• The Korean Journal of Physiology and Pharmacology
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• v.17 no.4
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• pp.315-320
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• 2013

Here, we show that radicicol, a fungal antibiotic, resulted in marked inhibition of inducible nitric oxide synthase (iNOS) transcription by the pancreatic beta cell line MIN6N8a in response to cytokine mixture (CM: TNF-${\alpha}$, IFN-${\gamma}$, and IL-$1{\beta}$). Treatment of MIN6N8a cells with radicicol inhibited CM-stimulated activation of NF-${\kappa}B$/Rel, which plays a critical role in iNOS transcription, in a dose-related manner. Nitrite production in the presence of PD98059, a specific inhibitor of the extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) pathway, was dramatically diminished, suggesting that the ERK1/2 pathway is involved in CM-induced iNOS expression. In contrast, SB203580, a specific inhibitor of p38, had no effect on nitrite generation. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking ERK1/2 signaling. Due to the critical role that NO release plays in mediating destruction of pancreatic beta cells, the inhibitory effects of radicicol on iNOS expression suggest that radicicol may represent a useful anti-diabetic activity.

• BMB Reports
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• v.49 no.8
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• pp.437-442
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• 2016

We aimed to study the role of protein L-isoaspartyl methyltransferase (PIMT) in neuronal differentiation using basic fibroblast growth factor (bFGF)-induced neuronal differentiation, characterized by cell-body shrinkage, long neurite outgrowth, and expression of neuronal differentiation markers light and medium neurofilaments (NF). The bFGF-mediated neuronal differentiation of PC12 cells was induced through activation of mitogen-activated protein kinase (MAPK) signaling molecules [MAPK kinase 1/2 (MEK1/2), extracellular signal-regulated kinase 1/2 (ERK1/2), and p90RSK], and phosphatidylinositide 3-kinase (PI3K)/Akt signaling molecules PI3Kp110β, PI3Kp110γ, Akt, and mTOR. Inhibitors (adenosine dialdehyde and S-adenosylhomocysteine) of protein methylation suppressed bFGF-mediated neuronal differentiation of PC12 cells. PIMT-eficiency caused by PIMT-specific siRNA inhibited neuronal differentiation of PC12 cells by suppressing phosphorylation of MEK1/2 and ERK1/2 in the MAPK signaling pathway and Akt and mTOR in the PI3K/Akt signaling pathway. Therefore, these results suggested that PIMT was critical for bFGF-mediated neuronal differentiation of PC12 cells and regulated the MAPK and Akt signaling pathways.

• The Plant Pathology Journal
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• v.21 no.1
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• pp.21-26
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• 2005

Homeotic proteins have pivotal roles during the development of both plant and animals. Many homeotic proteins exert control over cell fate in cells where their genes are not expressed, i.e., in a non-cell autonomous manner. Cell-to-cell communication, which delivers critical information for position-dependent specification of cell fate, is an essential biological process in multicellular organisms. In plants, there are two pathways for intercellular communication that have been identified: the ligand/receptor-mediated apoplastic pathway and the plasmodesmata-mediated symplasmic pathway. Regulatory proteins and RNAs traffic symplasmically via plasmodesmata and play a critical role in intercellular communication. Thus, the non-cell autonomous function of homeotic proteins can be explained by the recent discovery of cell-to-cell trafficking of proteins or RNAs. This article specifically focuses on understanding the intercellular movement of homeodomain proteins, a family of homeotic proteins.

• Molecules and Cells
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• v.45 no.6
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• pp.413-424
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• 2022

Suppressor of mothers against decapentaplegic homolog (SMAD) 4 is a pluripotent signaling mediator that regulates myriad cellular functions, including cell growth, cell division, angiogenesis, apoptosis, cell invasion, and metastasis, through transforming growth factor β (TGF-β)-dependent and -independent pathways. SMAD4 is a critical modulator in signal transduction and functions primarily as a transcription factor or cofactor. Apart from being a DNA-binding factor, the additional SMAD4 mechanisms in tumor suppression remain elusive. We previously identified methyl malonyl aciduria cobalamin deficiency B type (MMAB) as a critical SMAD4 binding protein using a proto array analysis. This study confirmed the interaction between SMAD4 and MMAB using bimolecular fluorescence complementation (BiFC) assay, proximity ligation assay (PLA), and conventional immunoprecipitation. We found that transient SMAD4 overexpression down-regulates MMAB expression via a proteasome-dependent pathway. SMAD4-MMAB interaction was independent of TGF-β signaling. Finally, we determined the effect of MMAB downregulation on cancer cells. siRNA-mediated knockdown of MMAB affected cancer cell metabolism in HeLa cells by decreasing ATP production and glucose consumption as well as inducing apoptosis. These findings suggest that SMAD4 controls cancer cell metabolism by regulating MMAB.

• Molecules and Cells
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• v.26 no.2
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• pp.200-205
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• 2008

The mitogen-activated protein kinase (MAPK) signaling pathway is activated in response to extracellular stimuli and regulates various activities in eukaryotic cells. Following exposure to stimuli, MAPK is known to be activated via dual phosphorylation at a conserved TxY motif in the activation loop; both threonine and tyrosine residues are phosphorylated by an upstream kinase. However, the mechanism underlying dual phosphorylation is not clearly understood. In the budding yeast Saccharomyces cerevisiae, the Hog1 MAPK mediates the high-osmolarity glycerol (HOG) signaling pathway. Tandem mass spectrometry and phosphospecific immunoblotting were performed to quantitatively monitor the dynamic changes occurring in the phosphorylation status of the TxY motif of Hog1 on exposure to osmotic stress. The results of our study suggest that the tyrosine residue is preferentially and dynamically phosphorylated following stimulation, and this in turn leads to the dual phosphorylation. The tyrosine residue was hyperphosphorylated in the absence of a threonine residue; this result suggests that the threonine residue is critical for the control of signaling noise and adaptation to osmotic stress.

