期刊
BIOMEDICINES
卷 6, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/biomedicines6020058
关键词
ER stress; cancer; infection; inflammation; unfolded protein response; NF-kappa B; I kappa B alpha; thapsigargin
资金
- Deutsche Forschungsgemeinschaft [SCHM 1417/8-3, SFB/TRR81, SFB1021, SFB1213, Kr1143/7-3, KR1143/9-1 (KLIFO309), TRR81/2]
- Deutsche Krebshilfe [111447]
- IMPRS program of the Max-Planck Society
- Excellence Cluster Cardio-Pulmonary System (ECCPS)
- LOEWE/UGMLC program
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-kappa B) 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-B 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, ATF6 alpha and the five NF-kappa B 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-kappa B (I kappa B)alpha degradation pathway. These data show that the UPR affects this major control point of NF-kappa B activation through several mechanisms. Taken together, available evidence indicates that the UPR and NF-kappa B interact at multiple levels. This crosstalk provides ample opportunities to fine-tune cellular stress responses and could also be exploited therapeutically in the future.
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