127 results on '"Bae, Gyu‐Un"'
Search Results
102. Hydrogen Peroxide Activates p70S6k Signaling Pathway
- Author
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Bae, Gyu-Un, primary, Seo, Dong-Wan, additional, Kwon, Hyoung-Keun, additional, Lee, Hoi Young, additional, Hong, Sungyoul, additional, Lee, Zee-Won, additional, Ha, Kwon-Soo, additional, Lee, Hyang-Woo, additional, and Han, Jeung-Whan, additional
- Published
- 1999
- Full Text
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103. Cooperation of H2O2-mediated ERK activation with Smad pathway in TGF-β1 induction of p21WAF1/Cip1
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Kim, Yong Kee, Bae, Gyu-Un, Kang, Jae Ku, Park, Jong Woo, Lee, Eun Kyung, Lee, Hoi Young, Choi, Wahn Soo, Lee, Hyang Woo, and Han, Jeung-Whan
- Subjects
- *
GROWTH factors , *CYTOKINES , *REACTIVE oxygen species , *CELLS - Abstract
Abstract: Although it has been demonstrated that p21WAF1/Cip1 could be induced by transforming growth factor-β1 (TGF-β1) in a Smad-dependent manner, the cross-talk of Smad signaling pathway with other signaling pathways still remains poorly understood. In this study, we investigated a possible role of hydrogen peroxide (H2O2)-ERK pathway in TGF-β1 induction of p21WAF1/Cip1 in human keratinocytes HaCaT cells. Using pharmacological inhibitors specific for MAP kinase family members, we found that ERK, but not JNK or p38, is required for TGF-β1 induction of p21WAF1/Cip1. ERK activation by TGF-β1 was significantly attenuated by treatment with N-acetyl-l-cysteine or catalase, indicating that reactive oxygen species (ROS) generated by TGF-β1, mainly H2O2, stimulates ERK signaling pathway to induce the p21WAF1/Cip1 expression. In support of this, TGF-β1 stimulation caused an increase in intracellular ROS level, which was completely abolished by pretreatment with catalase. ERK activation does not appear to be associated with nuclear translocation of Smad-3, because ERK inhibition did not affect nuclear translocation of Smads by TGF-β1, and H2O2 treatment alone did not cause nuclear translocation of Smad-3. On the other hand, ERK inhibition ablated the phosphorylation of Sp1 by TGF-β1, which was accompanied with the disruption of interaction between Smad-3 and Sp1 as well as of the recruitment of Sp1 to the p21WAF1/Cip1 promoter induced by TGF-β1, indicating that ERK signaling pathway might be necessary for their interaction. Taken together, these results suggest that activation of H2O2-mediated ERK signaling pathway is required for p21WAF1/Cip1 expression by TGF-β1 and led us to propose a cooperative model whereby TGF-β1-induced receptor activation stimulates not only a Smad pathway but also a parallel H2O2-mediated ERK pathway that acts as a key determinant for association between Smads and Sp1 transcription factor. [Copyright &y& Elsevier]
- Published
- 2006
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104. Hydrogen peroxide mediates arsenite activation of p70s6k and extracellular signal-regulated kinase
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Jung, Dong Keun, Bae, Gyu-Un, Kim, Yong Kee, Han, Seung-Hee, Choi, Wahn Soo, Kang, Hyeog, Seo, Dong Wan, Lee, Hoi Young, Cho, Eun-Jung, Lee, Hyang-Woo, and Han, Jeung-Whan
- Subjects
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TUMORS , *HYDROGEN peroxide , *CELLS - Abstract
To define the mechanism of arsenite-induced tumor promotion, we examined the role of reactive oxygen species (ROS) in the signaling pathways of cells exposed to arsenite. Arsenite treatment resulted in the persistent activation of p70s6k and extracellular signal-regulated kinase 1/2 (ERK1/2) which was accompanied by an increase in intracellular ROS production. The predominant produced appeared to be H2O2, because the arsenite-induced increase in dichlorofluorescein (DCF) fluorescence was completely abolished by pretreatment with catalase but not with heat-inactivated catalase. Elimination of H2O2 by catalase or N-acetyl-l-cysteine inhibited the arsenite-induced activation of p70s6k and ERK1/2, indicating the possible role of H2O2 in the arsenite activation of the p70s6k and the ERK1/2 signaling pathways. A specific inhibitor of p70s6k, rapamycin, and calcium chelators significantly blocked the activation of p70s6k induced by arsenite. While the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 completely abrogated arsenite activation of p70s6k, ERK1/2 activation by arsenite was not affected by these inhibitors, indicating that H2O2 might act as an upstream molecule of PI3K as well as ERK1/2. Consistent with these results, none of the inhibitors impaired H2O2 production by arsenite. DNA binding activity of AP-1, downstream of ERK1/2, was also inhibited by catalase, N-acetyl-l-cysteine, and the MEK inhibitor PD98059, which significantly blocked arsenite activation of ERK1/2. Taken together, these studies provide insight into mechanisms of arsenite-induced tumor promotion and suggest that H2O2 plays a critical role in tumor promotion by arsenite through activation of the ERK1/2 and p70s6k signaling pathways. [Copyright &y& Elsevier]
- Published
- 2003
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105. Constitutive activation of p70S6k in cancer cells.
