57 results on '"Heekyoung Chung"'
Search Results
2. A novel role for bone-derived cells in ankylosing spondylitis: Focus on IL-23
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Il Hoon Sung, Sungsin Jo, Bitnara Lee, Ye Soo Park, Eunji Kwon, Young Lim Lee, Bon San Koo, Tae Hwan Kim, and Heekyoung Chung
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Adult ,Male ,0301 basic medicine ,Biophysics ,Biology ,Interleukin-23 ,Biochemistry ,Bone and Bones ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Spondylitis, Ankylosing ,Molecular Biology ,Cells, Cultured ,030203 arthritis & rheumatology ,Gene knockdown ,Osteoblasts ,Endoplasmic reticulum ,Osteoblast ,Cell Biology ,Middle Aged ,Endoplasmic Reticulum Stress ,Molecular biology ,RUNX2 ,030104 developmental biology ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Immunology ,Unfolded protein response ,Cytokines ,Alkaline phosphatase ,Female ,Chromatin immunoprecipitation - Abstract
The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPβ to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPβ genes, leading to IL-23 production.
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- 2017
3. Korean red ginseng extract induces proliferation to differentiation transition of human acute promyelocytic leukemia cells via MYC-SKP2-CDKN1B axis
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Hongki Lee, Heekyoung Chung, Sungsin Jo, Chang Ho Lee, and Sojin Kim
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Acute promyelocytic leukemia ,Down-Regulation ,Panax ,Cycloheximide ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,Ginseng ,Leukemia, Promyelocytic, Acute ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,S-Phase Kinase-Associated Proteins ,Cell Proliferation ,Pharmacology ,Traditional medicine ,Plant Extracts ,business.industry ,Cell growth ,Cell Differentiation ,Cell cycle ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Cell biology ,chemistry ,Ectopic expression ,CDKN1B ,Protein stabilization ,business ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
Ethnopharmacological relevance Korean red ginseng has been used as traditional medicine in East Asia. Recent scientific research revealed multiple effects of Korean red ginseng, including anticancer activity. To evaluate the effect of Korean red ginseng extract (KRGE) in acute promyelocytic leukemia (APL) and elucidate its molecular mechanism. Materials and methods NB4 cells were treated with 1 mg/ml KRGE for 48 h and examined for cell proliferation and differentiation. Cell cycle distribution of KRGE-treated cells was analyzed and the expression level of G1 phase regulators was determined. MYC was overexpressed by retroviral transduction and its effect on SKP2 and CDKN1B gene expression, cell proliferation, cell cycle and differentiation was evaluated in KRGE-treated cells. Results KRGE alone was sufficient to induce granulocytic differentiation accompanied with growth inhibition. KRGE treatment resulted in cell cycle arrest at the G1 phase with augmented Cdkn1b proteins without changes in transcript levels. Cycloheximide treatment revealed reduced degradation of Cdkn1b protein by KRGE. In addition, KRGE treatment reduced expression of MYC and SKP2 genes, both at mRNA and protein levels. Upon ectopic expression of MYC, the effect of KRGE was reversed with lesser reduction and induction of SKP2 gene and Cdkn1b protein, respectively. Taken together, these results suggest a sequential molecular mechanism from MYC reduction, SKP2 reduction, Cdkn1b protein stabilization, G1 phase arrest to granulocytic differentiation by KRGE in human APL. Conclusions KRGE induces leukemic proliferation to differentiation transition in APL through modulation of the MYC-SKP2-CDKN1B axis.
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- 2013
4. Inhibition of PCGF2 enhances granulocytic differentiation of acute promyelocytic leukemia cell line HL-60 via induction of HOXA7
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Sang Soo Kang, Eun Mi Hwang, Jae Yong Park, Hongki Lee, Heekyoung Chung, Sungsin Jo, and Sojin Kim
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Transcriptional Activation ,Acute promyelocytic leukemia ,Cellular differentiation ,Biophysics ,HL-60 Cells ,Biology ,Biochemistry ,Marker gene ,Small hairpin RNA ,Leukemia, Promyelocytic, Acute ,Gene expression ,medicine ,Humans ,Gene silencing ,Molecular Biology ,Homeodomain Proteins ,Polycomb Repressive Complex 1 ,Cell Differentiation ,Cell Biology ,medicine.disease ,Molecular biology ,Chromatin ,Repressor Proteins ,Chromatin immunoprecipitation ,Granulocytes - Abstract
This study tested the hypothesis that Polycomb Repressive Complex 1 (PRC1) may play a negative role in the granulocytic differentiation of acute promyelocytic leukemia (APL) cells. We first examined the expression of PRC1 genes during all-trans retinoic acid (ATRA)-mediated differentiation of human HL-60 cells, and identified PCGF2 as a gene down-regulated by ATRA in a time-dependent manner. Upon gene silencing of PCGF2 with lentiviral short hairpin RNA, granulocytic differentiation was induced as assessed by differentiation marker gene expression, nitroblue tetrazolium staining, Wright-Giemsa staining, and cell cycle analysis. We next identified HOXA7 as a homeobox gene up-regulated by ATRA and successfully induced granulocytic differentiation by overexpression of HOXA7. We next tested the relationship between PCGF2 and HOXA7 by quantifying the changes in HOXA7 and PCGF2 expression upon PCGF2 gene silencing and HOXA7 overexpression, respectively. HOXA7 expression was up-regulated by PCGF2 gene silencing, while PCGF2 expression remained unchanged by ectopic HOXA7 expression, suggesting PCGF2 as acting upstream of HOXA7. Finally, chromatin immunoprecipitation assay was performed with HOXA7 chromatin. We observed gene-specific reduction in direct binding of Pcgf2 protein to HOXA7 chromatin upon PCGF2 gene silencing. Taken together, these results support the notion that down-regulation of PCGF2 is sufficient to induce granulocytic differentiation of HL-60 cells via de-repression of HOXA7 gene expression. In conclusion, we report that PCGF2, a PRC1 gene, played a negative role in the granulocytic differentiation of human APL cells.
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- 2011
5. A Newly Identified CG301269 Improves Lipid and Glucose Metabolism Without Body Weight Gain Through Activation of Peroxisome Proliferator–Activated Receptor α and γ
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Ho Seon Park, Hyunjung Shin, Woo-Sik Kim, Gha Young Lee, Joo-Won Lee, Junhee Lee, Han-Jae Lee, Kyong Soo Park, Kyung-Hee Kim, Hyo-Soo Kim, Seonggu Ro, Jae Bum Kim, Hyeon Kyu Lee, Sung Sik Choe, Seung Bum Park, Hyun-Woo Jeong, Heekyoung Chung, Eun Bok Choi, and Dongkyu Shin
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Peroxisome proliferator-activated receptor ,Myocardial Reperfusion Injury ,Biology ,Carbohydrate metabolism ,Transfection ,Proinflammatory cytokine ,Cell Line ,Mice ,Insulin resistance ,In vivo ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Humans ,Computer Simulation ,PPAR alpha ,Beta oxidation ,Oxazoles ,chemistry.chemical_classification ,Glucose tolerance test ,Analysis of Variance ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Body Weight ,Lipid metabolism ,Glucose Tolerance Test ,medicine.disease ,Lipid Metabolism ,Rats ,PPAR gamma ,Endocrinology ,Glucose ,chemistry ,Diabetes Mellitus, Type 2 ,Liver ,Carbohydrate Metabolism ,Thiazolidines ,Insulin Resistance ,Obesity Studies - Abstract
OBJECTIVE Peroxisome proliferator–activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.
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- 2011
6. Chromatin remodeling, development and disease
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Rho Hyun Seong, Heekyoung Chung, Myunggon Ko, and Dong H. Sohn
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Histone-modifying enzymes ,Chromosomal Proteins, Non-Histone ,T-Lymphocytes ,Health, Toxicology and Mutagenesis ,Embryonic Development ,Biology ,Chromatin remodeling ,Mice ,Higher Order Chromatin Structure ,Neoplasms ,Genetics ,Animals ,Humans ,Histone code ,Molecular Biology ,ChIA-PET ,DNA Helicases ,Nuclear Proteins ,Chromatin Assembly and Disassembly ,Mi-2/NuRD complex ,Hematopoiesis ,Cell biology ,Chromatin ,Gene Expression Regulation ,Growth and Development ,Genes, Switch ,Transcription Factors ,Bivalent chromatin - Abstract
Development is a stepwise process in which multi-potent progenitor cells undergo lineage commitment, differentiation, proliferation and maturation to produce mature cells with restricted developmental potentials. This process is directed by spatiotemporally distinct gene expression programs that allow cells to stringently orchestrate intricate transcriptional activation or silencing events. In eukaryotes, chromatin structure contributes to developmental progression as a blueprint for coordinated gene expression by actively participating in the regulation of gene expression. Changes in higher order chromatin structure or covalent modification of its components are considered to be critical events in dictating lineage-specific gene expression during development. Mammalian cells utilize multi-subunit nuclear complexes to alter chromatin structure. Histone-modifying complex catalyzes covalent modifications of histone tails including acetylation, methylation, phosphorylation and ubiquitination. ATP-dependent chromatin remodeling complex, which disrupts histone-DNA contacts and induces nucleosome mobilization, requires energy from ATP hydrolysis for its catalytic activity. Here, we discuss the diverse functions of ATP-dependent chromatin remodeling complexes during mammalian development. In particular, the roles of these complexes during embryonic and hematopoietic development are reviewed in depth. In addition, pathological conditions such as tumor development that are induced by mutation of several key subunits of the chromatin remodeling complex are discussed, together with possible mechanisms that underlie tumor suppression by the complex.
