes, the gene that encodes the Drosophila orthologue of checkpoint kinase 1 (CHK1). Knockdown of grapes by RNAi rescued eye development despite ongoing PERK activation. In mammalian cells, CHK1 was activated by agents that induce ER stress, which resulted in a G2 cell cycle delay. PERK was both necessary and sufficient for CHK1 activation. These findings indicate that non-genotoxic misfolded protein stress accesses DNA-damage-induced cell cycle checkpoints to couple the ISR to cell cycle arrest.

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Phosphorylation of Eukaryotic Translation Initiation Factor 2α Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress

Cited by 96 publications

References 61 publications

Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis

Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response

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