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Kwon, Hyoung-Keun, Bae, Gyu-Un, Yoon, Jong-Woo, Kim, Yong, Lee, Hoi-Young, Lee, Hyang-Woo, and Han, Jeung-Whan
- Abstract
The mitogen-stimulated serine/threonine kinase p70
S6k plays an important role in the progression of cells from Go /G1 , to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts family of mRNA transcripts which contain polypyrimidine tract at their 5 transcriptional start site. Here, we report that p70S6k was constitutively phosphorylated and activated to various degrees in serum-deprived AGS, A2058, HT-1376, MG63, MCA, MDA-MB-435S, MDA-MB-231 and MB-157. Rapamycin treatment induced a significant dephosphorylation and inactivation of p70S6k in all cancer cell lines, while wortmannin, a specific inhibitor of PI3-K, caused a mild dephosphorylation of p70S6k in AGS, MDA-MB-435S and MB-157. In addition, SQ20006, methylxanthine phosphodiesterase inhibitor, reduced the phosphorylation of p70S6k in all cancer cells tested. Consistent with inhibitory effect of rapamycin on p70S6k activity, rapamycin inhibited [3 H]-thymidine incorporation and increased the number of cells at Go /G1 phase. Furthermore, these inhibitory effects were accompanied by the decrease in growth of cancer cells. Taken together, the results indicate that the antiproliferative activity of rapamycin might be attributed to cell cycle arrest at Go /G1 phase in human cancer cells through the inhibition of constitutively activated p70S6k of cancer cells and suggest p70S6k as a potential target for therapeutic strategies aimed at preventing or inhibiting tumor growth. [ABSTRACT FROM AUTHOR]- Published
- 2002
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106. Boc modifies the holoprosencephaly spectrum of Cdo mutant mice
- Author
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Zhang, Wei, Hong, Mingi, Bae, Gyu-un, Kang, Jong-Sun, and Krauss, Robert S.
- Abstract
Holoprosencephaly (HPE) is caused by a failure to form the midline of the forebrain and/or midface. It is one of the most common human birth defects, but clinical expression is extremely variable. HPE is associated with mutations in the sonic hedgehog (SHH) pathway. Mice lacking the Shh pathway regulator Cdo (also called Cdon) display HPE with strain-dependent penetrance and expressivity, implicating silent modifier genes as one cause of the variability. However, the identities of potential HPE modifiers of this type are unknown. We report here that whereas mice lacking the Cdo paralog Boc do not have HPE, Cdo;Boc double mutants on a largely Cdo-resistant genetic background have lobar HPE with strong craniofacial anomalies and defects in Shh target gene expression in the developing forebrain. Boc is therefore a silent HPE modifier gene in mice. Furthermore, Cdo and Boc have specific, selective roles in Shh signaling in mammals, because Cdo;Boc double-mutant mice do not display the most severe HPE phenotype seen in Shh-null mice, nor do they have major defects in digit patterning or development of vertebrae, which are also Shh-dependent processes. This is in contrast to reported observations in Drosophila, where genetic removal of the Cdo and Boc orthologs Ihog and Boi results in a complete loss of response to the hedgehog ligand. Therefore, there is evolutionary divergence between mammals and insects in the requirement of the hedgehog pathway for Cdo/Ihog family members, with mammalian development involving additional factors and/or distinct mechanisms at this level of pathway regulation.
- Published
- 2011
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107. Activation of p21WAF1/Cip1Transcription through Sp1 Sites by Histone Deacetylase Inhibitor Apicidin
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Han, Jeung-Whan, Ahn, Seong Hoon, Kim, Yong Kee, Bae, Gyu-Un, Yoon, Jong Woo, Hong, Sungyoul, Lee, Hoi Young, Lee, Yin-Won, and Lee, Hyang-Woo
- Abstract
We previously reported that apicidin, a novel histone deacetylase inhibitor, inhibited the proliferation of tumor cells via induction of p21WAF1/Cip1. In this study, we determined the molecular mechanisms by which apicidin induced the p21WAF1/Cip1gene expression in HeLa cells. Apicidin induced p21WAF1/Cip1mRNA independent of the de novoprotein synthesis and activated the p21WAF1/Cip1promoter through Sp1–3 site located at −82 and −77 relative to the transcription start site. This transcriptional activation appears to be mediated by protein kinase C (PKC), because calphostin C, a PKC inhibitor, significantly attenuated the activation of p21WAF1/Cip1promoter via Sp1 sites, which was accompanied by a marked suppression of p21WAF1/Cip1mRNA and protein expression induced by apicidin. Consistent with the transcriptional activation of p21WAF1/Cip1promoter by apicidin, apicidin treatment led to the translocation of PKCε from cytosolic to particulate fraction, which was reversed by pretreatment with calphostin C, indicating the involvement of PKC in the transcriptional activation of p21WAF1/Cip1via Sp1 sites by apicidin. However, the PKC-mediated transcriptional activation of p21WAF1/Cip1by apicidin appears to be independent of the histone hyperacetylation, because apicidin-induced histone hyperacetylation was not affected by calphostin C. Furthermore, a PKC activator, phorbol 12,13-dibutyrate, alone induced the transcriptional activation of p21WAF1/Cip1promoter, p21WAF1/Cip1mRNA, and protein expression without induction of the histone hyperacetylation, suggesting that the transcriptional activation of p21WAF1/Cip1by apicidin might have been mediated by a mechanism other than chromatin remodeling through the histone hyperacetylation. Taken together, these results suggest that the PKC signaling pathway plays a pivotal role in the transcriptional activation of the p21WAF1/Cip1gene by apicidin.