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- 2008
7. Gene expression profiles of murine fatty liver induced by the administration of methotrexate
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Mingoo Kim, Byung-Hoon Lee, Heekyoung Chung, Ju Han Kim, Il Hong, Mi-Ock Lee, Kyung-Sun Kang, Min-Ho Lee, Hyung Lae Kim, Byung Il Yoon, and Gu Kong
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Male ,Ratón ,medicine.drug_class ,Administration, Oral ,Gene Expression ,Biology ,Pharmacology ,Toxicology ,Toxicogenetics ,Antimetabolite ,Mice ,chemistry.chemical_compound ,Gene expression ,medicine ,Animals ,RNA, Messenger ,Enzyme Inhibitors ,Oligonucleotide Array Sequence Analysis ,Mice, Inbred ICR ,Dose-Response Relationship, Drug ,Gene Expression Profiling ,Fatty liver ,Lipid Metabolism ,medicine.disease ,Fatty Liver ,Disease Models, Animal ,Methotrexate ,chemistry ,Antifolate ,Immunology ,Toxicogenomics ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Methotrexate (MTX) is used to treat a variety of chronic inflammatory and neoplastic diseases. However, it can induce hepatotoxicity such as microvesicular steatosis and necrosis. To explore the mechanisms of MTX-induced hepatic steatosis, we used microarray analysis to profile the gene expression patterns of mouse liver after MTX treatment. MTX was administered orally as a single dose of 10mg/kg (low dose) or 100 mg/kg (high dose) to ICR mice, and the livers were obtained 6 h, 24 h, and 72 h after treatment. Serum alanine aminotransferase, aspartate aminotransferase and triacylglycerol levels were not significantly altered in the experimental animals. Signs of steatosis were observed at 24 h after administration of high dose of MTX. From microarray data analysis, 908 genes were selected as MTX-responsive genes (P0.05, two-way ANOVA; cutoffor =1.5-fold). Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis revealed that the predominant biological processes associated with these genes are response to unfolded proteins, phosphate metabolism, and cellular lipid metabolism. Functional categorization of these genes identified 28 genes involved in lipid metabolism that was interconnected with the biological pathways of biosynthesis, catabolism, and transport of lipids and fatty acids. Taken together, these data provide a better understanding of the molecular mechanisms of MTX-induced steatogenic hepatotoxicity, and useful information for predicting hepatotoxicity through pattern recognition.
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- 2008
8. BAF60a Interacts with p53 to Recruit the SWI/SNF Complex
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Rho Hyun Seong, Myunggon Ko, Jaehak Oh, Dong H. Sohn, Heekyoung Chung, and Sung H. Jeon
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Small interfering RNA ,Transcription, Genetic ,Chromosomal Proteins, Non-Histone ,cells ,genetic processes ,Down-Regulation ,Apoptosis ,macromolecular substances ,Biochemistry ,Chromatin remodeling ,Cell Line ,Mice ,Transduction, Genetic ,Transcription (biology) ,Protein Interaction Mapping ,Animals ,Humans ,Amino Acid Sequence ,Chromatin structure remodeling (RSC) complex ,SMARCB1 ,Molecular Biology ,biology ,SWI/SNF complex ,Chemistry ,Cell Cycle ,Cell Biology ,Chromatin Assembly and Disassembly ,Molecular biology ,SWI/SNF ,Protein Structure, Tertiary ,enzymes and coenzymes (carbohydrates) ,Doxorubicin ,SMARCA4 ,biology.protein ,Mutant Proteins ,Tumor Suppressor Protein p53 ,biological phenomena, cell phenomena, and immunity ,Protein Binding ,Transcription Factors - Abstract
To understand the tumor-suppressing mechanism of the SWI/SNF chromatin remodeling complex, we investigated its molecular relationship with p53. Using the pREP4-luc episomal reporter, we first demonstrated that p53 utilizes the chromatin remodeling activity of the SWI/SNF complex to initiate transcription from the chromatin-structured promoter. Among the components of the SWI/SNF complex, we identified BAF60a as a mediator of the interaction with p53 by the yeast two-hybrid assay. p53 directly interacted only with BAF60a, but not with other components of the SWI/SNF complex, such as BRG1, SRG3, SNF5, or BAF57. We found out that multiple residues at the amino acid 108-150 region of BAF60a were involved in the interaction with the tetramerization domain of p53. The N-terminal fragment of BAF60a containing the p53-interacting region as well as small interfering RNA for baf60a inhibited the SWI/SNF complex-mediated transcriptional activity of p53. The uncoupling of p53 with the SWI/SNF complex resulted in the repression of both p53-dependent apoptosis and cell cycle arrest by the regulation of target genes. These results suggest that the SWI/SNF chromatin remodeling complex is involved in the suppression of tumors by the interaction with p53.
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- 2008
9. SRG3, a core component of mouse SWI/SNF complex, is essential for extra-embryonic vascular development
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Dong Hyun Sohn, Won Kyu Kim, Rho Hyun Seong, Shin Jeon, Heekyoung Chung, Daehee Han, Sangil Ahn, and Changjin Lee
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Vascular Endothelial Growth Factor A ,Transgene-rescue ,food.ingredient ,Chromosomal Proteins, Non-Histone ,Embryonic Development ,Neovascularization, Physiologic ,Mice, Transgenic ,Biology ,SRG3 ,Chromatin remodeling ,Visceral endoderm ,Mice ,food ,Yolk ,medicine ,Angiopoietin-1 ,Animals ,Transgenes ,Yolk sac ,Molecular Biology ,Genetics ,SWI/SNF complex ,Models, Genetic ,Embryogenesis ,Gene Expression Regulation, Developmental ,Embryo ,Cell Biology ,Embryo, Mammalian ,Embryonic stem cell ,Immunohistochemistry ,Cell biology ,Specific Pathogen-Free Organisms ,Platelet Endothelial Cell Adhesion Molecule-1 ,medicine.anatomical_structure ,embryonic structures ,Blood Vessels ,Blood vessel ,Angiogenesis ,Endoderm ,Transcription Factors ,Developmental Biology - Abstract
The SWI/SNF chromatin-remodeling complex functions as a transcriptional regulator and plays a significant role in cell proliferation, differentiation and embryonic development. SRG3, a homologue of human BAF155, is a core component of the mouse SWI/SNF chromatin remodeling complex. Mutant mice deficient in Srg3 expression are peri-implantation lethal. To investigate the role of SRG3 in the post-implantation stage, we generated SRG3 transgene-rescued (Srg3−/−Tg+) embryos by inducing exogenous gene expression. These Srg3−/−Tg+ embryos overcame early embryonic lethality and extended the life span until mid-gestation. However, the embryos displayed significant defects in blood vessel formation and fetal circulation within the yolk sac around embryonic day 10.5, which led to developmental retardation and death. We found that SRG3 expression was absent in the visceral endoderm of Srg3−/−Tg+ yolk sacs, while SRG3 was normally expressed in wild-type embryos. In addition, expression of angiogenesis-related genes, including Angiopoietin1, Tie2, EphrinB2, Ihh and Notch1, was markedly reduced in Srg3−/−Tg+ yolk sacs. During normal angiogenesis, maturation of the visceral endoderm development is observed in the yolk sac. However, in Srg3−/−Tg+ yolk sacs, the visceral endoderm did not develop normally. Our results indicate that SRG3 is required for angiogenesis and visceral endoderm development in the yolk sac.
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- 2008
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10. Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell linesin vitroand in nude mice xenografts
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Hyun-Jun Kim, Kiseok Jang, Young-mi Jung, Jeong-Yeon Lee, Dong-Hui Shin, Mi-Yun Oh, Kun Ho Son, Su Jin Jeon, Gu Kong, and Heekyoung Chung
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Cancer Research ,medicine.medical_specialty ,Programmed cell death ,Receptor, ErbB-2 ,Mice, Nude ,Estrogen receptor ,Apoptosis ,Breast Neoplasms ,Biology ,Mice ,chemistry.chemical_compound ,Wogonin ,Cyclin D1 ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Protein kinase B ,Cell Proliferation ,Mice, Inbred BALB C ,Cell growth ,Akt/PKB signaling pathway ,Estrogen Receptor alpha ,Xenograft Model Antitumor Assays ,Endocrinology ,Oncology ,chemistry ,Caspases ,Flavanones ,Cancer cell ,Cancer research ,Female ,Drugs, Chinese Herbal ,Signal Transduction - Abstract
Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of wogonin in human breast cancer. Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral wogonin was examined on tumor xenograft growth in athymic nude mice. The molecular changes associated with the biological effects of wogonin were analyzed by immunoblotting. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by upregulation of PARP and Caspase 3 cleavages as well as proapoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the downregulation of the Akt-mediated canonical Wnt signaling pathway. ER expression was downregulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemopreventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types.