• Journal of Ecology and Environment
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• v.31 no.2
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• pp.89-95
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• 2008

Sensing the approach of a predator is critical to the survival of prey, especially when the prey has no choice but to escape at a precisely timed moment. Escape behavior has been approached from both proximate and ultimate perspectives. On the proximate level, empirical research about electrophysiological mechanisms for detecting predators has focused on vision, an important modality that helps prey to sense approaching danger. Studies of looming-sensitive neurons in locusts are a good example of how the selective sensitivity of nervous systems towards specific targets, especially approaching objects, has been understood and realistically modeled in software and robotic systems. On the ultimate level, general optimality models have provided an evolutionary framework by considering costs and benefits of visually elicited escape responses. A recent paper showed how neural network models can be used to understand the evolution of visually mediated antipredatory behaviors. We discuss this new trend towards integration of these relatively disparate approaches, the proximate and the ultimate perspectives, for understanding of the evolution of behavior of predators and prey. Focusing on one of the best-studied escape pathway models, the Orthopteran LGMD/DCMD pathway, we discuss how ultimate-level optimality modeling can be integrated with proximate-level studies of escape behaviors in animals.

• Korean Journal of Environmental Biology
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• v.26 no.4
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• pp.377-384
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• 2008

A cell is the product of a long period of evolution and can be represented as an optimized system (homeostasis). Stimuli from the outside environment are received by sensory apparatus on the surface of the cell and transferred through complicated pathways and eventually regulate gene expression. These signals affect cell physiology, growth, and development, and the interaction among genes in the signal transduction pathway is a critical part of the regulation. In this study, the interactions of deletion mutants and overexpression of the extracopies of the genes were used to understand their relationships to each other. Also, green fluorescent protein (GFP reporter gene) was fused to the regulatory genes to elucidate their interactions. Cooverexpression of the two genes in extracopy plasmids suggested that patS acts at the downstream of hetR in the regulatory network. The experiments using gfp fusion in different genetic background cells also indicated the epistasis relationships between the two genes. A model describing the regulatory network that controls cell development is presented.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.57-62
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• 2012

Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8), a ubiquitin-like protein, mainly functions through covalent ligation to cullin proteins. Conjugation of NEDD8 with cullins can promote ubiquitination, which plays a critical role in the degradation of many proteins. UBA3 is the subunit of NEDD8-activating enzyme which is one of the keys for NEDD8 linkage to cullin proteins. Previous research showed NEDD8 conjugation to be up-regulated in highly proliferative cell lines. In the present study, up-regulated NEDD8 conjugation was observed in melanoma cell lines by Western blot analysis. After down-regulation with a RNAi to UBA3, proliferation of M14 was suppressed in vitro and in vivo. In conclusion, up-regulated NEDD8 conjugation may be involved in the development of melanoma. Interference in this pathway might offera promising method for melanoma therapy.

• CELLMED
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• v.8 no.3
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• pp.13.1-13.8
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• 2018

In the field of osteoporosis, there has been growing interest in anabolic agents that enhance bone formation. The purpose of this study was to examine the effects of NNMBS 246 osteoblastic differentiation with associated signaling pathways. NNMBS 246 markedly increased alkaline phosphatase (ALP) activity and calcium nodule formation. Stimulation with NNMBS 246 not only increased the differentiation markers (ALP, OPN, OCN) level and transcription markers (RUNX2, Osterix) mRNA expression but also upregulated the ECM molecules and OPG mRNA expression. Treatments of NNMBS 246 downregulated MMPs (MMP-1, MMP-2, MMP-9), but RANKL mRNA expression. Furthermore, NNMBS 246 activated osteoblastic differentiation markers and formed calcium nodules in human periodontal ligament cells (hPDLCs) and cementoblast cells. NNMBS 246 induced phosphorylation of MAPKs, Akt, nuclear p65 and IkB-${\alpha}$. BMP-2/Smad and ${\beta}$-catenin signaling pathways were activated by NNMBS 246. Sirtinol (SIRT1 inhibitor) inhibited NNMBS 246-induced osteoblastic differentiation markers mRNA expression. These results suggested that NNMBS 246 has the potential to enhance osteoblastogenesis probably through the activation of BMP/Smad and ${\beta}$-catenin signal pathways, and SIRT1 plays as critical mediator in bone anabolic effect of NNMBS 246.

• Development and Reproduction
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• v.17 no.2
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• pp.141-147
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• 2013

Keeping the intact germinal vesicle (GV) is essential for maintaining the capacity of mammals including human. It is maintained by very complex procedures along with folliculogenesis and is a critical step for getting competent oocyte. So far, a few mechanisms involved in folliculogenesis are known but GV arrest mechanisms are largely unrevealed. Cyclic AMP, a adenosine derived substance, have been used as inhibitor of germinal vesicle breakdown as a putative oocyte maturation inhibitor. In this study, we examined the potency of adenosine as GV maintainer and a possible signaling mediator for that. A1, A2b, and A3 were detected in cumulus cells of cumulus enclosed-oocyte (CEO). Intact of germinal vesicle was not kept like in follicle but the spontaneous maturation was inhibited by exogenous adenosine. It is inhibited with concentration dependent manners. Intracellular calcium level of cumulus was extensively increased after adenosine treatment. Based on these results it is suggested that one of the pathway for GV arrest by adenosine and its receptors is calcium mediated signaling pathway in CEO.