- Published
- 2001
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108. Hydrogen Peroxide Activates p70S6kSignaling Pathway*
- Author
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Bae, Gyu-Un, Seo, Dong-Wan, Kwon, Hyoung-Keun, Lee, Hoi Young, Hong, Sungyoul, Lee, Zee-Won, Ha, Kwon-Soo, Lee, Hyang-Woo, and Han, Jeung-Whan
- Abstract
We investigated a possible role of reactive oxygen species (ROS) in p70S6kactivation, which plays an important role in the progression of cells from G0/G1to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts that encode for components of the protein synthetic machinery. Treatment of mouse epidermal cell JB6 with H2O2generated extracellularly by glucose/glucose oxidase led to the activation of p70S6kand p90Rskand to phosphorylation of p42MAPK/p44MAPK. The activation of p70S6kand p90Rskwas dose-dependent and transient, maximal activities being in extracts treated for 15 and 30 min, respectively. Further characterization of ROS-induced activation of p70S6kusing specific inhibitors for p70S6ksignaling pathway, rapamycin, and wortmannin revealed that ROS acted upstream of the rapamycin-sensitive component FRAP/RAFT and wortmannin-sensitive component phosphatidylinositol 3-kinase, because both inhibitors caused the inhibition of ROS-induced p70S6kactivity. In addition, Ca2+chelation also inhibited ROS-induced activation of p70S6k, indicating that Ca2+is a mediator of p70S6kactivation by ROS. However, down-regulation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive protein kinase C (PKC) by chronic pretreatment with TPA or a specific PKC inhibitor Ro-31-8220 did not block the activation of p70S6kby ROS, indicating that the activation of TPA-responsive PKC was not required for stimulation of p70S6kactivity by H2O2in JB6 cells. Exposure of JB6 cells to platelet-derived growth factor or epidermal growth factor led to a rapid increase in H2O2, phosphorylation, and activation of p70S6k, which were antagonized by the pretreatment of catalase. Taken together, the results suggest that ROS act as a messenger in growth factor-induced p70S6ksignaling pathway.
- Published
- 1999
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109. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activates promyogenic signaling pathways, thereby promoting myoblast differentiation
- Author
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Bae, Gyu-Un [Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)]
- Published
- 2016
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110. Antidiabetic effect of SN158 through PPARα/γ dual activation in ob/ob mice.
- Author
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Jung, Yujung, Cao, Yongkai, Paudel, Suresh, Yoon, Goo, Cheon, Seung Hoon, Bae, Gyu-Un, Jin, Li Tai, Kim, Yong Kee, and Kim, Su-Nam
- Subjects
- *
HYPOGLYCEMIC agents , *PEROXISOME proliferator-activated receptors , *TRANSCRIPTION factors , *ADIPOGENESIS , *FATTY acids - Abstract
In this study, we aimed to demonstrate the antidiabetic potential of (E)-N-(4-(3-(5-bromo-4-hydroxy-2-methoxyphenyl)acryloyl) phenyl)-4- tert -butylbenzamide (SN158) through peroxisome proliferator-activated receptor (PPAR)-α/γ dual activation. SN158 interacted with both PPARα and PPARγ, and increased their transcriptional activities. Simultaneously, SN158 treatment led to an increase in adipogenic differentiation of 3T3-L1 preadipocytes and fatty acid oxidation in hepatocytes. In addition, glucose uptake in myotubes was significantly increased by SN158 treatment. Finally, SN158 significantly lowered the plasma levels of glucose, triglycerides, and free fatty acids in ob/ob mice without severe weight gain and hepatomegaly. These results suggest that SN158 can be useful as a potential therapeutic agent against type 2 diabetes and related metabolic disorders by alleviating glucose and lipid abnormalities. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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111. Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease.
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Zhang Y, Wei S, Jin EJ, Jo Y, Oh CM, Bae GU, Kang JS, and Ryu D
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- Humans, Animals, Methylation, Cardiovascular Diseases metabolism, Metabolic Diseases metabolism, Protein-Arginine N-Methyltransferases metabolism, Protein-Arginine N-Methyltransferases antagonists & inhibitors
- Abstract
Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.
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- 2024
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112. Epsti1 Regulates the Inflammatory Stage of Early Muscle Regeneration through STAT1-VCP Interaction.
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Kim JW, Bae JH, Go GY, Lee JR, Jeong Y, Kim JY, Kim TH, Kim YK, Han JW, Oh JE, Hahn MJ, Kang JS, and Bae GU
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- Animals, Mice, Signal Transduction, Inflammation metabolism, Muscle, Skeletal metabolism, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Mice, Inbred C57BL, Mice, Knockout, STAT1 Transcription Factor metabolism, Regeneration physiology, Interferon-gamma metabolism
- Abstract
During muscle regeneration, interferon-gamma (IFN- γ ) coordinates inflammatory responses critical for activation of quiescent muscle stem cells upon injury via the Janus kinase (JAK) - signal transducer and activator of transcription 1 (STAT1) pathway. Dysregulation of JAK-STAT1 signaling results in impaired muscle regeneration, leading to muscle dysfunction or muscle atrophy. Until now, the underlying molecular mechanism of how JAK-STAT1 signaling resolves during muscle regeneration remains largely elusive. Here, we demonstrate that epithelial-stromal interaction 1 (Epsti1), an interferon response gene, has a crucial role in regulating the IFN- γ -JAK-STAT1 signaling at early stage of muscle regeneration. Epsti1-deficient mice exhibit impaired muscle regeneration with elevated inflammation response. In addition, Epsti1-deficient myoblasts display aberrant interferon responses. Epsti1 interacts with valosin-containing protein (VCP) and mediates the proteasomal degradation of IFN- γ -activated STAT1, likely contributing to dampening STAT1-mediated inflammation. In line with the notion, mice lacking Epsti1 exhibit exacerbated muscle atrophy accompanied by increased inflammatory response in cancer cachexia model. Our study suggests a crucial function of Epsti1 in the resolution of IFN- γ -JAK-STAT1 signaling through interaction with VCP which provides insights into the unexplored mechanism of crosstalk between inflammatory response and muscle regeneration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
- Published
- 2024
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113. PRMT7 ablation in cardiomyocytes causes cardiac hypertrophy and fibrosis through β-catenin dysregulation.