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- 2008
11. Gene expression profiles of murine fatty liver induced by the administration of valproic acid
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Kyung-Sun Kang, Byung-Il Yoon, Il Hong, Mi-Ock Lee, Hyung Lae Kim, Mingoo Kim, Byunghoon Lee, Gu Kong, Minho Lee, Heekyoung Chung, and Ju-Han Kim
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Male ,medicine.medical_specialty ,Microvesicular Steatosis ,Biology ,Toxicology ,Mice ,Internal medicine ,medicine ,Animals ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,chemistry.chemical_classification ,Mice, Inbred ICR ,Valproic Acid ,Catabolism ,Gene Expression Profiling ,Fatty Acids ,Fatty liver ,Fatty acid ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,Fatty Liver ,Gene expression profiling ,Endocrinology ,Liver ,chemistry ,Anticonvulsants ,Steroids ,lipids (amino acids, peptides, and proteins) ,Steatosis ,Signal Transduction ,medicine.drug - Abstract
Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, we profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 h after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 h with low-dose and at 24 h and 72 h with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biological pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.
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- 2007
12. PCGF2 negatively regulates arsenic trioxide-induced PML-RARA protein degradation via UBE2I inhibition in NB4 cells
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Young Lim Lee, Heekyoung Chung, Hongki Lee, Sungsin Jo, and Sojin Kim
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0301 basic medicine ,Acute promyelocytic leukemia ,Time Factors ,Oncogene Proteins, Fusion ,SUMO protein ,Fluorescent Antibody Technique ,Antineoplastic Agents ,Protein degradation ,Transfection ,Arsenicals ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ubiquitin ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,Arsenic trioxide ,Molecular Biology ,Polycomb Repressive Complex 1 ,biology ,HEK 293 cells ,Ubiquitination ,Sumoylation ,Oxides ,Cell Biology ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,HEK293 Cells ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Proteolysis ,Ubiquitin-Conjugating Enzymes ,biology.protein ,UBE2I ,RNA Interference ,Protein Binding ,Signal Transduction - Abstract
Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4. Knockdown of PCGF2 in NB4 cells, in the absence of ATO treatment, was sufficient to induce sumoylation-, ubiquitylation- and PML nuclear body-mediated degradation of PML-RARA protein. Moreover, overexpression of PCGF2 protected ATO-mediated degradation of ectopic and endogenous PML-RARA in 293T and NB4 cells, respectively. In 293T cells, UBE2I-mediated PML-RARA degradation was reduced upon PCGF2 co-expression. In addition, UBE2I-mediated sumoylation of PML-RARA was reduced upon PCGF2 co-expression and PCGF2-UBE2I interaction was confirmed by co-immunoprecipitation. Likewise, endogenous PCGF2-UBE2I interaction was detected by co-immunoprecipitation and immunofluorescence assays in NB4 cells. Intriguingly, upon ATO-treatment, such interaction was disrupted and UBE2I was co-immunoprecipitated or co-localized with its SUMO substrate, PML-RARA. Taken together, our results suggested a novel role of PCGF2 in ATO-mediated degradation of PML-RARA that PCGF2 might act as a negative regulator of UBE2I via direct interaction.
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- 2015
13. Comprehensive analysis of differential gene expression profiles on diclofenac-induced acute mouse liver injury and recovery
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Yong-Sung Lee, Mingoo Kim, Hyun-Jun Kim, Heekyoung Chung, Kiseok Jang, Ju Han Kim, Jungeun Yang, and Gu Kong
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Male ,Diclofenac ,Microarray ,Gene Expression ,Biology ,Toxicology ,Andrology ,Transcriptome ,Mice ,Gene expression ,medicine ,Animals ,Gene ,Oligonucleotide Array Sequence Analysis ,Liver injury ,Mice, Inbred ICR ,Reverse Transcriptase Polymerase Chain Reaction ,Microarray analysis techniques ,Gene Expression Profiling ,Anti-Inflammatory Agents, Non-Steroidal ,General Medicine ,medicine.disease ,Liver Regeneration ,Oxidative Stress ,Liver ,Biochemistry ,Chemical and Drug Induced Liver Injury ,DNA microarray ,medicine.drug - Abstract
Microarray analysis of RNA from diclofenac-administered mouse livers was performed to establish a global gene expression profile during injury and recovery stages at two different doses. A single dose of diclofenac at 9.5 mg/kg or 0.95 mg/kg body weight was given orally, and the liver samples were obtained after 6, 24, and 72 h. Histopathologic studies enabled the classification of the diclofenac effect into injury (6, 24 h) and recovery (72 h) stages. By using the Applied Biosystems Mouse Genome Survey Microarray, a total of 7370 out of 33,315 (22.1%) genes were found to be statistically reliable at p < 0.05 by two-way ANOVA, and 602 (1.8%) probes at false discovery rate
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- 2006
14. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers
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Young Ha Oh, Kiseok Jang, Seung Sam Paik, Gu Kong, and Heekyoung Chung
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Adult ,Cancer Research ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Antigens, CD34 ,Breast Neoplasms ,medicine.disease_cause ,Histone Deacetylases ,Metastasis ,Neovascularization ,Breast cancer ,medicine ,Humans ,Survival analysis ,Neoplasm Staging ,Retrospective Studies ,Neovascularization, Pathologic ,business.industry ,Carcinoma, Ductal, Breast ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Repressor Proteins ,Survival Rate ,Phenotype ,Oncology ,Data Interpretation, Statistical ,Trans-Activators ,Cancer research ,Female ,medicine.symptom ,business ,Carcinogenesis - Abstract
Metastasis associated antigen 1 (MTA1) is a recently identified candidate metastasis-associated gene that plays an important role in tumorigenesis and tumor aggressiveness, especially tumor invasiveness and metastasis. We analyzed the relationship between MTA1 expression and variable clinicopathological features and characterized its role in tumor angiogenesis in human breast cancers. Two hundred and sixty-three breast cancer cases that successfully underwent surgery at Hanyang University Hospital (Seoul, Korea) between January 1989 and December 1997 were enrolled. MTA1 expression was observed by immunohistochemical staining and correlated with intratumoral microvessel density (MVD) and other clinicopathological parameters. MTA1 overexpression correlated significantly with higher tumor grade (grades 1 and 2 vs grade 3, P = 0.009). However, MTA1 expression did not correlate with tumor stage, status of estrogen and progesterone receptors, or axillary lymph node metastasis. Interestingly, MTA1 expression was found to correlate significantly with tumor MVD (P = 0.002). Survival analysis did not show a significant difference between MTA1 overexpression and poorer survival. In conclusion, MTA1 overexpression was found to be closely associated with higher tumor grade and increased tumor angiogenesis. These findings suggest MTA1 as a predictor of aggressive phenotype and a possible target molecule for anti-angiogenic drugs in breast cancer treatment. (Cancer Sci 2006)
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- 2006
15. Nitric Oxide Inhibits Glucocorticoid-induced Apoptosis of Thymocytes by Repressing the SRG3 Expression
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Seung Jeong, Dongho Shin, Sung H. Jeon, Kyoo Y. Lee, Rho Hyun Seong, and Heekyoung Chung
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Thymoma ,Transcription, Genetic ,Sp1 Transcription Factor ,Blotting, Western ,Down-Regulation ,Heterologous ,Apoptosis ,Thymus Gland ,Biology ,Nitric Oxide ,Transfection ,Biochemistry ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Immune system ,Genes, Reporter ,Transcription (biology) ,medicine ,Animals ,Nitric Oxide Donors ,Promoter Regions, Genetic ,Glucocorticoids ,Molecular Biology ,Cell Nucleus ,Sp1 transcription factor ,Dose-Response Relationship, Drug ,Penicillamine ,DNA ,Cell Biology ,Blotting, Northern ,Flow Cytometry ,medicine.disease ,Molecular biology ,Mice, Inbred C57BL ,Gene Expression Regulation ,chemistry ,Electrophoresis, Polyacrylamide Gel ,Oxidation-Reduction ,Glucocorticoid ,Plasmids ,Protein Binding ,Transcription Factors ,medicine.drug - Abstract
Nitric oxide (NO) plays many roles in the immune system. It has been known that NO rescues thymocytes from glucocorticoid (GC)-induced apoptosis. However, the downstream target of NO in the protection from GC-induced thymocyte apoptosis has yet to be identified. We previously reported that GC sensitivity of developing thymocytes is dependent on the expression level of SRG3. In the present report, we found that NO repressed the SRG3 expression in both primary thymocytes and 16610D9 thymoma cells. Specifically, NO down-regulated the transcription of SRG3 via the inactivation of the transcription factor Sp1 DNA-binding activity to the SRG3 promoter. In addition, overexpression of SRG3 by a heterologous promoter reduced NO-mediated rescue of thymocytes from GC-induced apoptosis. These observations strongly suggest that NO may be involved in protecting immature thymocytes from GC-induced apoptosis by repressing the SRG3 expression in thymus.
