Endocrinology and Metabolism

Original Articles

Sumoylation of Hes6 Regulates Protein Degradation and Hes1-Mediated Transcription: Jiwon Lee, Sung Kook Chun, Gi Hoon Son, Kyungjin Kim; Endocrinol Metab. 2015;30(3):381-388. Published online May 18, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.3.381

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Background

Hes6 is a transcriptional regulator that induces transcriptional activation by binding to transcription repressor Hes1 and suppressing its activity. Hes6 is controlled by the ubiquitin-proteosome-mediated degradation system. Here we investigated the sumoylation of Hes6 and its functional role in its rhythmic expression.

Methods

Hes6, SUMO, and ubiquitin were transfected into HeLa cells and the expression pattern was observed by Western blot and immunoprecipitation. To confirm the effect of sumoylation on the rhythmic expression of Hes6, we generated mouse Hes6 promoter-driven GFP-Hes6 fusion constructs and expressed these constructs in NIH 3T3 cells.

Results

Overexpression of SUMO led to sumoylation of Hes6 at both lysine 27 and 30. Protein stability of Hes6 was decreased by sumoylation. Moreover, expression of a Hes6 sumoylation-defective mutant, the 2KR (K27/30R) mutant, or co-expression of SUMO protease SUSP1 with native Hes6, strongly reduced ubiquitination. In addition, sumoylation was associated with both the rhythmic expression and transcriptional regulation of Hes6. Wild type Hes6 showed oscillatory expression with about 2-hour periodicity, whereas the 2KR mutant displayed a longer period. Furthermore, sumoylation of Hes6 derepressed Hes1-induced transcriptional repression.

Conclusion

Hes6 sumoylation plays an important role in the regulation of its stability and Hes1-mediated transcription. These results suggest that sumoylation may be crucial for rhythmic expression of Hes6 and downstream target genes.

Citations

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Identification of genes with oscillatory expression in glioblastoma: the paradigm of SOX2
Richard Zhiming Fu, Oliver Cottrell, Luisa Cutillo, Andrew Rowntree, Zsolt Zador, Heiko Wurdak, Nancy Papalopulu, Elli Marinopoulou
Scientific Reports.2024;[Epub] CrossRef

Effect of Mefloquine, a Gap Junction Blocker, on Circadian Period2 Gene Oscillation in the Mouse Suprachiasmatic Nucleus Ex Vivo: Jinmi Koo, Han Kyoung Choe, Hee-Dae Kim, Sung Kook Chun, Gi Hoon Son, Kyungjin Kim; Endocrinol Metab. 2015;30(3):361-370. Published online December 9, 2014; DOI: https://doi.org/10.3803/EnM.2015.30.3.361

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Background

In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions.

Methods

We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system.

Results

Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms.

Conclusion

These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock.

Citations

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High-Throughput Screening Assay for Detecting Drug-Induced Changes in Synchronized Neuronal Oscillations and Potential Seizure Risk Based on Ca2+ Fluorescence Measurements in Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neuronal 2D and 3D Cultures
Hua-Rong Lu, Manabu Seo, Mohamed Kreir, Tetsuya Tanaka, Rie Yamoto, Cristina Altrocchi, Karel van Ammel, Fetene Tekle, Ly Pham, Xiang Yao, Ard Teisman, David J. Gallacher
Cells.2023; 12(6): 958. CrossRef
The role of gap junctions in cell death and neuromodulation in the retina
Gergely Szarka, Márton Balogh, ÁdámJ Tengölics, Alma Ganczer, Béla Völgyi, Tamás Kovács-Öller
Neural Regeneration Research.2021; 16(10): 1911. CrossRef
Programming effects of maternal stress on the circadian system of adult offspring
Seongsik Yun, Eun Jeong Lee, Han Kyoung Choe, Gi Hoon Son, Kyungjin Kim, Sooyoung Chung
Experimental & Molecular Medicine.2020; 52(3): 473. CrossRef
Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization
Doyeon Kim, Sangwon Jang, Jeongah Kim, Inah Park, Kyojin Ku, Mijung Choi, Sukwon Lee, Won Do Heo, Gi Hoon Son, Han Kyoung Choe, Kyungjin Kim
Neuroendocrinology.2020; 110(11-12): 1010. CrossRef

Obesity and Metabolism
Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex: Insung Park, Yool Lee, Hee-Dae Kim, Kyungjin Kim; Endocrinol Metab. 2014;29(3):379-387. Published online September 25, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.3.379

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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.

Citations

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Preface

2013 Preface: On the Occasion of Publishing the Endocrinology and Metabolism in English: Kyungjin Kim, Moo-Il Kang; Endocrinol Metab. 2013;28(1):1-2. Published online March 25, 2013; DOI: https://doi.org/10.3803/EnM.2013.28.1.1

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Citations

Citations to this article as recorded by

Contribution of subcutaneous abdominal fat on ultrasonography to carotid atherosclerosis in patients with type 2 diabetes mellitus
Chan-Hee Jung, Bo-Yeon Kim, Kyu-Jin Kim, Sang-Hee Jung, Chul-Hee Kim, Sung-Koo Kang, Ji-Oh Mok
Cardiovascular Diabetology.2014;[Epub] CrossRef

Review Article

Biological Rhythms and Neuroendocrine Systems.: Gi Hoon Son, Sooyoung Chung, Kyungjin Kim; Endocrinol Metab. 2010;25(4):249-257. Published online December 1, 2010; DOI: https://doi.org/10.3803/EnM.2010.25.4.249

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Abstract PDF

No abstract available.

Citations

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Effect of Mefloquine, a Gap Junction Blocker, on Circadian Period2 Gene Oscillation in the Mouse Suprachiasmatic NucleusEx Vivo
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Endocrinology and Metabolism.2015; 30(3): 361. CrossRef

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