- Author
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Ahn BY, Jeong MH, Pyun JH, Jeong HJ, Vuong TA, Bae JH, An S, Kim SW, Kim YK, Ryu D, Kim HJ, Cho H, Bae GU, and Kang JS
- Subjects
- Angiotensins, Animals, Cardiomegaly chemically induced, Cardiomegaly metabolism, Fibrosis, Gene Expression Profiling methods, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardium pathology, Protein-Arginine N-Methyltransferases deficiency, RNA-Seq methods, Wnt Signaling Pathway genetics, beta Catenin metabolism, Mice, Cardiomegaly genetics, Myocardium metabolism, Myocytes, Cardiac metabolism, Protein-Arginine N-Methyltransferases genetics, beta Catenin genetics
- Abstract
Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/β-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited the cardiac hypertrophy and fibrosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-deficient hearts revealed the alteration in gene expression profile related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of β-catenin. PRMT7 deficiency decreases symmetric dimethylation of β-catenin. Mechanistic studies reveal that methylation of arginine residue 93 in β-catenin decreases the activity of β-catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of β-catenin activity., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Published
- 2022
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114. Understanding of sarcopenia: from definition to therapeutic strategies.
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Kim JW, Kim R, Choi H, Lee SJ, and Bae GU
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- Animals, Antibodies, Monoclonal, Humanized, Functional Status, Humans, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscle, Skeletal physiopathology, Myostatin antagonists & inhibitors, Myostatin metabolism, Sarcopenia diagnosis, Sarcopenia metabolism, Sarcopenia physiopathology, Treatment Outcome, Histone Deacetylase Inhibitors therapeutic use, Muscle Strength, Muscle, Skeletal drug effects, Nutritional Support, Resistance Training, Sarcopenia therapy
- Abstract
Sarcopenia refers to the gradual loss of skeletal muscle mass and function along with aging and is a social burden due to growing healthcare cost associated with a super-aging society. Therefore, researchers have established guidelines and tests to diagnose sarcopenia. Several studies have been conducted actively to reveal the cause of sarcopenia and find an economic therapy to improve the quality of life in elderly individuals. Sarcopenia is caused by multiple factors such as reduced regenerative capacity, imbalance in protein turnover, alteration of fat and fibrotic composition in muscle, increased reactive oxygen species, dysfunction of mitochondria and increased inflammation. Based on these mechanisms, nonpharmacological and pharmacological strategies have been developed to prevent and treat sarcopenia. Although several studies are currently in progress, no treatment is available yet. This review presents the definition of sarcopenia and summarizes recent understanding on the detailed mechanisms, diagnostic criteria, and strategies for prevention and treatment., (© 2021. The Pharmaceutical Society of Korea.)
- Published
- 2021
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115. Inducible Prmt1 ablation in adult vascular smooth muscle leads to contractile dysfunction and aortic dissection.
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Pyun JH, Ahn BY, Vuong TA, Kim SW, Jo Y, Jeon J, Baek SH, Kim J, Park S, Bae GU, Choi JH, Kim JR, Ryu D, Lee SJ, and Kang JS
- Subjects
- Aged, Animals, Cells, Cultured, Humans, Mice, Muscle Contraction, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle metabolism, Phenotype, Protein-Arginine N-Methyltransferases genetics, Protein-Arginine N-Methyltransferases metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Aortic Dissection genetics, Aortic Dissection metabolism, Aortic Dissection pathology, Aortic Aneurysm metabolism
- Abstract
Vascular smooth muscle cells (VSMCs) have remarkable plasticity in response to diverse environmental cues. Although these cells are versatile, chronic stress can trigger VSMC dysfunction, which ultimately leads to vascular diseases such as aortic aneurysm and atherosclerosis. Protein arginine methyltransferase 1 (Prmt1) is a major enzyme catalyzing asymmetric arginine dimethylation of proteins that are sources of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Although a potential role of Prmt1 in vascular pathogenesis has been proposed, its role in vascular function has yet to be clarified. Here, we investigated the role and underlying mechanism of Prmt1 in vascular smooth muscle contractility and function. The expression of PRMT1 and contractile-related genes was significantly decreased in the aortas of elderly humans and patients with aortic aneurysms. Mice with VSMC-specific Prmt1 ablation (smKO) exhibited partial lethality, low blood pressure and aortic dilation. The Prmt1-ablated aortas showed aortic dissection with elastic fiber degeneration and cell death. Ex vivo and in vitro analyses indicated that Prmt1 ablation significantly decreased the contractility of the aorta and traction forces of VSMCs. Prmt1 ablation downregulated the expression of contractile genes such as myocardin while upregulating the expression of synthetic genes, thus causing the contractile to synthetic phenotypic switch of VSMCs. In addition, mechanistic studies demonstrated that Prmt1 directly regulates myocardin gene activation by modulating epigenetic histone modifications in the myocardin promoter region. Thus, our study demonstrates that VSMC Prmt1 is essential for vascular homeostasis and that its ablation causes aortic dilation/dissection through impaired myocardin expression., (© 2021. The Author(s).)
- Published
- 2021
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116. Protein arginine methyltransferases: promising targets for cancer therapy.