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- 2004
16. T Cell Receptor Signaling Inhibits Glucocorticoid-induced Apoptosis by Repressing the SRG3 Expression via Ras Activation
- Author
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Kyu Young Lee, Sung H. Jeon, Jiho Jang, Rho Hyun Seong, Jeongeun Ahn, Heekyoung Chung, and Myunggon Ko
- Subjects
MAPK/ERK pathway ,Time Factors ,Transcription, Genetic ,Pyridines ,Apoptosis ,Biochemistry ,Dexamethasone ,Mice ,Phosphatidylinositol 3-Kinases ,Genes, Reporter ,Transcription (biology) ,Gene expression ,Cytotoxic T cell ,Enzyme Inhibitors ,Luciferases ,Promoter Regions, Genetic ,Receptor ,Imidazoles ,Flow Cytometry ,Plasmids ,Protein Binding ,Signal Transduction ,Immunoblotting ,Receptors, Antigen, T-Cell ,Down-Regulation ,Mice, Transgenic ,Thymus Gland ,Biology ,Transfection ,Binding, Competitive ,Immune system ,Proto-Oncogene Proteins ,Animals ,Glucocorticoids ,Molecular Biology ,Transcription factor ,Cell Nucleus ,Flavonoids ,Binding Sites ,Dose-Response Relationship, Drug ,Proto-Oncogene Proteins c-ets ,T-cell receptor ,Cell Biology ,Blotting, Northern ,Precipitin Tests ,Molecular biology ,Enzyme Activation ,Mice, Inbred C57BL ,Repressor Proteins ,Kinetics ,Mutagenesis, Site-Directed ,Trans-Activators ,ras Proteins ,Transcription Factors - Abstract
Activation of T cell antigen receptor (TCR) signaling inhibits glucocorticoid (GC)-induced apoptosis of T cells. However, the detailed mechanism regarding how activated T cells are protected from GC-induced apoptosis is unclear. Previously, we have shown that the expression level of SRG3, a murine homolog of BAF155 in humans, correlated well with the GC sensitivity of T cells either in vitro or in vivo. Intriguingly, the expression of SRG3 decreased upon positive selection in the thymus. Here we have shown that TCR signaling inhibits the SRG3 expression via Ras activation and thereby renders primary thymocytes and some thymoma cells resistant to GC-mediated apoptosis. By using pharmacological inhibitors, we have shown that Ras-mediated down-regulation of the SRG3 gene expression is mediated by MEK/ERK and phosphatidylinositol 3-kinase pathways. Moreover, TCR signals repressed the SRG3 transcription through the putative binding sites for E proteins and Ets family transcription factors in the proximal region of the SRG3 promoter. Introduction of mutations in these elements rendered the SRG3 promoter immune to the Ras or TCR signals. Taken together, these observations suggest that TCR signals result in GC desensitization in immature T cells by repressing SRG3 gene expression via Ras activation.
- Published
- 2004
17. E2A/HEB and Id3 Proteins Control the Sensitivity to Glucocorticoid-induced Apoptosis in Thymocytes by Regulating the SRG3 Expression
- Author
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Sung H. Jeon, Changjin Lee, Rho Hyun Seong, Myunggon Ko, Hee-Y. Chung, Jeongeun Ahn, and Heekyoung Chung
- Subjects
MAPK/ERK pathway ,Transcription, Genetic ,Cellular differentiation ,Apoptosis ,Biochemistry ,Dexamethasone ,Mice ,Genes, Reporter ,Basic Helix-Loop-Helix Transcription Factors ,Promoter Regions, Genetic ,Genetics ,Cell Death ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Differentiation ,hemic and immune systems ,Flow Cytometry ,Neoplasm Proteins ,Cell biology ,DNA-Binding Proteins ,Thymocyte ,Plasmids ,Protein Binding ,Genetic Vectors ,Green Fluorescent Proteins ,Down-Regulation ,Repressor ,Mice, Transgenic ,chemical and pharmacologic phenomena ,E-box ,Thymus Gland ,Biology ,DNA-binding protein ,Animals ,Glucocorticoids ,Molecular Biology ,Transcription factor ,Cell Nucleus ,Dose-Response Relationship, Drug ,T-cell receptor ,DNA ,Cell Biology ,Blotting, Northern ,Protein Structure, Tertiary ,Repressor Proteins ,Luminescent Proteins ,Retroviridae ,Mutagenesis, Site-Directed ,Trans-Activators ,Inhibitor of Differentiation Proteins ,Transcription Factors - Abstract
The E protein family transcription factors encoded by the E2A and HEB genes are known to play critical roles in the coordinate regulation of lymphocyte development. Previous studies have shown that T cell receptor (TCR) signals rapidly induce Id3, a dominant negative antagonist of E2A activity and allow thymocytes to survive selection events in the thymus. Here we show that SRG3 acts as a novel downstream target of E2A/HeLa E box-binding (HEB) complex and modulates glucocorticoid (GC) susceptibility in thymocytes in response to TCR signals. We have identified a putative E box element in the SRG3 promoter that is required for optimal promoter activity. The transcription factors E2A and HEB specifically associate with the E box element. Moreover, E2A-HEB heterodimers cooperated to activate SRG3 transcription, which was inhibited by the expression of Id proteins. TCR-mediated signals rapidly induced Id3 via MEK/ERK activation and thereby kept the E2A/HEB complex from binding to the E box element in the SRG3 promoter. Retroviral transduction of Id3 also repressed the SRG3 expression by inhibiting the E box binding activity of the E2A/HEB complex. Intriguingly, enforced Id3 expression conferred thymocyte resistance to GCs, which could be overcome by the overexpression of SRG3. Taken together, these results suggest that Id3 may enhance the viability of immature thymocytes by at least rendering them resistant to GCs through SRG3 down-regulation.
- Published
- 2004
18. Srg3, a Mouse Homolog of Yeast SWI3, Is Essential for Early Embryogenesis and Involved in Brain Development
- Author
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Dongho Shin, Keesook Lee, Changjin Lee, Rho Hyun Seong, Sang D. Park, Hyun Kim, Ju-Suk Nam, Joong K. Kim, Heekyoung Chung, Han W. Lee, Heonsik Choi, and Sung-Oh Huh
- Subjects
Male ,Heterozygote ,Saccharomyces cerevisiae Proteins ,Cellular differentiation ,Mutant ,Gene Expression ,Saccharomyces cerevisiae ,Exencephaly ,Biology ,Chromatin remodeling ,Fungal Proteins ,Gene product ,Embryonic and Fetal Development ,Mice ,Mammalian Genetic Models with Minimal or Complex Phenotypes ,medicine ,Animals ,Humans ,Inner cell mass ,Neural Tube Defects ,Molecular Biology ,Mice, Knockout ,Brain ,Nuclear Proteins ,Embryo ,Cell Biology ,medicine.disease ,Null allele ,Molecular biology ,Mice, Inbred C57BL ,Repressor Proteins ,Trans-Activators ,Female - Abstract
Srg3 (SWI3-related gene product) is a mouse homolog of yeast SWI3, Drosophila melanogaster MOIRA (also named MOR/BAP155), and human BAF155 and is known as a core subunit of SWI/SNF complex. This complex is involved in the chromatin remodeling required for the regulation of transcriptional processes associated with development, cellular differentiation, and proliferation. We generated mice with a null mutation in the Srg3 locus to examine its function in vivo. Homozygous mutants develop in the early implantation stage but undergo rapid degeneration thereafter. An in vitro outgrowth study revealed that mutant blastocysts hatch, adhere, and form a layer of trophoblast giant cells, but the inner cell mass degenerates after prolonged culture. Interestingly, about 20% of heterozygous mutant embryos display defects in brain development with abnormal organization of the brain, a condition known as exencephaly. Histological examination suggests that exencephaly is caused by the failure in neural fold elevation, resulting in severe brain malformation. Our findings demonstrate that Srg3 is essential for early embryogenesis and plays an important role in the brain development of mice.
- Published
- 2001
19. Lobarstin enhances chemosensitivity in human glioblastoma T98G cells
- Author
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Sojin, Kim, Sungsin, Jo, Hongki, Lee, Tae Ue, Kim, Il-Chan, Kim, Joung Han, Yim, and Heekyoung, Chung
- Subjects
Base Sequence ,DNA Repair ,Brain Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Antineoplastic Agents ,Drug Synergism ,Dacarbazine ,O(6)-Methylguanine-DNA Methyltransferase ,Cell Line, Tumor ,Hydroxybenzoates ,Temozolomide ,Humans ,Comet Assay ,Glioblastoma ,Benzofurans ,DNA Damage ,DNA Primers - Abstract
Lobarstin is a metabolite occurring from the Antarctic lichen Stereocaulon alpnum. Human glioblastoma is highly resistant to chemotherapy with temozolomide. Lobarstin was examined for its effect on glioblastoma.Temozolomide-resistant T98G cells were subjected to toxicity test with temozolomide and/or lobarstin. DNA damage and recovery was assessed by the alkaline comet assay and expression of DNA repair genes was examined by RT-PCR and western blot analysis.Lobarstin alone at 40 μM was toxic against T98G, but had no effect in primary human fibroblasts. Co-treatment of lobarstin with temozolomide yielded enhanced toxicity. Temozolomide-alone or with lobarstin co-treatment gave similar extent of DNA damage. However, the recovery was reduced in co-treated cells. Expression of DNA repair genes, O(6)-methylguanine-DNA methyltransferase, poly(ADP-ribose) polymerase 1 and ligase 3 were reduced in lobarstin-treated cells.Enhanced sensitivity to temozolomide by lobarstin co-treatment may be attributed to reduced DNA repair.
