Repression of the Promoter Activity Mediated by Liver Receptor Homolog-1 through Interaction with Ku Proteins
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概要
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Nuclear receptor liver receptor homolog-1 (LRH-1; NR5A2) plays a crucial role in the homeostasis of bile acids and cholesterol by controlling the expression of genes central to bile acid synthesis and efflux, reverse cholesterol transport, and high density lipoprotein-remodeling. However, the molecular mechanisms that modulate the transactivation activity of LRH-1 remain unclear. It is proposed that LRH-1s activity is regulated by post-modifications, the binding of small heterodimer partner (SHP), or the binding of coregulators. To search for cofactors that regulate the transactivation activity of LRH-1, we performed a pull-down assay using glutathione Stransferase (GST) fused to the N-terminal portion of LRH-1 and nuclear extracts from HeLa cells, and identified Ku proteins as interacting proteins with LRH-1. We also found that Ku proteins associate with LRH-1 through its DNA-binding domain and hinge region. Luciferase reporter assays revealed that Ku proteins repressed the SHP promoter activity mediated by LRH-1. Furthermore, Ku proteins suppressed the coactivating effect of peroxisome proliferator-activated receptor (PPAR) coactivator-1α (PGC-1α), an LRH-1 coactivator, on the LRH-1-mediated SHP promoter activity. Previously, we showed that Ku proteins interacted with nuclear receptor farnesoid X receptor (FXR; NR1H4) and decreased the expression of its target gene. In this study, we demonstrated that Ku proteins also interacted with not only LRH-1 but various nuclear receptors, such as the estrogen receptor, PPAR, and Rev-erb. Ku proteins may function as corepressors for various nuclear receptors including LRH-1.
著者
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OSADA Shigehiro
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Osada Shigehiro
Department Of Molecular Biology Graduate School Of Pharmaceutical Sciences Nagoya City University
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Nishizuka Makoto
Department Of Molecular Biology Graduate School Of Pharmaceutical Sciences Nagoya City University
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Imagawa Masayoshi
Department Of Environmental Biochemistry Faculty Of Pharmaceutical Sciences Osaka University
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Suzuki Eiko
Department Of Developmental Medical Sciences Institute Of International Health Graduate School Of Me
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Ohno Masae
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Komakine Jun
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Osada Shigehiro
Department of Environmental Biochemistry, Faculty of Pharmaceutical Sciences, Osaka University
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