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Depletion of HES1 increased cell death in response to endoplasmic reticulum stress in mouse and human cells, in a manner that depended on the pro-apoptotic gene growth arrest and DNA damage-inducible protein GADD34.
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Findings highlight that the phosphatase regulator, GADD34, also functions as a kinase scaffold in response to chronic oxidative stress and recruits CK1 and oxidized TDP-43 to facilitate its phosphorylation, as seen in TDP-43 proteinopathies.
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established Neuro2a cells with edited GADD34 and ATF4/GADD34 genes and found that ATF4 acts as a proapoptotic factor, but GADD34 depletion did not attenuate the expression of cleaved caspase-3 induced by tunicamycin treatment.
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In response to endoplasmic reticulum stress, activation of PERK coordinates the integrated stress response by phosphorylating eIF2alpha, which is then quickly dephosphorylated by the GADD34 complex. Data imply dual role of the ISR in promoting and inhibiting medulloblastoma tumorigenesis.
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GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation.
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Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-beta mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of interferon observed in dsRNA-activated cells.
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Results highlighted the essential roles played by GADD34 and CReP in regulating mRNA translation during unstressed conditions and following endoplasmic reticulum stress.
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Sustained protein synthesis sensitized cells to pharmacological induction of the Unfolded Protein Response (UPR), and the observed decrease in cell viability was restored upon inhibition of GADD34 activity. We conclude that NMP4 is a key regulator of ribosome biogenesis and the UPR, which together play a central role in determining cell viability during endoplasmic reticulum stress.
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Through aging or a high fat diet, insulin signaling in GADD34-deficient liver converted to be down regulated compared with WT mice.
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Results show that GADD34 plays a vital role in promoting cell death following proteasome inhibition via enhancing protein synthesis involved in endoplasmic reticulum stress, reactive oxygen species production and autophagy formation.
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avidity for the substrate plays an important role in imparting specificity on the PPP1R15B-PP1G-actin ternary complex.
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GADD34 enhances autophagy and suppresses apoptosis stimulated by LPS combined with amino acid deprivation through regulation of mTOR signaling pathway in macrophages.
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GADD34 upregulated pro-inflammatory mediator.
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GADD34 promotes cell survival and adaptation to increased extracellular osmolarity by increasing the uptake of small neutral amino acids via the amino acid transporter SNAT2.
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GADD34 expression was upregulated in the liver of mice after exposure to a carcinogen, diethylnitrosamine (DEN). In both acute and chronic DEN treatment models, GADD34 deficiency not only decreased oncogene expression, but also reduced hepatic damage.
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Thus these results indicate that GADD34 appears to suppress myofibroblast differentiation through inhibiting Smad3-dependent TGFbeta signal pathway and promote its apoptosis by activating caspase-3 pathway
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GADD34 works to inhibit the proliferation and differentiation of HSCs or myeloid precursor cells and maintains homeostatic differentiation of neutrophil-lineage cells to avoid early immunological senescence.
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Data indicate that GADD34 is the regulatory subunit of rotein phosphatase-1 (PP1) to specify PP1 to dephosphorylate TGF-beta-activated kinase 1 (TAK1) Ser412.
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Traumatic brain injury induces the expression of GADD34 by stimulating binding of a stress inducible transcription factor, ATF4, to the GADD34 promoter.
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GADD34 phosphorylation on tyrosine 262 modulates endoplasmic reticulum stress signaling and cell fate.
