• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.155-162
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• 2018

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant-like effects in animal models of depression. However, the molecular mechanisms underlying these behavioral actions remain unknown. Here, we demonstrate that CPP rapidly stimulates histone deacetylase (HDAC) 5 phosphorylation and nuclear export in rat hippocampal neurons. These effects are accompanied by calcium/calmodulin kinase II (CaMKII) and protein kinase D (PKD) phosphorylation. Behavioral experiments revealed that viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant effects of CPP in stressed animals. Taken together, our results imply that CPP acts via HDAC5 and suggest that HDAC5 is a common regulator contributing to the antidepressant actions of NMDA receptor antagonists such as CPP.

• Molecules and Cells
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• 제28권3호
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• pp.149-154
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• 2009

Faithful and accurate replication of the DNA molecule is essential for eukaryote organisms. Nonetheless, in the last few years it has become evident that inheritance of the chromatin states associated with different regions of the genome is as important as the faithful inheritance of the DNA sequence itself. Such chromatin states are determined by a multitude of factors that act to modify not only the DNA molecule, but also the histone proteins associated with it. For instance, histones can be posttranslationally modified, and it is well established that these posttranslational marks are involved in several essential nuclear processes such as transcription and DNA repair. However, recent evidence indicates that posttranslational modifications of histones might be relevant during DNA replication. Hence, the aim of this review is to describe the most recent publications related to the role of histone posttranslational modifications during DNA replication.

• Molecules and Cells
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• 제40권7호
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• pp.485-494
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• 2017

Oleanolic acid (OA) has neurotrophic effects on neurons, although its use as a neurological drug requires further research. In the present study, we investigated the effects of OA and OA derivatives on the neuronal differentiation of rat hippocampal neural progenitor cells. In addition, we investigated whether the class II histone deacetylase (HDAC) 5 mediates the gene expression induced by OA. We found that OA and OA derivatives induced the formation of neurite spines and the expression of synapse-related molecules. OA and OA derivatives stimulated HDAC5 phosphorylation, and concurrently the nuclear export of HDCA5 and the expression of HDAC5 target genes, indicating that OA and OA derivatives induce neural differentiation and synapse formation via a pathway that involves HDAC5 phosphorylation.

• BMB Reports
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• 제41권4호
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• pp.310-315
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• 2008

BirA ligase is a prokaryotic ortholog of holocarboxylase synthetase (HCS) that can biotinylate proteins. This study tested the hypothesis that BirA ligase catalyzes the biotinylation of eukaryotic histones. If so, this would mean that recombinant BirA ligase is a useful surrogate for HCS in studies of histone biotinylation. The biological activity of recombinant BirA ligase was confirmed by enzymatic biotinylation of p67. In particular, it was found that BirA ligase biotinylated both calf thymus histone H1 and human bulk histone extracts. Incubation of recombinant BirA ligase with H3-based synthetic peptides showed that lysines 4, 9, 18, and 23 in histone H3 are the targets for the biotinylation by BirA ligase. Modification of the peptides (e.g., serine phosphorylation) affected the subsequent biotinylation by BirA ligase, suggesting crosstalk between modifications. In conclusion, this study suggests that prokaryotic BirA ligase is a promiscuous enzyme and biotinylates eukaryotic histones. Moreover the biotinylation of histones by BirA ligase is consistent with the proposed role of human HCS in chromatin.

• Biomolecules & Therapeutics
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• 제22권4호
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• pp.308-313
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• 2014

Activator protein-1 (AP-1) is an inducible transcription factor that contributes to the generation of chronic inflammation in response to oxidative and electrophilic stress. Previous studies have demonstrated that the PI3K/Akt1 pathway plays an important role in the transcriptional regulation of AP-1 expression. Although the histone post-translational modifications (PTMs) are assumed to affect the AP-1 transcriptional regulation by the PI3K/Akt pathway, the detailed mechanisms are completely unknown. In the present study, we show that heterochromatin 1 gamma ($HP1{\gamma}$) plays a negative role in TPA-induced c-Jun and c-Fos expression. We show that TPA-induced Akt1 directly phosphorylates $HP1{\gamma}$, abrogates its suppressive function and increases the interaction between histone H3 and 14-3-$3{\varepsilon}$. Collectively, these our data illustrate that the activation of PI3K/Akt pathway may play a permissive role in the recruitment of histone readers or other coactivators on the chromatin, thereby affecting the degree of AP-1 transcription.

• BMB Reports
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• 제48권3호
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• pp.131-138
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• 2015

Cardiac hypertrophy is a form of global remodeling, although the initial step seems to be an adaptation to increased hemodynamic demands. The characteristics of cardiac hypertrophy include the functional reactivation of the arrested fetal gene program, where histone deacetylases (HDACs) are closely linked in the development of the process. To date, mammalian HDACs are divided into four classes: I, II, III, and IV. By structural similarities, class II HDACs are then subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular function and regulation of class IIa HDACs depend largely on the phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take place primarily in the nucleus. In response to stresses, posttranslational modification (PTM) processes, dynamic modifications after the translation of proteins, are involved in the regulation of the activities of those hypertrophy-related HDACs. In this article, we briefly review 1) the activation of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and its implications in the regulation of HDAC2 activity.

