Translational Regulation of Gene Expression during Conditions of Cell Stress

Spriggs, Keith A.; Bushell, Martin; Willis, Anne E.

doi:10.1016/j.molcel.2010.09.028

Cited by 640 publications

(614 citation statements)

References 110 publications

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“…1b). In contrast, ATF4 mRNA (which escapes eIF2a-P-mediated inhibition of translation, owing to the presence of upstream open reading frames in its 59 untranslated region (UTR) 17,18 ), showed increased active translation, represented by a right shift to a higher polysomal fraction ( Fig. 2j and Supplementary Figs 4 and 5).…”

Section: Research Lettermentioning

confidence: 99%

“…PrP mRNA did not show reduced translation, possibly because of the existence of similar translational control elements within the PrP gene. Indeed, human PrP mRNA has multiple upstream AUG upstream open reading frames in its 59 UTR, which could allow it to escape eIF2a-P translational inhibition in the same way as ATF4 does 17,18 ( Supplementary Fig. 6).…”

Section: Research Lettermentioning

confidence: 99%

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Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

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617

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The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the a-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2a-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases 1-4 , but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2a-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2a-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2a-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2a-P dephosphorylation 5 , increased eIF2a-P levels, exacerbating neurotoxicity and significantly reducing survival in priondiseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.Neurodegenerative diseases pose an ever-increasing challenge for society and health care systems worldwide, but their molecular pathogenesis is still largely unknown and no curative treatments exist. Alzheimer's (AD), Parkinson's (PD) and prion diseases are separate clinical and pathological conditions, but it is likely they share common mechanisms leading to neuronal death. Mice with prion disease show misfolded prion protein (PrP) accumulation and develop extensive neurodegeneration (with profound neurological deficits), in contrast to mouse models of AD or PD, in which neuronal loss is rare. Uniquely therefore, prion-infected mice allow access to mechanisms linking protein misfolding with neuronal death. Prion replication involves the conversion of cellular PrP, PrP C , to its misfolded, aggregating conformer, PrP Sc , a process leading ultimately to neurodegeneration 6 . We have previously shown rescue of neuronal loss and reversal of early cognitive and morphological changes in prion-infected mice by depleting PrP in neurons, preventing prion replication and ab...

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Section: Research Lettermentioning

confidence: 99%

Section: Research Lettermentioning

confidence: 99%

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

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562

617

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“…In this study, we showed that FXR is a novel target of miR-421 in HCC cells, and downregulation of FXR may be a new oncogenic mechanism of miR-421. miRNAs can target mRNAs at the 3 0 -UTR/5 0 -UTR, even at the open reading frame (ORF) by partial sequence homology, leading to translation repression/mRNA degradation (20)(21)(22). The current miRNA databases, such as miRBase, TargetScan, miRanda, and so on, are usually used for predicting the miRNAs for a target gene or predicting the targets of a miRNA based on the 3 0 -UTR sequences of mRNAs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Zhang

Gong

Dai

et al. 2012

Molecular Cancer Research

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The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenal gland, and intestine. It plays an important role in regulating the progression of several cancers including hepatocellular carcinoma (HCC). So it is necessary to study the regulation of FXR. In this study, we found that the expression of miR-421 was inversely correlated with FXR protein level in HCC cell lines. Treatment with miR-421 mimic repressed FXR translation. The reporter assay revealed that miR-421 targeted 3 0 untranslated region of human FXR mRNA. Furthermore, downregulation of FXR by miR-421 promoted the proliferation, migration, and invasion of HCC cells. These results suggest that miR-421 may serve as a novel molecular target for manipulating FXR expression in hepatocyte and for the treatment of HCC. Mol Cancer Res; 10(4); 516-22. Ó2012 AACR. IntroductionThe farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that is mainly expressed in liver, intestine, kidney, and adrenal gland (1). Ligand-activated FXR binds to response elements of target genes either as a classical FXRRXRa (retinoid X receptor alpha) heterodimer or as a monomer (2-4). FXR plays an important role in regulating the metabolisms of bile acid, cholesterol, triglyceride, and glucose (5). Recent studies show that FXR is also involved in the regulation of liver regeneration and protection against the liver carcinogenesis (6). Therefore, FXR has received increasing attention as a therapeutic target for the treatments of certain metabolic diseases and liver carcinoma.As a multiple functional transcriptional factor, FXR regulates so many target genes, but its own regulation is not well known. It has been reported that several transcriptional coregulators, including PGC-1a, Brg-1, p300, CARM1, PRMT1, and ASCOM, can potentially modulate FXR expression (7). Moreover, glucose and insulin (8) as well as the cytokines tumor necrosis factor-a and interleukin-1 (9) have also been identified to regulate FXR level. Recently, posttranslational modifications, such as phosphorylation,

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“…41,42 Hypoxic culture conditions for MCF7 cells transfected with pRuF plasmids caused a significant increase in Fluc activity for the plasmids harboring either c-MYC or PTCH1b 5'UTR, but not when the putative PTCH1b IRES motif was deleted (Fig. 6, left panel).…”

Section: Hypoxia Can Stimulate Ptch1b 5'utr-mediated Cap-independentmentioning

confidence: 97%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

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Translational Regulation of Gene Expression during Conditions of Cell Stress

Cited by 640 publications

References 110 publications

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

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