Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death
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- Hye Jin Jo
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea
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- Jin Won Yang
- College of Pharmacy, Woosuk University, Wanju 55338, Jeonbuk, Korea
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- Ji Hye Park
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea
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- Eul Sig Choi
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea
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- Chae-Seok Lim
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea
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- Seoul Lee
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea
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- Chang Yeob Han
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea
Description
<jats:p>Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.</jats:p>
Journal
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- International Journal of Molecular Sciences
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International Journal of Molecular Sciences 20 (18), 4369-, 2019-09-05
MDPI AG
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Details 詳細情報について
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- CRID
- 1360292618951069696
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- ISSN
- 14220067
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- Data Source
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- Crossref