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Journal article
Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex
Endocrinology and metabolism (Seoul), Vol.29(3), pp.379-387
09/01/2014
PMID: 25309798
Abstract
Background: In mammals, the CLOCK/BMAL1 heterodimer is a key transcription factor complex that drives the cyclic expression of clock-controlled genes involved in various physiological functions and behavioral consequences. Recently, a growing number of studies have reported a molecular link between the circadian clock and metabolism. In the present study, we explored the regulatory effects of SIRTUIN1 (SIRT1), an NAD+-dependent deacetylase, on CLOCK/BMAL1-mediated clock gene expression.
Methods: To investigate the interaction between SIRT1 and CLOCK/BMAL1, we conducted bimolecular fluorescence complementation (BiFC) analyses supplemented with immunocytochemistry assays. BiFC experiments employing deletion-specific mutants of BMAL1 were used to elucidate the specific domains that are necessary for the SIRT1-BMAL1 interaction. Additionally, luciferase reporter assays were used to delineate the effects of SIRT1 on circadian gene expression.
Results: BiFC analysis revealed that SIRT1 interacted with both CLOCK and BMAL1 in most cell nuclei. As revealed by BiFC assays using various BMAL1 deletion mutants, the PAS-B domain of BMAL1 was essential for interaction with SIRT1. Activation of SIRT1 with resveratrol did not exert any significant change on the interaction with the CLOCK/BMAL1 complex. However, promoter analysis using Per1-Luc and Ebox-Luc reporters showed that SIRT1 significantly downregulated both promoter activities. This inhibitory effect was intensified by treatment with resveratrol, indicating a role for SIRT1 and its activator in CLOCK/BMAL1-mediated transcription of clock genes.
Conclusion: These results suggest that SIRT1 may form a regulatory complex with CLOCK/BMAL1 that represses clock gene expression, probably via deacetylase activity.
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Details
- Title
- Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex
- Creators
- Insung Park - Seoul National UniversityYool Lee - Seoul National UniversityHee-Dae Kim - Seoul National UniversityKyungjin Kim - Daegu Gyeongbuk Institute of Science and Technology
- Publication Details
- Endocrinology and metabolism (Seoul), Vol.29(3), pp.379-387
- Academic Unit
- Elson S. Floyd College of Medicine
- Publisher
- Korean Endocrine Soc
- Number of pages
- 9
- Grant note
- 2009K001287 / Korea Ministry of Education, Science, and Technology (MEST) through the Brain Research Center of the 21st Century Frontier Research Program 10Z20130012420 / BK21 Plus program through the National Research Foundation of Korea - Ministry of Education
- Identifiers
- 99901132535201842
- Language
- English
- Resource Type
- Journal article