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Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways
BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress....
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117566/ https://www.ncbi.nlm.nih.gov/pubmed/25077945 http://dx.doi.org/10.1371/journal.pone.0103828 |
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author | Olivares, Shantel Green, Richard M. Henkel, Anne S. |
author_facet | Olivares, Shantel Green, Richard M. Henkel, Anne S. |
author_sort | Olivares, Shantel |
collection | PubMed |
description | BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex. METHODS: Human hepatocellular carcinoma (HepG2) cells and C57BL/6J mice were subjected to pharmacologic ER stress and the expression of AP-1-associated genes and proteins was assessed. To determine the role of MAPK signaling in ER stress-induced AP-1 activation, ER stress was induced in JNK- and ERK-inhibited HepG2 cells. RESULTS: Induction of ER stress promoted the activation of both Jun- and Fos-related genes and proteins of the AP-1 complex in HepG2 cells and murine liver. Inhibition of ERK phosphorylation in HepG2 cells completely prevented ER stress-induced activation of the fos-related components of AP-1 whereas activation of Jun-related components was only partially attenuated. Conversely, inhibition of JNK phosphorylation in HepG2 cells reduced ER stress-induced activation of Jun-related components but did not prevent activation of fos-related components. CONCLUSIONS: ER stress activates the hepatic AP-1 complex via MAPK-dependent signaling pathways. ER stress-induced activation of Fos-related components is dependent primarily on ERK activation whereas ER stress-induced activation of Jun-related components is dependent primarily on JNK activation, although there is interplay between these regulatory pathways. These data implicate a novel signaling pathway by which sustained ER stress, as observed in many chronic liver diseases, may promote hepatic carcinogenesis. |
format | Online Article Text |
id | pubmed-4117566 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41175662014-08-04 Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways Olivares, Shantel Green, Richard M. Henkel, Anne S. PLoS One Research Article BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex. METHODS: Human hepatocellular carcinoma (HepG2) cells and C57BL/6J mice were subjected to pharmacologic ER stress and the expression of AP-1-associated genes and proteins was assessed. To determine the role of MAPK signaling in ER stress-induced AP-1 activation, ER stress was induced in JNK- and ERK-inhibited HepG2 cells. RESULTS: Induction of ER stress promoted the activation of both Jun- and Fos-related genes and proteins of the AP-1 complex in HepG2 cells and murine liver. Inhibition of ERK phosphorylation in HepG2 cells completely prevented ER stress-induced activation of the fos-related components of AP-1 whereas activation of Jun-related components was only partially attenuated. Conversely, inhibition of JNK phosphorylation in HepG2 cells reduced ER stress-induced activation of Jun-related components but did not prevent activation of fos-related components. CONCLUSIONS: ER stress activates the hepatic AP-1 complex via MAPK-dependent signaling pathways. ER stress-induced activation of Fos-related components is dependent primarily on ERK activation whereas ER stress-induced activation of Jun-related components is dependent primarily on JNK activation, although there is interplay between these regulatory pathways. These data implicate a novel signaling pathway by which sustained ER stress, as observed in many chronic liver diseases, may promote hepatic carcinogenesis. Public Library of Science 2014-07-31 /pmc/articles/PMC4117566/ /pubmed/25077945 http://dx.doi.org/10.1371/journal.pone.0103828 Text en © 2014 Olivares et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Olivares, Shantel Green, Richard M. Henkel, Anne S. Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways |
title | Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways |
title_full | Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways |
title_fullStr | Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways |
title_full_unstemmed | Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways |
title_short | Endoplasmic Reticulum Stress Activates the Hepatic Activator Protein 1 Complex via Mitogen Activated Protein Kinase-Dependent Signaling Pathways |
title_sort | endoplasmic reticulum stress activates the hepatic activator protein 1 complex via mitogen activated protein kinase-dependent signaling pathways |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117566/ https://www.ncbi.nlm.nih.gov/pubmed/25077945 http://dx.doi.org/10.1371/journal.pone.0103828 |
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