The QKI-6 RNA Binding Protein Localizes with the MBP mRNAs in Stress Granules of Glial Cells

Wang, Yunling; Lacroix, Geneviève; Haines, Jeffery D.; Doukhanine, Evgueni; Almazán, Guillermina; Richard, Stéphane

doi:10.1371/journal.pone.0012824

Cited by 31 publications

(36 citation statements)

References 40 publications

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“…The siRNAs and miRNA mimics were purchased from Dharmacon Inc. The siRNAs used were siLuciferase (siCTL, 5=-CGU ACG CGG AAU ACU UCG AdTdT-3=), siQKI (5=-GGA CUU ACA GCC AAA CAA CdTdT-3=) (35), siQKI-1 (5=-GAC GAA GAA AUU AGC AGA GUA dTdT-3=) (36), and siQKI-2 (5=-CCA GCU GGC CCU ACC AUA AdTdT-3=). miR-7 miRCURY LNA microRNA inhibitor and a negative control were purchased from Exiqon Inc.…”

Section: Methodsmentioning

confidence: 99%

“…Antisense pri-miR-7-1 probe was labeled with digoxigenin-UTP (Roche) by in vitro transcription with T7 RNA polymerase using a MEGA Script T7 kit (Ambion) according to the manufacturer's instructions. In situ hybridizations were performed on siRNA-treated U343 cells as described previously (35).…”

Section: Methodsmentioning

confidence: 99%

“…The human U343 glioblastoma cell line, known to express the QKI-5, -6, and -7 isoforms, was transfected with siRNAs targeting luciferase (control) or the qkI mRNAs (35). The efficient knockdown of the QKI isoforms was confirmed by immunoblotting using pan-anti-QKI antibodies (37), while the anti-␤-tubulin antibody was used as a loading control (Fig.…”

Section: Identification Of Qki-regulated Mirnas In Glial Cellsmentioning

confidence: 99%

“…We have recently shown that the QKI proteins interact with argonaute 2 (Ago2), a core component of RISC, during the stress response (35). To determine whether the QKI proteins regulate the expression of selected miRNAs, we monitored the expression of miRNAs by microarray analysis of small interfering RNA (siRNA)-mediated QKI depletion of U343 glioblastoma cells.…”

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confidence: 99%

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The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

Wang

Vogel

et al. 2013

Molecular and Cellular Biology

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The quaking (qkI) gene encodes 3 major alternatively spliced isoforms that contain unique sequences at their C termini dictating their cellular localization. QKI-5 is predominantly nuclear, whereas QKI-6 is distributed throughout the cell and QKI-7 is cytoplasmic. The QKI isoforms are sequence-specific RNA binding proteins expressed mainly in glial cells modulating RNA splicing, export, and stability. Herein, we identify a new role for the QKI proteins in the regulation of microRNA (miRNA) processing. We observed that small interfering RNA (siRNA)-mediated QKI depletion of U343 glioblastoma cells leads to a robust increase in miR-7 expression. The processing from primary to mature miR-7 was inhibited in the presence QKI-5 and QKI-6 but not QKI-7, suggesting that the nuclear localization plays an important role in the regulation of miR-7 expression. The primary miR-7-1 was bound by the QKI isoforms in a QKI response element (QRE)-specific manner. We observed that the pri-miR-7-1 RNA was tightly bound to Drosha in the presence of the QKI isoforms, and this association was not observed in siRNA-mediated QKI or Drosha-depleted U343 glioblastoma cells. Moreover, the presence of the QKI isoforms led to an increase presence of pri-miR-7 in nuclear foci, suggesting that pri-miR-7-1 is retained in the nucleus by the QKI isoforms. miR-7 is known to target the epidermal growth factor (EGF) receptor (EGFR) 3= untranslated region (3=-UTR), and indeed, QKI-deficient U343 cells had reduced EGFR expression and decreased ERK activation in response to EGF. Elevated levels of miR-7 are associated with cell cycle arrest, and it was observed that QKI-deficient U343 that harbor elevated levels of miR-7 exhibited defects in cell proliferation that were partially rescued by the addition of a miR-7 inhibitor. These findings suggest that the QKI isoforms regulate glial cell function and proliferation by regulating the processing of certain miRNAs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Identification Of Qki-regulated Mirnas In Glial Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

Wang

Vogel

et al. 2013

Molecular and Cellular Biology

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“…Patlb which is involved in decapping in PBs , and QKI-6 which is a RNA binding protein in SGs (Wang et al 2010). Localization to the specific compartments of a cell helps these enzymes to be placed in a substrate-concentrated environment where they can function more efficiently.…”

Section: Co-localization Of Apel With Pbs And/or Sgsmentioning

confidence: 99%

Investigating the Cellular Localization of APE1.

Kim¹

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Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2

Lizarazo

Yook

Tsai

2022

Journal Cellular Physiology

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Alzheimer's disease (AD) is the most common cause of dementia, with the accumulation of amyloid beta peptide (Aβ) being one of the main causes of the disease. Fragile X mental retardation protein (FMRP), encoded by fragile X mental retardation 1 (Fmr1), is an RNA‐binding protein that represses translation of its bound mRNAs or exerts other indirect mechanisms that result in translational suppression. Because the accumulation of Aβ has been shown to cause translational suppression resulting from the elevated cellular stress response, in this study we asked whether and how Fmr1 is involved in Aβ‐induced translational regulation. Our data first showed that the application of synthetic Aβ peptide induces the expression of Fmr1 in cultured primary neurons. We followed by showing that Fmr1 is required for Aβ‐induced translational suppression, hyposynchrony of neuronal firing activity, and loss of excitatory synapses. Mechanistically, we revealed that Fmr1 functions to repress the expression of phosphatases including protein phosphatase 2A (PP2A) and protein phosphatase 1 (PP1), leading to elevated phosphorylation of eukaryotic initiation factor 2‐α (eIF2α) and eukaryotic elongation factor 2 (eEF2), and subsequent translational suppression. Finally, our data suggest that such translational suppression is critical to Aβ‐induced hyposynchrony of firing activity, but not the loss of synapses. Altogether, our study uncovers a novel mechanism by which Aβ triggers translational suppression and we reveal the participation of Fmr1 in altered neural plasticity associated with Aβ pathology. Our study may also provide information for a better understanding of Aβ‐induced cellular stress responses in AD.

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The QKI-6 RNA Binding Protein Localizes with the MBP mRNAs in Stress Granules of Glial Cells

Cited by 31 publications

References 40 publications

The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

Investigating the Cellular Localization of APE1.

Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2

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