- Published
- 2013
20. Isolation of UV-Inducible Transcripts from Schizosaccharomyces pombe
- Author
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Cheol O. Joe, Seung Hwan Hong, Heekyoung Chung, Joon Kyu Lee, Eun Jung Park, and Sang Dai Park
- Subjects
Methylnitronitrosoguanidine ,DNA, Complementary ,Ultraviolet Rays ,Molecular Sequence Data ,Saccharomyces cerevisiae ,Biophysics ,Biochemistry ,Fungal Proteins ,chemistry.chemical_compound ,Mitotic cell cycle ,Complementary DNA ,Schizosaccharomyces ,Nucleotide ,Amino Acid Sequence ,RNA, Messenger ,DNA, Fungal ,Molecular Biology ,Gene ,Glycoproteins ,chemistry.chemical_classification ,Base Sequence ,biology ,Subtraction hybridization ,Dose-Response Relationship, Radiation ,Sequence Analysis, DNA ,Cell Biology ,Methyl Methanesulfonate ,biology.organism_classification ,Molecular biology ,Kinetics ,chemistry ,Schizosaccharomyces pombe ,DNA ,DNA Damage - Abstract
Four UV-inducible cDNA clones, UV115 , UV118 , UV122 and UV131 , were isolated from Schizosaccharomyces pombe by subtraction hybridization. All transcripts of these clones were rapidly induced about 5 to 10 fold within 1 hour after UV-irradiation and the nucleotide sequences of these clones did not showed any significant sequence homology to the known genes in the data bases. Transcripts of UV118 and UV131 were induced only by UV-irradiation and those of UV122 were also induced by alkylating agents, suggesting that inductions of these transcripts are specific responses to DNA damages. However, transcript levels of UV115 were also increased by other cytotoxic agents including heat shock. These results indicate that UV115 might be a stress responsive gene.
- Published
- 1994
21. A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice
- Author
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Dongkyu Shin, Sung Hee Choi, Young Sun Chung, Gyu Hwan Yon, Gha Young Lee, Seonggu Ro, Hyun-Woo Jeong, Hye Ryung Kim, Sung Sik Choe, Heekyoung Chung, Hyunjung Shin, Bongjun Cho, Hyun-Kyu Lee, Jun Hee Lee, Joo-Won Lee, Eun Bok Choi, W. S. Kim, Jae Bum Kim, and Seung Bum Park
- Subjects
Agonist ,medicine.medical_specialty ,Transcription, Genetic ,medicine.drug_class ,Peroxisome proliferator-activated receptor ,Mice, Obese ,Carbohydrate metabolism ,Biology ,Mice ,Insulin resistance ,Internal medicine ,medicine ,Adipocytes ,Animals ,PPAR alpha ,PPAR delta ,Receptor ,Beta oxidation ,Oxazoles ,Cells, Cultured ,Pharmacology ,chemistry.chemical_classification ,Macrophages ,Fatty Acids ,Lipid metabolism ,Stereoisomerism ,medicine.disease ,Lipid Metabolism ,Endocrinology ,Glucose ,chemistry ,Gene Expression Regulation ,Matrix Metalloproteinase 9 ,Cyclooxygenase 2 ,Pipecolic Acids ,Molecular Medicine ,Cytokines ,Peroxisome proliferator-activated receptor delta ,Insulin Resistance ,Oxidation-Reduction - Abstract
Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPARα agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPARγ agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPARα/γ dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPARα/γ dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPARα/γ dual agonist, (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPARα and PPARγ and induced expression of their target genes in a PPARα- and PPARγ-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPARα/γ agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.
- Published
- 2010
22. Normal Adult Hippocampal Neurogenesis in SRG3-overexpressing Transgenic Mice
- Author
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Heekyoung Chung, Byung-Woo Kim, Hyeon Son, Rho Hyun Seong, and Eu-Gene Lee
- Subjects
Genetically modified mouse ,proliferation ,Embryogenesis ,Neurogenesis ,SWI/SNF complx ,differentiation ,Biology ,Hippocampal formation ,Embryonic stem cell ,adult hippocampal neurogenesis ,survival ,Chromatin remodeling ,Neural stem cell ,Cell biology ,Cellular and Molecular Neuroscience ,Knockout mouse ,Neurology (clinical) ,Original Research Article ,SRG3 (SWI3-related gene) ,Neuroscience - Abstract
SRG3 (SWI3-related gene) is a core subunit of mouse SWI/SNF complex and is known to play a critical role in stabilizing the SWI/SNF complex by attenuating its proteasomal degradation. SWI/SNF chromatin remodeling complex is reported to act as an important endogenous regulator in the proliferation and differentiation of mammalian neural stem cells. Because limited expression of SRG3 occurs in the brain and thymus during mouse embryogenesis, it was hypothesized that the altered SRG3 expression level might affect the process of adult hippocampal neurogenesis. Due to the embryonic lethality of homozygous knockout mice, this study focuses on dissecting the effect of overexpressed SRG3 on adult hippocampal neurogenesis. The BrdU incorporation assay, immunostaing with neuronal markers for each differentiation stage, and imunoblotting analysis with intracellular molecules involved in survival in adult hippocampal neurogenesis found no alteration, suggesting that the overexpression of SRG3 protein in mature neurons had no effect on the entire process of adult hippocampal neurogenesis including proliferation, differentiation, and survival.
- Published
- 2010
23. Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors
- Author
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Deok-Jin Jang, Min Zhuo, Nuribalhae Lee, Sunghyun Kim, Yong-Seok Kim, Woon Ryoung Kim, Heekyoung Chung, Junehee Son, Ted Abel, Bong-Kiun Kaang, Hyeon Son, Byung-Woo Kim, Jeong-Sik Lee, Mun-Yong Lee, Hyoung-Gon Ko, Hyoung F. Kim, and Woong Sun
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Electrophoretic Mobility Shift Assay ,Hippocampal formation ,chemistry.chemical_compound ,Mice ,Cyclic AMP ,Vasoconstrictor Agents ,RNA, Small Interfering ,Receptor ,Cell Line, Transformed ,Neurons ,biology ,Behavior, Animal ,Depression ,General Neuroscience ,Neurogenesis ,CREB-Binding Protein ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Antidepressive Agents, Second-Generation ,medicine.medical_specialty ,Chromatin Immunoprecipitation ,Mice, Transgenic ,Transfection ,Article ,Food Preferences ,Receptors, Biogenic Amine ,Internal medicine ,Fluoxetine ,medicine ,Animals ,Humans ,CREB-binding protein ,Maze Learning ,Octopamine ,Brain-derived neurotrophic factor ,Analysis of Variance ,Dentate gyrus ,Brain-Derived Neurotrophic Factor ,Feeding Behavior ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,nervous system ,Bromodeoxyuridine ,Gene Expression Regulation ,Dentate Gyrus ,biology.protein ,Exploratory Behavior - Abstract
The cAMP cascade and vascular endothelial growth factor (VEGF) are critical modulators of depression. Here we have tested whether the antidepressive effect of the cAMP cascade is mediated by VEGF in the adult hippocampus. We used a conditional genetic system in which the Aplysia octopamine receptor (Ap oa(1)), a G(s)-coupled receptor, is transgenically expressed in the forebrain neurons of mice. Chronic activation of the heterologous Ap oa(1) by its natural ligand evoked antidepressant-like behaviors, accompanied by enhanced phosphorylation of cAMP response element-binding protein and transcription of VEGF in hippocampal dentate gyrus (DG) neurons. Selective knockdown of VEGF in these cells during the period of cAMP elevation inhibited the antidepressant-like behaviors. These findings reveal a molecular interaction between the cAMP cascade and VEGF expression, and the pronounced behavioral consequences of this interaction shed light on the mechanism underlying neuronal VEGF functions in antidepression.
