YB-1 Binds to GluR2 mRNA and CaM1 mRNA in the Brain and Regulates their Translational Levels in an Activity-Dependent Manner

Tanaka, Toru; Ohashi, Sachiyo; Funakoshi, Tomoko; Kobayashi, Shunsuke

doi:10.1007/s10571-010-9541-9

Cited by 15 publications

(10 citation statements)

References 72 publications

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“…We subsequently analysed YB-1 bound and input RNA using whole genome microarrays and found among others YB-1 mRNA itself, α - tubulin , EEF2 and UBC mRNA enriched in the PCT IP sample, which is in agreement with published data from both in-vitro systems and cell lines. 29–31 Importantly, MYC mRNA was found within the top 100 entries. Moreover, we observed a significant enrichment of several mRNAs associated with MYC pathways among the top 500 IP-specific entries (Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The presence of known targets of YB-1 assisted translation ( α - tubulin , EEF2 , UBC ) validated our approach, but the majority of mRNAs presented here have not been identified as YB-1 targets before and hence are novel. 29,31 GSEA analysis of IP transcripts in each sample showed a significant enrichment for either directly MYC-driven pathways or those that had an indirect relationship to MYC (Supplementary Table 2). Taken together, the data on co-expression and direct binding of YB-1 to wild-type MYC mRNA imply that YB-1 is involved in MYC overexpression.…”

Section: Discussionmentioning

confidence: 99%

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The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival

et al. 2012

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Y-box binding protein 1 (YB-1) functions as a translational regulator and has been suggested to elevate MYC mRNA translation via an internal ribosome entry segment (IRES) point mutation in multiple myeloma (MM). We show that YB-1-mediated translation of MYC mRNA occurs independently of the reported IRES mutation, as 87 MM patients (n = 88) and all tested human MM cell lines (HMCLs) were negative for the mutation. We show for the first time that positive MYC staining predicts YB-1 co-expression in malignant plasma cells and YB-1/MYC co-expression increases from 30% in medullary to 70% in extramedullary MM. YB-1 knockdown in HMCLs reduced both MYC protein levels and MYC mRNA in the polysomal fraction, providing a mechanism by which YB-1 controls MYC translation. MYC transcription of YB-1 is demonstrated in HMCLs as MYC knockdown resulted in reduced YB-1 protein and mRNA levels. Furthermore, MYC activation in non-malignant mouse embryonic fibroblasts (MEFs) increased YB-1 mRNA, clearly indicating that MYC drives YB-1 transcription. Importantly, perturbation of the MYC/YB-1 oncogenic circuit leads to apoptosis in HMCLs. Here, we demonstrate that these two proteins co-regulate each other via combined transcriptional/translational activity establishing their pivotal role in MM cell survival. We therefore suggest that targeting the YB-1/mRNA interaction provides a new strategy for MM drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival

et al. 2012

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“…Y-boxbinding protein 1 (YB-1) is a multifunctional protein that binds DNA and RNA and plays an important role in transcriptional and translational regulation (30,31). A recent study indicated that YB-1 interacts with Eaat2 mRNAs in the mouse brain (32). To examine whether YB-1 is involved in compound-activated EAAT2 translation, we performed siRNA knockdown experiments and found that depletion of YB-1 markedly reduced LDN/OSU-0212320-induced EAAT2 expression in PA-EAAT2 cells ( Figure 6A).…”

Section: Figurementioning

confidence: 99%

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Kong¹,

Chang²,

Takahashi³

et al. 2014

J. Clin. Invest.

122

136

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Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.

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“…This raises the exciting possibility that this mechanism of translational control might regulate Nodal signaling in different developmental, physiological, and pathological contexts in humans, and warrants further exploration. Notably, human YBX1 has been found in mRNPs in neurons, a cell type known for extensive RNA transport, subcellular localization and localized translation ( 71 – 74 ). Furthermore, Ybx1 has been proposed as a facilitator of RNA transport/localization by recruiting RNAs to the cytoskeleton ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Translational co-regulation of a ligand and inhibitor by a conserved RNA element

Zaucker

Nagorska

Kumari

et al. 2017

Nucleic Acids Research

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In many organisms, transcriptional and post-transcriptional regulation of components of pathways or processes has been reported. However, to date, there are few reports of translational co-regulation of multiple components of a developmental signaling pathway. Here, we show that an RNA element which we previously identified as a dorsal localization element (DLE) in the 3′UTR of zebrafish nodal-related1/squint (ndr1/sqt) ligand mRNA, is shared by the related ligand nodal-related2/cyclops (ndr2/cyc) and the nodal inhibitors, lefty1 (lft1) and lefty2 mRNAs. We investigated the activity of the DLEs through functional assays in live zebrafish embryos. The lft1 DLE localizes fluorescently labeled RNA similarly to the ndr1/sqt DLE. Similar to the ndr1/sqt 3′UTR, the lft1 and lft2 3′UTRs are bound by the RNA-binding protein (RBP) and translational repressor, Y-box binding protein 1 (Ybx1), whereas deletions in the DLE abolish binding to Ybx1. Analysis of zebrafish ybx1 mutants shows that Ybx1 represses lefty1 translation in embryos. CRISPR/Cas9-mediated inactivation of human YBX1 also results in human NODAL translational de-repression, suggesting broader conservation of the DLE RNA element/Ybx1 RBP module in regulation of Nodal signaling. Our findings demonstrate translational co-regulation of components of a signaling pathway by an RNA element conserved in both sequence and structure and an RBP, revealing a ‘translational regulon’.

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YB-1 Binds to GluR2 mRNA and CaM1 mRNA in the Brain and Regulates their Translational Levels in an Activity-Dependent Manner

Cited by 15 publications

References 72 publications

The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival

The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Translational co-regulation of a ligand and inhibitor by a conserved RNA element

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