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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Mamrosh, JL; Lee, JM; Wagner, M; Stambrook, PJ; Whitby, RJ; Sifers, RN; Wu, SP; Tsai, MJ; Demayo, FJ; Moore, DD.
Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution.
Elife. 2014; 3(6):e01694-e01694 Doi: 10.7554/eLife.01694 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Wagner Martin
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Abstract:
Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress. DOI: http://dx.doi.org/10.7554/eLife.01694.001.
Find related publications in this database (using NLM MeSH Indexing)
Activating Transcription Factor 2 - genetics
Animals -
Cell Death -
Cells, Cultured -
Endoplasmic Reticulum Stress -
Hepatocytes - physiology
Liver - physiopathology
Mice -
Mice, Knockout -
Protein-Serine-Threonine Kinases - genetics
Receptors, Cytoplasmic and Nuclear - genetics

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