- Published
- 2009
24. Time- and dose-based gene expression profiles produced by a bile-duct-damaging chemical, 4,4'-methylene dianiline, in mouse liver in an acute phase
- Author
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Byung Il Yoon, Jung Yeon Yi, Hyung Lae Kim, Jae Wong Hwang, Mingoo Kim, Byung-Hoon Lee, Ju Han Kim, Gu Kong, Joon Suk Park, Sun Bom Kwon, Heekyoung Chung, Mi-Ock Lee, and Kyung-Sun Kang
- Subjects
medicine.medical_specialty ,Pathology ,Time Factors ,Chemical compound ,Ratón ,Apoptosis ,Pharmacology ,Biology ,Toxicology ,Models, Biological ,Toxicogenetics ,Pathology and Forensic Medicine ,chemistry.chemical_compound ,Mice ,Random Allocation ,Liver Function Tests ,Oral administration ,Gene expression ,medicine ,Animals ,Aspartate Aminotransferases ,RNA, Messenger ,Acute-Phase Reaction ,Molecular Biology ,Mice, Inbred ICR ,Aniline Compounds ,Dose-Response Relationship, Drug ,Gene Expression Profiling ,Cell Cycle ,Alanine Transaminase ,Bilirubin ,Cell Biology ,Th1 Cells ,Specific Pathogen-Free Organisms ,Genes, cdc ,Oxidative Stress ,chemistry ,Liver ,Biliary tract ,Toxicity ,Carcinogens ,Histopathology ,Bile Ducts ,Toxicogenomics - Abstract
A toxicogenomics study was performed in the mouse liver after treatment of a bile-duct–damaging chemical, 4,4′-methylene dianiline (MDA), across multiple doses and sampling times in an acute phase using the AB Expression Array System. Imprinting control region (ICR) mice were given a single oral administration of a low (10 mg/kg b.w.) or high (100 mg/kg b.w.) dose of MDA. Mice were sacrificed six, twenty-four, and seventy-two hours after treatment for serum chemistry, histopathology, and mRNA preparation from liver samples. Treatment with MDA increased liver-toxicity–related enzymes in blood and induced bile-duct cell injury, followed by regeneration. To explore potential biomarker gene profiles, the altered genes were categorized into four expression patterns depending on dose and time. Numerous functionally defined and unclassified genes in each category were up- or down-regulated throughout the period from cellular injury to the recovery phase, verified by RT-PCR. Many genes associated with liver toxicity and diseases belonged to one of these categories. The chemokine-mediated Th1 pathway was implicated in the inflammatory process. The genes associated with oxidative stress, apoptosis, and cell-cycle regulation were also dynamically responsive to MDA treatment. The Wnt/β-catenin signaling pathway was likely responsible for the reconstitution process of the MDA-injured liver.
- Published
- 2008
25. Id-1 regulates Bcl-2 and Bax expression through p53 and NF-kappaB in MCF-7 breast cancer cells
- Author
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Gu Kong, Hyun-Jun Kim, Yong-Seok Kim, Heekyoung Chung, Hwan Kim, Jeong-Yeon Lee, and Mi-Yun Oh
- Subjects
Inhibitor of Differentiation Protein 1 ,Cancer Research ,Programmed cell death ,Indoles ,Time Factors ,Tumor suppressor gene ,Paclitaxel ,Cell ,Apoptosis ,Breast Neoplasms ,Biology ,Cell Line, Tumor ,Gene expression ,medicine ,Humans ,MTT assay ,bcl-2-Associated X Protein ,Interleukin-6 ,NF-kappa B ,Cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,MCF-7 ,Proto-Oncogene Proteins c-bcl-2 ,Cancer research ,Breast disease ,Tumor Suppressor Protein p53 ,Subcellular Fractions - Abstract
Although increasing evidence supports the protective role of inhibitor of differentiation and DNA binding-1 (Id-1) against anticancer drug-induced apoptosis, the underlying molecular mechanisms seem to vary depending on the tumor system. Here, we examined the direct role of Id-1 in MCF-7 breast cancer cells by ectopically overexpressing Id-1 under serum-free condition, where the endogenous Id-1 expression was suppressed. Id-1 expression resulted in increased number of viable cells, reduced Bax expression, enhanced Bcl-2 expression, but no change in Bcl-xL expression. The expression of nuclear factor-kappaB (NF-kappaB) was augmented, while those of p53 and IkappaB were reduced. Such changes in p53 and NF-kappaB pathways were also functional, as assessed by real-time polymerase chain reactions and reporter assays of their known downstream targets, p21 and Il-6, as well as Bax and Bcl-2 genes. Finally, Id-1 played a protective role against taxol-induced apoptosis in breast cancer cells as assessed by MTT assay and apoptotic cell count upon taxol treatment (0-200 nM). Reduced Bax expression and enhanced Bcl-2 expression by Id-1 were also noted in the presence of taxol. Taken together, we present a molecular mechanism where Id-1 regulates p53 and NF-kappaB pathways, which in turn regulates Bax and Bcl-2 genes, thus providing a survival advantage under exogenous stress such as serum-free or taxol treatment in MCF-7 breast cancer cells. In this regard, inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of breast cancer progression and anti-cancer drug resistance.
- Published
- 2007
26. Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver
- Author
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Byung Il Yoon, Byung-Hoon Lee, Gu Kong, Mi-Ock Lee, Mingoo Kim, Ju Han Kim, Kyung-Sun Kang, Hyung Lae Kim, Heekyoung Chung, and Min-Ho Lee
- Subjects
Male ,medicine.medical_specialty ,Administration, Oral ,Gene Expression ,Biology ,Toxicology ,Biological pathway ,chemistry.chemical_compound ,Mice ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Triglycerides ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,chemistry.chemical_classification ,Valproic Acid ,Mice, Inbred ICR ,Triglyceride ,Dose-Response Relationship, Drug ,Cholesterol ,Gene Expression Profiling ,Fatty liver ,Fatty acid ,Lipid metabolism ,medicine.disease ,Lipid Metabolism ,Fatty Liver ,Endocrinology ,chemistry ,Liver ,lipids (amino acids, peptides, and proteins) ,Anticonvulsants ,Chemical and Drug Induced Liver Injury ,Toxicogenomics ,medicine.drug - Abstract
Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceride concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P0.05) and fold change (1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid beta-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity.
- Published
- 2007
27. Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha
- Author
-
Jeong-Yeon Lee, Mi-Ock Lee, Hyun-Jun Kim, Heekyoung Chung, Hwan Kim, Gu Kong, and Young-Gun Yoo
- Subjects
MAPK/ERK pathway ,Inhibitor of Differentiation Protein 1 ,Vascular Endothelial Growth Factor A ,Cancer Research ,Transcription, Genetic ,MAP Kinase Signaling System ,Biology ,Vascular endothelial growth inhibitor ,Transfection ,chemistry.chemical_compound ,Humans ,Cyclic AMP Response Element-Binding Protein ,Promoter Regions, Genetic ,Molecular Biology ,Cells, Cultured ,Tube formation ,Cell Nucleus ,Kinase ,Endothelial Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell biology ,Vascular endothelial growth factor B ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Protein Transport ,Oncology ,Hypoxia-inducible factors ,chemistry ,Gene Expression Regulation ,Cancer research ,Protein Binding - Abstract
Inhibitor of DNA binding 1 (Id-1) has been implicated in tumor angiogenesis by regulating the expression of vascular endothelial growth factor (VEGF), but its molecular mechanism has not been fully understood. Here, we show the cross talk between Id-1 and hypoxia-inducible factor-1α (HIF-1α), that Id-1 induces VEGF by enhancing the stability and activity of HIF-1α in human endothelial and breast cancer cells. Although both the transcript and proteins levels of VEGF were induced by Id-1, only the protein expression of HIF-1α was induced without transcriptional changes in both human umbilical endothelial cells and MCF7 breast cancer cells. Such induction of the HIF-1α protein did not require de novo protein synthesis but was dependent on the active extracellular response kinase (ERK) pathway. In addition, stability of the HIF-1α protein was enhanced in part by the reduced association of the HIF-1α protein with von Hippel-Lindau protein in the presence of Id-1. Furthermore, Id-1 enhanced nuclear translocation and the transcriptional activity of HIF-1α. Transcriptional activation of HIF-1–dependent promoters was dependent on the active ERK pathway, and the association of HIF-1α protein with cyclic AMP-responsive element binding protein was enhanced by Id-1. Finally, Id-1 induced tube formation in human umbilical endothelial cells, which also required active ERK signaling. In conclusion, we provide the molecular mechanism of the cross talk between HIF-1α and Id-1, which may play a critical role in tumor angiogenesis. (Mol Cancer Res 2007;5(4):321–9)
- Published
- 2007
28. SRG3 interacts directly with the major components of the SWI/SNF chromatin remodeling complex and protects them from proteasomal degradation
- Author
-
Changjin Lee, Kyoo Y. Lee, Jaehak Oh, Dong H. Sohn, Sung H. Jeon, Heekyoung Chung, and Rho Hyun Seong
- Subjects
Proteasome Endopeptidase Complex ,Saccharomyces cerevisiae Proteins ,Chromosomal Proteins, Non-Histone ,cells ,Cellular differentiation ,genetic processes ,Cell Cycle Proteins ,macromolecular substances ,Saccharomyces cerevisiae ,Biochemistry ,Chromatin remodeling ,Mice ,Chlorocebus aethiops ,Animals ,Drosophila Proteins ,Chromatin structure remodeling (RSC) complex ,SMARCB1 ,Molecular Biology ,Gene ,Cells, Cultured ,Mice, Knockout ,COS cells ,biology ,Sequence Homology, Amino Acid ,Chemistry ,DNA Helicases ,Nuclear Proteins ,Cell Biology ,SMARCB1 Protein ,Chromatin Assembly and Disassembly ,Molecular biology ,SWI/SNF ,Cell biology ,enzymes and coenzymes (carbohydrates) ,COS Cells ,biology.protein ,Trans-Activators ,Drosophila ,biological phenomena, cell phenomena, and immunity ,SANT domain ,Transcription Factors - Abstract
The mammalian SWI/SNF complex is an evolutionarily conserved ATP-dependent chromatin remodeling complex that consists of nine or more components. SRG3, a murine homologue of yeast SWI3, Drosophila MOIRA, and human BAF155, is a core component of the murine SWI/SNF complex required for the regulation of transcriptional processes associated with development, cellular differentiation, and proliferation. Here we report that SRG3 interacts directly with other components of the mammalian SWI/SNF complex such as SNF5, BRG1, and BAF60a. The SWIRM domain and the SANT domain were required for SRG3-SNF5 and SRG3-BRG1 interactions, respectively. In addition, SRG3 stabilized SNF5, BRG1, and BAF60a by attenuating their proteasomal degradation, suggesting its general role in the stabilization of the SWI/SNF complex. Such a stabilization effect of SRG3 was not only observed in the in vitro cell system, but also in cells isolated from SRG3 transgenic mice or knock-out mice haploinsufficient for the Srg3 gene. Taken together, these results suggest the critical role of SRG3 in the post-transcriptional stabilization of the major components of the SWI/SNF complex.