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Hwang JW, Cho Y, Bae GU, Kim SN, and Kim YK
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- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Arginine metabolism, Cell Cycle, DNA Damage, Disease Management, Disease Susceptibility, Drug Development, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Humans, Methylation, Molecular Targeted Therapy, Neoplasms drug therapy, Neoplasms etiology, Neoplasms pathology, Protein Processing, Post-Translational, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Protein-Arginine N-Methyltransferases genetics, Biomarkers, Tumor, Neoplasms metabolism, Protein-Arginine N-Methyltransferases metabolism
- Abstract
Protein methylation, a post-translational modification (PTM), is observed in a wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements in epigenetic research, the importance of protein methylation has been highlighted. The methylation of histone proteins that contributes to the epigenetic histone code is not only dynamic but is also finely controlled by histone methyltransferases and demethylases, which are essential for the transcriptional regulation of genes. In addition, many nonhistone proteins are methylated, and these modifications govern a variety of cellular functions, including RNA processing, translation, signal transduction, DNA damage response, and the cell cycle. Recently, the importance of protein arginine methylation, especially in cell cycle regulation and DNA repair processes, has been noted. Since the dysregulation of protein arginine methylation is closely associated with cancer development, protein arginine methyltransferases (PRMTs) have garnered significant interest as novel targets for anticancer drug development. Indeed, several PRMT inhibitors are in phase 1/2 clinical trials. In this review, we discuss the biological functions of PRMTs in cancer and the current development status of PRMT inhibitors in cancer therapy.
- Published
- 2021
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117. Ginsenoside Rb1 and Rb2 upregulate Akt/mTOR signaling-mediated muscular hypertrophy and myoblast differentiation.
- Author
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Go GY, Jo A, Seo DW, Kim WY, Kim YK, So EY, Chen Q, Kang JS, Bae GU, and Lee SJ
- Abstract
Background: As a process of aging, skeletal muscle mass and function gradually decrease. It is reported that ginsenoside Rb1 and Rb2 play a role as AMP-activated protein kinase activator, resulting in regulating glucose homeostasis, and Rb1 reduces oxidative stress in aged skeletal muscles through activating the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway. We examined the effects of Rb1 and Rb2 on differentiation of the muscle stem cells and myotube formation., Methods: C2C12 myoblasts treated with Rb1 and/or Rb2 were differentiated and induced to myotube formation, followed by immunoblotting for myogenic marker proteins, such as myosin heavy chain, MyoD, and myogenin, or immunostaining for myosin heavy chain or immunoprecipitation analysis for heterodimerization of MyoD/E-proteins., Results: Rb1 and Rb2 enhanced myoblast differentiation through accelerating MyoD/E-protein heterodimerization and increased myotube hypertrophy, accompanied by activation of Akt/mammalian target of rapamycin signaling. In addition, Rb1 and Rb2 induced the MyoD-mediated transdifferentiation of the rhabdomyosarcoma cells into myoblasts. Furthermore, co-treatment with Rb1 and Rb2 had synergistically enhanced myoblast differentiation through Akt activation., Conclusion: Rb1 and Rb2 upregulate myotube growth and myogenic differentiation through activating Akt/mammalian target of rapamycin signaling and inducing myogenic conversion of fibroblasts. Thus, our first finding indicates that Rb1 and Rb2 have strong potential as a helpful remedy to prevent and treat muscle atrophy, such as age-related muscular dystrophy., (© 2019 The Korean Society of Ginseng, Published by Elsevier Korea LLC.)
- Published
- 2020
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118. Prmt7 promotes myoblast differentiation via methylation of p38MAPK on arginine residue 70.
- Author
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Jeong HJ, Lee SJ, Lee HJ, Kim HB, Anh Vuong T, Cho H, Bae GU, and Kang JS
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- Animals, Cell Differentiation, Methylation, Mice, Mice, Knockout, Myoblasts cytology, Protein-Arginine N-Methyltransferases deficiency, Arginine metabolism, Myoblasts metabolism, Protein-Arginine N-Methyltransferases metabolism, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
MyoD functions as a master regulator to induce muscle-specific gene expression and myogenic differentiation. Here, we demonstrate a positive role of Protein arginine methyltransferase 7 (Prmt7) in MyoD-mediated myoblast differentiation through p38MAPK activation. Prmt7 depletion in primary or C2C12 myoblasts impairs cell cycle withdrawal and myogenic differentiation. Furthermore, Prmt7 depletion decreases the MyoD-reporter activities and the MyoD-mediated myogenic conversion of fibroblasts. Together with MyoD, Prmt7 is recruited to the Myogenin promoter region and Prmt7 depletion attenuates the recruitment of MyoD and its coactivators. The mechanistic study reveals that Prmt7 methylates p38MAPKα at the arginine residue 70, thereby promoting its activation which in turn enhances MyoD activities. The arginine residue 70 to alanine mutation in p38MAPKα impedes MyoD/E47 heterodimerization and the recruitment of Prmt7, MyoD and Baf60c to the Myogenin promoter resulting in blunted Myogenin expression. In conclusion, Prmt7 promotes MyoD-mediated myoblast differentiation through methylation of p38MAPKα at arginine residue 70.
- Published
- 2020
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119. Ginsenoside Rg1 augments oxidative metabolism and anabolic response of skeletal muscle in mice.
