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Biomedicines 2018, 6(2), 58; https://doi.org/10.3390/biomedicines6020058

The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection

1
Institute of Biochemistry, Justus Liebig University Giessen, D-35392 Giessen, Germany
2
Rudolf-Buchheim-Institute of Pharmacology, Justus Liebig University Giessen, D-35392 Giessen, Germany
3
Rudolf-Buchheim-Institute of Pharmacology, Universities of Giessen and Marburg Lung Center (UGMLC), Schubertstrasse 81, D-35392 Giessen, Germany
Member of the German Center for Lung Research.
*
Author to whom correspondence should be addressed.
Received: 21 April 2018 / Revised: 8 May 2018 / Accepted: 11 May 2018 / Published: 16 May 2018
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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Abstract

Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds but also by cytokines, toll-like receptor ligands, nucleic acids, lipids, bacteria and viruses. Despite representing unique signaling cascades, new data indicate that the UPR and NF-κB pathways converge within the nucleus through ten major transcription factors (TFs), namely activating transcription factor (ATF)4, ATF3, CCAAT/enhancer-binding protein (CEBP) homologous protein (CHOP), X-box-binding protein (XBP)1, ATF6α and the five NF-κB subunits. The combinatorial occupancy of numerous genomic regions (enhancers and promoters) coordinates the transcriptional activation or repression of hundreds of genes that collectively determine the balance between metabolic and inflammatory phenotypes and the extent of apoptosis and autophagy or repair of cell damage and survival. Here, we also discuss results from genetic experiments and chemical activators of endoplasmic reticulum (ER) stress that suggest a link to the cytosolic inhibitor of NF-κB (IκB)α degradation pathway. These data show that the UPR affects this major control point of NF-κB activation through several mechanisms. Taken together, available evidence indicates that the UPR and NF-κB interact at multiple levels. This crosstalk provides ample opportunities to fine-tune cellular stress responses and could also be exploited therapeutically in the future. View Full-Text
Keywords: ER stress; cancer; infection; inflammation; unfolded protein response; NF-κB; IκBα; thapsigargin ER stress; cancer; infection; inflammation; unfolded protein response; NF-κB; IκBα; thapsigargin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Schmitz, M.L.; Shaban, M.S.; Albert, B.V.; Gökçen, A.; Kracht, M. The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection. Biomedicines 2018, 6, 58.

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