• 통합자연과학논문집
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• 제12권4호
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• pp.133-141
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• 2019

Mesenchymal stem cells (MSCs) are known to differentiate into multiple lineages, making neurogenic differentiation an important target in the clinical field. In the present study, we induced the neurogenic differentiation of cells using histone deacetylase (HDAC) inhibitors and studied their mechanisms for further differentiation in vitro. We treated cells with the HDAC inhibitors, MS-275 and NaB; and found that the cells had neuron-like features such as distinct bipolar or multipolar morphologies with branched processes. The mRNA expressions encoding for NEFL, MAP2, TUJ1, OLIG2, and SYT was significantly increased following HDAC inhibitors treatment compared to without HDAC inhibitors; high protein levels of MAP2 and Tuj1 were detected by immunofluorescence staining. We examined the mechanisms of differentiation and found that the Wnt signaling pathway and downstream mitogen-activate protein kinase were involved in neurogenic differentiation of MSCs. Importantly, Wnt4, Wnt5a/b, and Wnt11 protein levels were highly increased after treatment with NaB; signals were activated through the regulation of Dvl2 and Dvl3. Interestingly, NaB treatment increased the levels of JNK and upregulated JNK phosphorylation. After MS-275 treatment, Wnt protein levels were decreased and GSK-3β was phosphorylated. In this cell, HDAC inhibitors controlled the non-canonical Wnt expression by activating JNK phosphorylation and the canonical Wnt signaling by targeting GSK-3β.

• BMB Reports
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• 제55권6호
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• pp.287-292
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• 2022

The acute response to hypoxia is mainly driven by hypoxia-inducible factors, but their effects gradually subside with time. Hypoxia-specific histone modifications may be important for the stable maintenance of long-term adaptation to hypoxia. However, little is known about the molecular mechanisms underlying the dynamic alterations of histones under hypoxic conditions. We found that the phosphorylation of histone H3 at Ser-10 (H3S10) was noticeably attenuated after hypoxic challenge, which was mediated by the inhibition of aurora kinase B (AURKB). To understand the role of AURKB in epigenetic regulation, DNA microarray and transcription factor binding site analyses combined with proteomics analysis were performed. Under normoxia, phosphorylated AURKB, in concert with the repressor element-1 silencing transcription factor (REST), phosphorylates H3S10, which allows the AURKB-REST complex to access the MDM2 proto-oncogene. REST then acts as a transcriptional repressor of MDM2 and downregulates its expression. Under hypoxia, AURKB is dephosphorylated and the AURKB-REST complex fails to access MDM2, leading to the upregulation of its expression. In this study, we present a case of hypoxia-specific epigenetic regulation of the oxygen-sensitive AURKB signaling pathway. To better understand the cellular adaptation to hypoxia, it is worthwhile to further investigate the epigenetic regulation of genes under hypoxic conditions.

• BMB Reports
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• 제49권8호
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• pp.401-402
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• 2016

S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression. S6K1-mediated suppression of Wnt genes facilitates adipogenic differentiation through the expression of adipogenic transcription factors PPARγ and Cebpa. White adipose tissues from S6K1-deficient mice consistently exhibit marked reduction in H2BS36 phosphorylation (H2BS36p) and H3K27 trimethylation (H3K27me3), leading to enhanced expression of Wnt genes. In addition, expression levels of H2BS36p and H3K27me3 are highly elevated in white adipose tissues from mice fed on high-fat diet or from obese humans. These findings describe a novel role of S6K1 as a transcriptional regulator controlling an epigenetic network initiated by phosphorylation of H2B and trimethylation of H3, thus shutting off Wnt gene expression in early adipogenesis.

• Applied Biological Chemistry
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• 제23권1호
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• pp.23-30
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• 1980

분리된 간세포핵을 $[{\gamma}-32P]$ ATP와 5분간 $37^{\circ}C$ 에서 배양한 뒤 Chromatin 단백질의 32P labelling을 관찰했다. 32P labelling의 pattern을 48시간 단식상태 및 48시간 굶긴 쥐에게 탄수화물 농도가 높은 먹이를 준 다음 12시간 경과한 쥐와 streptozotocin으로 당뇨병을 유발시킨 쥐에 인슈린을 투여한 뒤 6시간 경과한 쥐의 세포핵으로부터 추출한 핵단백질을 sodium dodecyl sulfate 전기영동으로 조사하였다. 48시간 굶은 쥐의 간세포핵의 경우에서는 0.14M NaCl에 용해하는 단백질의 인산화 수준은 정상적으로 먹이를 준 쥐에 비하여 분자량이 $41,000{\sim}200,000$ daltons 사이의 단백질에서는 감소되었다. 48시간 굶긴 쥐에서 본 인산화 감소를 12시간 내에 역전시켜 정상적으로 먹이를 준 쥐에서 관찰한 인산화 수준에까지 끌어 올렸다. 폐놀용해성 핵단백질의 인산화 수준은 분자량이 59,000 daltons보다 큰 5단백질에서 48시간 굶긴 쥐에서 정상적으로 먹이를 준 쥐의 결과와 비교하였을 때 낮았다. 아울러 단식은 히스톤의 인산화도 감소되었다. Streptozotocin으로 당뇨병을 유발시킨 쥐에게 인슈린 주사를 준 다음 6시간 경과한 쥐의 인산화 수준은 0.14M NaCl 용해성 핵단백질중 분자량이 130,000 daltons 단백질과 페놀용해성 단백질의 경우에는 155,000 daltons 단백질에서 인슈린을 주지 않은 당뇨병을 가진 쥐와 비교하였을 때 증가를 보였다. 그러나 히스톤의 인산화 수준에는 큰 변화가 나타나지 않았다. 여기에 나타난 실험결과가 0,14M NaCl 용해성 핵단백질과 $H_1$ 히스톤의 인산화와 탈인산화가 다른 핵단백질에 선행해서 일어난다는 가능성을 시사해 주고 있다. 그리고 인슈린 신호가 핵단백질의 인산화와 관련이 있는 반면 그루카곤(glucagon)은 핵단백질의 탈인산화와 상관관계가 있음은 매우 흥미있는 사실이다.