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Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death.
Jo, Hye Jin; Yang, Jin Won; Park, Ji Hye; Choi, Eul Sig; Lim, Chae-Seok; Lee, Seoul; Han, Chang Yeob.
Afiliación
  • Jo HJ; Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea. 546chj@naver.com.
  • Yang JW; College of Pharmacy, Woosuk University, Wanju 55338, Jeonbuk, Korea. jwyang@woosuk.ac.kr.
  • Park JH; Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea. ks7384@gmail.com.
  • Choi ES; Brain Research Institute, Wonkwang University, Iksan 54538, Jeonbuk, Korea. ks7384@gmail.com.
  • Lim CS; Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea. eschoie@hanmail.net.
  • Lee S; Brain Research Institute, Wonkwang University, Iksan 54538, Jeonbuk, Korea. eschoie@hanmail.net.
  • Han CY; Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Jeonbuk, Korea. cslimwk1@wku.ac.kr.
Int J Mol Sci ; 20(18)2019 Sep 05.
Article en En | MEDLINE | ID: mdl-31491992
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / EIF-2 Quinasa / Hepatocitos / Factor de Transcripción CHOP / Fosfatasas de Especificidad Dual / Estrés del Retículo Endoplásmico Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Int J Mol Sci Año: 2019 Tipo del documento: Article Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / EIF-2 Quinasa / Hepatocitos / Factor de Transcripción CHOP / Fosfatasas de Especificidad Dual / Estrés del Retículo Endoplásmico Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Int J Mol Sci Año: 2019 Tipo del documento: Article Pais de publicación: Suiza