- Author
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Jeong HJ, So HK, Jo A, Kim HB, Lee SJ, Bae GU, and Kang JS
- Abstract
Background: The ginsenoside Rg1 has been shown to exert various pharmacological activities with health benefits. Previously, we have reported that Rg1 promoted myogenic differentiation and myotube growth in C2C12 myoblasts. In this study, the in vivo effect of Rg1 on fiber-type composition and oxidative metabolism in skeletal muscle was examined., Methods: To examine the effect of Rg1 on skeletal muscle, 3-month-old mice were treated with Rg1 for 5 weeks. To assess muscle strength, grip strength tests were performed, and the lower hind limb muscles were harvested, followed by various detailed analysis, such as histological staining, immunoblotting, immunostaining, and real-time quantitative reverse transcription polymerase chain reaction. In addition, to verify the in vivo data, primary myoblasts isolated from mice were treated with Rg1, and the Rg1 effect on myotube growth was examined by immunoblotting and immunostaining analysis., Results: Rg1 treatment increased the expression of myosin heavy chain isoforms characteristic for both oxidative and glycolytic muscle fibers; increased myofiber sizes were accompanied by enhanced muscle strength. Rg1 treatment also enhanced oxidative muscle metabolism with elevated oxidative phosphorylation proteins. Furthermore, Rg1-treated muscles exhibited increased levels of anabolic S6 kinase signaling., Conclusion: Rg1 improves muscle functionality via enhancing muscle gene expression and oxidative muscle metabolism in mice.
- Published
- 2019
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120. Shifting Retroviral Vector Integrations Away from Transcriptional Start Sites via DNA-Binding Protein Domain Insertion into Integrase.
- Author
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Nam JS, Lee JE, Lee KH, Yang Y, Kim SH, Bae GU, Noh H, and Lim KI
- Abstract
The unique ability of retroviruses to integrate genes into host genomes is of great value for long-term expression in gene therapy, but only when integrations occur at safe genomic sites. To reap the benefit of using retroviruses without severe detrimental effects, we developed several murine leukemia virus (MLV)-based gammaretroviral vectors with safer integration patterns by perturbing the structure of the integrase via insertion of DNA-binding zinc-finger domains (ZFDs) into an internal position of the enzyme. ZFD insertion significantly reduced the inherent, strong MLV integration preference for genomic regions near transcriptional start sites (TSSs), which are the most dangerous spots. The altered retroviral integration pattern was related to increased formation of residual primer-binding site sequences at the 3' end of proviruses. Several ZFD insertion mutants showed lower frequencies of integrations into the TSS genome regions when having the residual primer-binding site sequences in the proviruses. Our findings not only can extend the use of retroviruses in biomedical applications, but also provide a glimpse into the mechanisms underlying retroviral integration.
- Published
- 2018
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121. Bisphenol A and estradiol impede myoblast differentiation through down-regulating Akt signaling pathway.
- Author
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Go GY, Lee SJ, Jo A, Lee JR, Kang JS, Yang M, and Bae GU
- Subjects
- Animals, Cell Line, Dose-Response Relationship, Drug, Gene Expression Regulation, Mice, Muscle Proteins genetics, Muscle Proteins metabolism, Myoblasts enzymology, Myoblasts pathology, Phosphorylation, Benzhydryl Compounds toxicity, Cell Differentiation drug effects, Endocrine Disruptors toxicity, Estradiol toxicity, Muscle Development drug effects, Myoblasts drug effects, Phenols toxicity, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects
- Abstract
Bisphenol A (BPA), one of the most widespread endocrine disrupting chemicals, is known as an artificial estrogen, which interacts with estrogen receptor (ER). In this study, we investigated the effects of BPA and estradiol on myoblast differentiation and the underlying signaling mechanism. Exposure to BPA (0.01-1 μM) in mouse myoblast C2C12 cells attenuated myogenic differentiation via the reduced expression of muscle-specific genes, such as myosin heavy chain (MHC), MyoD, and Myogenin, without the alteration of cell proliferation and viability. BPA-exposed C2C12 myoblasts also showed a reduction of Akt phosphorylation ((37-61) %, p < 0.001), a key event for myogenesis. Similarly to BPA, estradiol (0.01-1 μM) reduced the expression of muscle-specific proteins and the formation of multinucleated myotubes, and attenuated the muscle differentiation-specific phosphorylation of Akt ((42-59) %, p < 0.001). We conclude that BPA and estradiol suppress myogenic differentiation through the inhibition of Akt signaling., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
122. Black ginseng activates Akt signaling, thereby enhancing myoblast differentiation and myotube growth.
- Author
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Lee SY, Go GY, Vuong TA, Kim JW, Lee S, Jo A, An JM, Kim SN, Seo DW, Kim JS, Kim YK, Kang JS, Lee SJ, and Bae GU
- Abstract
Background: Black ginseng (BG) has greatly enhanced pharmacological activities relative to white or red ginseng. However, the effect and molecular mechanism of BG on muscle growth has not yet been examined. In this study, we investigated whether BG could regulate myoblast differentiation and myotube hypertrophy., Methods: BG-treated C2C12 myoblasts were differentiated, followed by immunoblotting for myogenic regulators, immunostaining for a muscle marker, myosin heavy chain or immunoprecipitation analysis for myogenic transcription factors., Results: BG treatment of C2C12 cells resulted in the activation of Akt, thereby enhancing heterodimerization of MyoD and E proteins, which in turn promoted muscle-specific gene expression and myoblast differentiation. BG-treated myoblasts formed larger multinucleated myotubes with increased diameter and thickness, accompanied by enhanced Akt/mTOR/p70S6K activation. Furthermore, the BG treatment of human rhabdomyosarcoma cells restored myogenic differentiation., Conclusion: BG enhances myoblast differentiation and myotube hypertrophy by activating Akt/mTOR/p70S6k axis. Thus, our study demonstrates that BG has promising potential to treat or prevent muscle loss related to aging or other pathological conditions, such as diabetes.