- Published
- 2007
29. Comprehensive analysis of differential gene expression profiles on D-galactosamine-induced acute mouse liver injury and regeneration
- Author
-
Hyung Lae Kim, Byung-Hoon Lee, Hyun-Jun Kim, Ju Han Kim, Kiseok Jang, Kyung-Sun Kang, Mingoo Kim, Yong Sung Lee, Byung Il Yoon, Heekyoung Chung, Jungeun Yang, Gu Kong, and Mi-Ock Lee
- Subjects
Male ,Microarray ,Molecular Sequence Data ,Gene Expression ,Galactosamine ,Biology ,Toxicology ,Transcriptome ,Mice ,Gene expression ,medicine ,Animals ,RNA, Messenger ,Gene ,Oligonucleotide Array Sequence Analysis ,Liver injury ,Messenger RNA ,Mice, Inbred ICR ,Microarray analysis techniques ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Cell Cycle ,medicine.disease ,Molecular biology ,Liver Regeneration ,Liver ,Acute Disease ,DNA microarray ,Chemical and Drug Induced Liver Injury - Abstract
Microarray analysis of RNA from d-galactosamine (GalN)-administered mouse livers was performed to establish a global gene expression profile during injury and regeneration stages at two different doses. A single dose of GalN at 266 or 26.6 mg/kg body weight was given intraperitoneally, and the liver samples were obtained after 6, 24, and 72 h. Histopathologic studies enabled the classification of the d-galactosamine effect into injury (6, 24 h) and regeneration (72 h) stages. By using the Applied Biosystems mouse genome survey microarray, a total of 7267 out of 33,315 (21.8%) genes were found to be statistically reliable at p < 0.05 by two-way ANOVA, and 1469 (4.4%) probes at false discovery rate
- Published
- 2006
30. The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers
- Author
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Hyun-Jun Kim, Sung-Dae Cho, Lak Shin Jeong, Heekyoung Chung, Dae Hong Shin, Ji-Youn Jung, Hwan Kim, Kyung-A Hong, Gu Kong, Hea Ok Kim, Dong-Hui Shin, and Hyuk Woo Lee
- Subjects
Agonist ,Cancer Research ,Adenosine ,medicine.drug_class ,Receptor, ErbB-2 ,Estrogen receptor ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Pharmacology ,Biology ,Mice ,Adenosine A3 Receptor Agonists ,medicine ,Enzyme-linked receptor ,Animals ,Humans ,Receptor ,Estrogen receptor beta ,Cell Proliferation ,Thionucleosides ,Caspase 3 ,Wnt signaling pathway ,Estrogen Receptor alpha ,Xenograft Model Antitumor Assays ,Wnt Proteins ,Oncology ,Caspases ,Estrogen-related receptor gamma ,Poly(ADP-ribose) Polymerases ,Estrogen receptor alpha ,Cyclin-Dependent Kinase Inhibitor p27 ,Signal Transduction - Abstract
Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) α status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c–poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27kip was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types. [Mol Cancer Ther 2006;5(3):685–92]
- Published
- 2006
31. Rescuing developing thymocytes from death by neglect
- Author
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Myunggon Ko, Young In Choi, Rho Hyun Seong, and Heekyoung Chung
- Subjects
Transcriptional Activation ,Programmed cell death ,Cellular differentiation ,T-Lymphocytes ,T-cell receptor ,Receptors, Antigen, T-Cell ,Apoptosis ,Cell Differentiation ,General Medicine ,Thymus Gland ,Biology ,Biochemistry ,Protein Structure, Tertiary ,Crosstalk (biology) ,Antigen ,Immunology ,Animals ,Humans ,Signal transduction ,Receptor ,Molecular Biology ,Neuroscience ,Glucocorticoids ,Signal Transduction - Abstract
The major function of the thymus is to eliminate developing thymocytes that are potentially useless or autoreactive, and select only those that bear functional T cell antigen receptors (TCRs) through fastidious screening. It is believed that glucocorticoids (GCs) are at least in part responsible for cell death during death by neglect. In this review, we will mainly cover the topic of the GC-induced apoptosis of developing thymocytes. We will also discuss how thymocytes that are fated to die by GCs can be rescued from GC-induced apoptosis in response to a variety of signals with antagonizing properties for GC receptor (GR) signaling. Currently, a lot of evidence supports the notion that the decision is made as a result of the integration of the multiple signal transduction networks that are triggered by GR, TCR, and Notch. A few candidate molecules at the converging point of these multiple signaling pathyways will be discussed. We will particularly describe the role of the SRG3 protein as a potent modulator of GC-induced apoptosis in the crosstalk.
- Published
- 2005
32. Protein kinase D1 and the beta 1 integrin cytoplasmic domain control beta 1 integrin function via regulation of Rap1 activation
- Author
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Deborah M. Dickey, Rebecca Vasconcellos Botelho de Medeiros, Heekyoung Chung, Yoji Shimizu, Lakshmi R. Nagarajan, Angie C. Quale, and Daniel D. Billadeau
- Subjects
endocrine system ,Cytoplasm ,Recombinant Fusion Proteins ,T-Lymphocytes ,Integrin ,Immunology ,Biology ,urologic and male genital diseases ,CD49c ,Collagen receptor ,03 medical and health sciences ,Jurkat Cells ,0302 clinical medicine ,Genes, Reporter ,Cell Adhesion ,Immunology and Allergy ,Humans ,Integrin-linked kinase ,Protein Kinase C ,030304 developmental biology ,0303 health sciences ,Integrin beta1 ,rap1 GTP-Binding Proteins ,female genital diseases and pregnancy complications ,Cell biology ,Fibronectins ,Protein Structure, Tertiary ,Pleckstrin homology domain ,enzymes and coenzymes (carbohydrates) ,Infectious Diseases ,Integrin alpha M ,030220 oncology & carcinogenesis ,embryonic structures ,Mutation ,biology.protein ,Integrin, beta 6 ,ITGA6 - Abstract
The functional activity of integrins is dynamically regulated by T cell receptor stimulation and by protein kinase C (PKC). We report a novel function for the PKC effector protein kinase D1 (PKD1) in integrin activation. Constitutively active and kinase-inactive PKD1 mutants lacking the PKD1 pleckstrin homology (PH) domain block phorbol ester- and TCR-mediated activation and clustering of beta1 integrins. The PH domain of PKD1 mediates the association of PKD1 with the GTPase Rap1 and is central to Rap1 activation and membrane translocation in T cells. Furthermore, PKD1 and Rap1 associate with beta1 integrins in a manner that is dependent on the carboxy-terminal end of the beta1 integrin subunit cytoplasmic domain. beta1 integrin expression is required for Rap1 activation and membrane localization of the PKD1-Rap1 complex. Therefore, PKD1 promotes integrin activation in T cells by regulating Rap1 activation and membrane translocation via interactions with the beta1 integrin subunit cytoplasmic domain.
