期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 461, 期 C, 页码 178-187出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2017.09.012
关键词
Glucocorticoids; Longevity; Protein-protein interaction; Transcriptome
资金
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [Z01 HD008732-05 HNT]
- Sidra Medical and Research Center
- Asahikawa Medical University
Glucocorticoids have strong effects on diverse human activities through the glucocorticoid receptor (GR). Sirtuin 1 (SIRT1) is a NAD(+)-dependent histone deacetylase and promotes longevity by influencing intermediary metabolism and other regulatory activities including mitochondrial function. In this study, we examined the effects of SIRT1 on GR-mediated transcriptional activity. We found that SIRT1 enhanced GR-induced transcriptional activity on endogenous and exogenous glucocorticoid-responsive genes, whereas knockdown of SIRT1 attenuated it. This effect of SIRT1 was independent to its deacetylase activity, as the SIRT1 mutant defective in this activity (H363Y) enhanced GR transcriptional activity, and the compounds inhibiting or activating the SIRT1 deacetylase activity did not influence it. RNA-seq analysis revealed that SIRT1 knockdown influenced similar to 30% of the glucocorticoid-responsive transcriptome for most of which it acted as an enhancer for positive/negative effects of this hormone. SIRT1 physically interacted with GR, and was attracted to GR-bound glucocorticoid response elements in a glucocorticoid-dependent fashion. SIRT1 cooperatively activated GR transcriptional activity with the PPAR gamma coactivator-1 alpha also in its deacetylase activity-independent fashion. Thus, SIRT1 is a novel transcriptional enhancer of GR-induced transcriptional activity possibly by functioning as a scaffold for the transcriptional complex formed on GR. Published by Elsevier Ireland Ltd.
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