- Published
- 2018
- Full Text
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123. Marmesin-mediated suppression of VEGF/VEGFR and integrin β1 expression: Its implication in non-small cell lung cancer cell responses and tumor angiogenesis.
- Author
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Kim JH, Kim MS, Lee BH, Kim JK, Ahn EK, Ko HJ, Cho YR, Lee SJ, Bae GU, Kim YK, Oh JS, and Seo DW
- Subjects
- A549 Cells, Carcinoma, Non-Small-Cell Lung blood supply, Carcinoma, Non-Small-Cell Lung genetics, Cells, Cultured, Down-Regulation drug effects, Gene Expression Regulation, Neoplastic drug effects, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells physiology, Humans, Lung Neoplasms blood supply, Lung Neoplasms genetics, Carcinoma, Non-Small-Cell Lung pathology, Coumarins pharmacology, Integrin beta1 genetics, Lung Neoplasms pathology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Receptors, Vascular Endothelial Growth Factor genetics, Vascular Endothelial Growth Factor A genetics
- Abstract
In the present study, we investigated the effects and molecular mechanism of marmesin, a natural coumarin compound isolated from Broussonetia kazinoki, on non-small cell lung cancer (NSCLC) cell responses and tumor angiogenesis. Marmesin abrogated mitogen-stimulated proliferation and invasion in both p53 wild-type A549 and p53-deficient H1299 NSCLC cells. These antitumor activities of marmesin were mediated by the inactivation of mitogenic signaling pathways and downregulation of cell signaling-related proteins including vascular endothelial growth factor receptor-2 (VEGFR-2), integrin β1, integrin-linked kinase and matrix metalloproteinases-2. Furthermore, marmesin suppressed the expression and secretion of VEGF in both NSCLC cells, leading to inhibition of capillary-like structure formation in human umbilical vein endothelial cells. Collectively, these findings demonstrate the pharmacological roles and molecular targets of marmesin in regulating NSCLC cell responses and tumor angiogenesis.
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- 2017
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124. Cdo promotes neuronal differentiation via activation of the p38 mitogen-activated protein kinase pathway.
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Oh JE, Bae GU, Yang YJ, Yi MJ, Lee HJ, Kim BG, Krauss RS, and Kang JS
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Adhesion Molecules deficiency, Cell Line, Cell Lineage, Enzyme Activation, Mice, Mice, Knockout, Neurogenesis, Cell Adhesion Molecules physiology, Cell Differentiation, Neurons cytology, Signal Transduction, cdc42 GTP-Binding Protein metabolism, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
Neural basic helix-loop-helix transcription factors (bHLHs) control many aspects of neurogenesis, such as proliferation, fate determination, and differentiation. We have previously shown that the promyogenic cell surface receptor Cdo modulates the Cdc42 and p38 mitogen-activated protein kinase (MAPK) pathways via a direct association with two scaffold-type proteins, JLP and Bnip-2, to regulate activities of myogenic bHLH factors and myogenic differentiation. We report here that Cdo uses similar regulatory mechanisms to promote neuronal differentiation. Expression of JLP, a scaffold protein for p38MAPK, and Bnip-2, a regulator of Cdc42, is increased during differentiation of C17.2 neural precursor cells and P19 embryonal carcinoma cells. These molecules regulate Cdc42 and p38MAPK activities, which increase in a Cdo-dependent manner during neuronal differentiation of C17.2 cells and retinoic acid-treated P19 cells. Furthermore, enhancement or reduction of Cdc42 and p38MAPK activities enhances or reduces, respectively, neuronal differentiation of these cell lines. Cdc42 and p38MAPK activities also promote heterodimerization of neurogenin1 and E47, suggesting that one way they promote neurogenesis is via regulation of neural bHLH factor activities. These results imply that a conserved intracellular signaling mechanism initiated by Cdo regulates the activities of tissue-specific bHLH factors and therefore functions as a key regulator of differentiation of several different cell lineages.
- Published
- 2009
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125. Cooperation of H2O2-mediated ERK activation with Smad pathway in TGF-beta1 induction of p21WAF1/Cip1.
- Author
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Kim YK, Bae GU, Kang JK, Park JW, Lee EK, Lee HY, Choi WS, Lee HW, and Han JW
- Subjects
- Active Transport, Cell Nucleus, Cell Line, Cell Nucleus metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Enzyme Activation, Humans, Hydrogen Peroxide pharmacology, MAP Kinase Signaling System, Reactive Oxygen Species metabolism, Sp1 Transcription Factor metabolism, Transforming Growth Factor beta1, Cyclin-Dependent Kinase Inhibitor p21 biosynthesis, Extracellular Signal-Regulated MAP Kinases metabolism, Hydrogen Peroxide metabolism, Signal Transduction, Smad Proteins metabolism, Transforming Growth Factor beta pharmacology
- Abstract
Although it has been demonstrated that p21WAF1/Cip1 could be induced by transforming growth factor-beta1 (TGF-beta1) in a Smad-dependent manner, the cross-talk of Smad signaling pathway with other signaling pathways still remains poorly understood. In this study, we investigated a possible role of hydrogen peroxide (H2O2)-ERK pathway in TGF-beta1 induction of p21WAF1/Cip1 in human keratinocytes HaCaT cells. Using pharmacological inhibitors specific for MAP kinase family members, we found that ERK, but not JNK or p38, is required for TGF-beta1 induction of p21WAF1/Cip1. ERK activation by TGF-beta1 was significantly attenuated by treatment with N-acetyl-l-cysteine or catalase, indicating that reactive oxygen species (ROS) generated by TGF-beta1, mainly H2O2, stimulates ERK signaling pathway to induce the p21WAF1/Cip1 expression. In support of this, TGF-beta1 stimulation caused an increase in intracellular ROS level, which was completely abolished by pretreatment with catalase. ERK activation does not appear to be associated with nuclear translocation of Smad-3, because ERK inhibition did not affect nuclear translocation of Smads by TGF-beta1, and H2O2 treatment alone did not cause nuclear translocation of Smad-3. On the other hand, ERK inhibition ablated the phosphorylation of Sp1 by TGF-beta1, which was accompanied with the disruption of interaction between Smad-3 and Sp1 as well as of the recruitment of Sp1 to the p21WAF1/Cip1 promoter induced by TGF-beta1, indicating that ERK signaling pathway might be necessary for their interaction. Taken together, these results suggest that activation of H2O2-mediated ERK signaling pathway is required for p21WAF1/Cip1 expression by TGF-beta1 and led us to propose a cooperative model whereby TGF-beta1-induced receptor activation stimulates not only a Smad pathway but also a parallel H2O2-mediated ERK pathway that acts as a key determinant for association between Smads and Sp1 transcription factor.
- Published
- 2006
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- View/download PDF
126. Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signaling.
- Author
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Itoh K, Brott BK, Bae GU, Ratcliffe MJ, and Sokol SY
- Subjects
- Adaptor Proteins, Signal Transducing, Amino Acid Sequence genetics, Animals, Blastomeres physiology, Cells, Cultured, Cytoplasm physiology, Dishevelled Proteins, Frizzled Receptors physiology, Gene Expression Regulation physiology, Gene Order genetics, Green Fluorescent Proteins, Humans, Molecular Sequence Data, Mutation genetics, Nuclear Export Signals genetics, Nuclear Export Signals physiology, Oligopeptides physiology, Phosphoproteins genetics, Rats, Sequence Alignment, Xenopus embryology, Xenopus Proteins, Cell Nucleus physiology, Phosphoproteins physiology, Wnt Proteins physiology, Xenopus physiology, beta Catenin physiology
- Abstract
Background: Dishevelled (Dsh) is a key component of multiple signaling pathways that are initiated by Wnt secreted ligands and Frizzled receptors during embryonic development. Although Dsh has been detected in a number of cellular compartments, the importance of its subcellular distribution for signaling remains to be determined., Results: We report that Dsh protein accumulates in cell nuclei when Xenopus embryonic explants or mammalian cells are incubated with inhibitors of nuclear export or when a specific nuclear-export signal (NES) in Dsh is disrupted by mutagenesis. Dsh protein with a mutated NES, while predominantly nuclear, remains fully active in its ability to stimulate canonical Wnt signaling. Conversely, point mutations in conserved amino-acid residues that are essential for the nuclear localization of Dsh impair the ability of Dsh to activate downstream targets of Wnt signaling. When these conserved residues of Dsh are replaced with an unrelated SV40 nuclear localization signal, full Dsh activity is restored. Consistent with a signaling function for Dsh in the nucleus, treatment of cultured mammalian cells with medium containing Wnt3a results in nuclear accumulation of endogenous Dsh protein., Conclusions: These findings suggest that nuclear localization of Dsh is required for its function in the canonical Wnt/beta-catenin signaling pathway. We discuss the relevance of these findings to existing models of Wnt signal transduction to the nucleus.
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- 2005
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127. Autotaxin promotes motility via G protein-coupled phosphoinositide 3-kinase gamma in human melanoma cells.
- Author
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Lee HY, Bae GU, Jung ID, Lee JS, Kim YK, Noh SH, Stracke ML, Park CG, Lee HW, and Han JW
- Subjects
- Androstadienes pharmacology, Animals, COS Cells, Chromones pharmacology, Class Ib Phosphatidylinositol 3-Kinase, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes pharmacology, Melanoma drug therapy, Morpholines pharmacology, Pertussis Toxin, Phosphatidylinositol 3-Kinases pharmacology, Phosphodiesterase I, Phosphoinositide-3 Kinase Inhibitors, Phosphoric Diester Hydrolases, Protein Subunits, Pyrophosphatases, Tumor Cells, Cultured, Virulence Factors, Bordetella pharmacology, Wortmannin, Cell Movement drug effects, GTP-Binding Proteins metabolism, Glucose-6-Phosphate Isomerase pharmacology, Glycoproteins pharmacology, Isoenzymes metabolism, Melanoma metabolism, Multienzyme Complexes, Phosphatidylinositol 3-Kinases metabolism
- Abstract
Autotaxin (ATX), an exo-nucleotide pyrophosphatase and phosphodiesterase, stimulates tumor cell motility at sub-nanomolar levels and augments invasiveness and angiogenesis. We investigated the role of G protein-coupled phosphoinositide 3-kinase gamma (PI3Kgamma) in ATX-mediated tumor cell motility stimulation. Pretreatment of human melanoma cell line A2058 with wortmannin or LY294002 inhibited ATX-induced motility. ATX increased the PI3K activity in p110gamma, but not p85, immunoprecipitates. This effect was abrogated by PI3K inhibitors or inhibited by pertussis toxin. Furthermore, stimulation of tumor cell motility by ATX was inhibited by catalytically inactive form of PI3Kgamma, strongly indicating the crucial role of PI3Kgamma for ATX-mediated motility in human melanoma cells
- Published
- 2002
- Full Text
- View/download PDF
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