- Published
- 2005
33. Differential gene expression profiles in the steatosis/fibrosis model of rat liver by chronic administration of carbon tetrachloride
- Author
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Dong-Mi Shin, Joon-Ik Ahn, Hyun-Jun Kim, Gu Kong, Kiseok Jang, Doo-Pyo Hong, Heekyoung Chung, and Yong-Sung Lee
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Time Factors ,Biology ,Toxicology ,Drug Administration Schedule ,Rats, Sprague-Dawley ,Fibrosis ,Internal medicine ,Gene expression ,medicine ,Animals ,Aspartate Aminotransferases ,Carbon Tetrachloride ,Pharmacology ,Microarray analysis techniques ,Gene Expression Profiling ,Fatty liver ,Hepatotoxin ,Alanine Transaminase ,medicine.disease ,Microarray Analysis ,Rats ,Fatty Liver ,Disease Models, Animal ,Endocrinology ,Significance analysis of microarrays ,Steatosis - Abstract
Global gene expression profile was analyzed by microarray analysis of rat liver RNA after chronic carbon tetrachloride (CCl 4 ) administration. Rats received 0.5 ml CCl 4 /kg three times a week, and the liver samples were obtained after 0, 30, 60, and 90 days of injection. Histopathologic studies of liver tissues enabled the classification of the CCl 4 effect into mild and severe fatty liver/steatosis (30 and 60 days, respectively) and fibrosis/cirrhosis (90 days) stages. The expression levels of 4900 clones on a custom rat gene microarray were analyzed and the results were confirmed by semi-quantitative RT-PCR. Four hundred thirty-eight clones were differentially expressed with more than a 1.625-fold difference (which equals 0.7 in log2 scale) at one or more time points. Multiple genes involved in lipid metabolism and ribosome biogenesis showed differential transcript levels upon chronic CCl 4 administration, which was previously seen in acute rat model as well. In addition, a total of 149 clones were identified as fibrosis/cirrhosis-specific genes by either fold changes or Significance Analysis of Microarrays. In conclusion, we report microarray analysis results in rat liver upon chronic CCl 4 administration with a full chronological profile that not only covered fatty liver/steatosis but also later points of fibrosis/cirrhosis. These data will provide the insight of specific gene expression profiles that is implicated in the multistep process of fatty liver/steatosis and fibrosis/cirrhosis after chronic hepatotoxin exposure.
- Published
- 2005
34. Comprehensive analysis of differential gene expression profiles on carbon tetrachloride-induced rat liver injury and regeneration
- Author
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Kiseok Jang, Yhun-Yhong Sheen, Hyun-Jun Kim, Yong-Sung Lee, Gu Kong, Doo-Pyo Hong, Joon-Ik Ahn, Heekyoung Chung, and Ji-Youn Jung
- Subjects
Pharmacology ,Regulation of gene expression ,Male ,Microarray analysis techniques ,Carbon Tetrachloride Poisoning ,Regeneration (biology) ,Fatty liver ,CCL4 ,Biology ,Toxicology ,medicine.disease ,digestive system ,Molecular biology ,Liver regeneration ,Liver Regeneration ,Rats ,Fatty Liver ,Rats, Sprague-Dawley ,Gene Expression Regulation ,Gene expression ,medicine ,Animals ,Gene ,Oligonucleotide Array Sequence Analysis ,Signal Transduction - Abstract
Microarray analysis of RNA from carbon tetrachloride (CCl4)-administered rat livers was performed at various time points to establish a global gene expression profile during injury and regeneration stages. A single dose of 1 ml/kg of CCl4 was given by ip injection, and the liver samples were obtained after 6, 24, 48 h, and 2 weeks. Histopathologic, biochemical, and immunohistochemical studies enabled the classification of the CCl4 effect into injury (6 and 24 h) and regeneration (48 h and 2 weeks) stages. The expression levels of 5180 clones on a custom rat gene microarray were analyzed and 587 clones yielded changeable gene expression on at least single time point. One hundred seventy-nine clones were classified as injury-specific clones, while 38 clones as regeneration-specific clones. Characteristic gene expression profiles could be associated with CCl4-induced gene expression with the disruption of lipid metabolism, which is known to cause the fatty liver induced by CCl4 treatment. In addition, induction of the transcripts for many ribosomal proteins was detected during the injury stage, particularly at the 24-h time point, despite the previous report of decreased protein synthesis rate upon CCl4 treatment. Several genes with known functions were also identified as CCl4-regulated genes. In conclusion, we established a global gene expression profile utilizing microarray analysis in rat liver upon acute CCl4 administration with a full chronological profile that not only covers injury stage but also later points of regeneration stage.
- Published
- 2004
35. CD104
- Author
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Jonathan T. Pribila, Heekyoung Chung, and Yoji Shimizu
- Published
- 2002
36. Notch1 confers a resistance to glucocorticoid-induced apoptosis on developing thymocytes by down-regulating SRG3 expression
- Author
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Joong K. Kim, Sung H. Jeon, Heekyoung Chung, Han W. Lee, Young Il Choi, Rho Hyun Seong, Sunmi Han, Sang D. Park, Hee Y. Chung, and Jiho Jang
- Subjects
Male ,Cellular differentiation ,Transgene ,T-Lymphocytes ,Drug Resistance ,Repressor ,Down-Regulation ,Apoptosis ,Mice, Transgenic ,Receptors, Cell Surface ,Biology ,Dexamethasone ,Cell Line ,Mice ,Downregulation and upregulation ,hemic and lymphatic diseases ,medicine ,Animals ,RNA, Messenger ,Receptor, Notch1 ,Promoter Regions, Genetic ,Transcription factor ,Glucocorticoids ,DNA Primers ,Multidisciplinary ,Base Sequence ,Membrane Proteins ,Cell Differentiation ,Biological Sciences ,Molecular biology ,Mice, Inbred C57BL ,Repressor Proteins ,Cell culture ,embryonic structures ,cardiovascular system ,Trans-Activators ,Female ,sense organs ,biological phenomena, cell phenomena, and immunity ,Glucocorticoid ,medicine.drug ,Transcription Factors - Abstract
We previously have reported that SRG3 is required for glucocorticoid (GC)-induced apoptosis in the S49.1 thymoma cell line. Activation of Notch1 was shown to induce GC resistance in thymocytes. However, the specific downstream target of Notch1 that confers GC resistance on thymocytes is currently unknown. We found that the expression level of SRG3 was critical in determining GC sensitivity in developing thymocytes. The expression of SRG3 also was down-regulated by the activated form of Notch1 (NotchIC). The promoter activity of the SRG3 gene also was down-regulated by NotchIC. Expression of transgenic SRG3 resulted in the restoration of GC sensitivity in thymocytes expressing transgenic Notch1. These results suggest that SRG3 is the downstream target of Notch1 in regulating GC sensitivity of thymocytes.
- Published
- 2001
37. Peripheral T cells become sensitive to glucocorticoid- and stress-induced apoptosis in transgenic mice overexpressing SRG3
- Author
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Sunmi Han, Jae-B. Kim, Heonsik Choi, Rho Hyun Seong, Young Il Choi, Heekyoung Chung, Joong K. Kim, Dong H. Sohn, Dongho Shin, Myunggon Ko, Han W. Lee, and Sang D. Park
- Subjects
Genetically modified mouse ,Receptor complex ,Thymoma ,Transgene ,Immunology ,Drug Resistance ,Apoptosis ,Mice, Inbred Strains ,Mice, Transgenic ,Thymus Gland ,Biology ,Dexamethasone ,Immobilization ,Mice ,Receptors, Glucocorticoid ,Stress, Physiological ,T-Lymphocyte Subsets ,medicine ,Tumor Cells, Cultured ,Immunology and Allergy ,Animals ,Receptor ,Cells, Cultured ,medicine.disease ,Molecular biology ,Peptide Fragments ,Repressor Proteins ,Cell culture ,Trans-Activators ,Glucocorticoid ,medicine.drug - Abstract
Immature double-positive thymocytes are sensitive to glucocorticoid (GC)-induced apoptosis, whereas mature single-positive T cells are relatively resistant. Thymocytes seem to acquire resistance to GCs during differentiation into mature single-positive thymocytes. However, detailed knowledge concerning what determines the sensitivity of thymocytes to GCs and how GC sensitivity is regulated in thymocytes during development is lacking. We have previously reported that the murine SRG3 gene (for SWI3-related gene) is required for GC-induced apoptosis in a thymoma cell line. Herein, we provide results suggesting that the expression level of SRG3 protein determines the GC sensitivity of T cells in mice. SRG3 associates with the GC receptor in the thymus, but rarely in the periphery. Transgenic overexpression of the SRG3 protein in peripheral T cells induces the formation of the complex and renders the cells sensitive to GC-induced apoptosis. Our results also show that blocking the formation of the SRG3-GC receptor complex with a dominant negative mutant form of SRG3 decreases GC sensitivity in thymoma cells. In addition, mice overexpressing the SRG3 protein appear to be much more susceptible to stress-induced deletion of peripheral T cells than normal mice, which may result in an immunosuppressive state in an animal.
- Published
- 2001
38. Regulation of beta 1 integrin-mediated adhesion by T cell receptor signaling involves ZAP-70 but differs from signaling events that regulate transcriptional activity
- Author
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Nadine Ottoson, Yoji Shimizu, Heekyoung Chung, Jennifer A. Epler, and Rugao Liu
- Subjects
Transcriptional Activation ,T cell ,Phenylalanine ,T-Lymphocytes ,Immunology ,PTK2 ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Jurkat cells ,chemistry.chemical_compound ,Jurkat Cells ,medicine ,Cell Adhesion ,Immunology and Allergy ,Humans ,Point Mutation ,Luciferases ,Adaptor Proteins, Signal Transducing ,ZAP-70 Protein-Tyrosine Kinase ,NFATC Transcription Factors ,Integrin beta1 ,T-cell receptor ,Membrane Proteins ,Nuclear Proteins ,hemic and immune systems ,Tyrosine phosphorylation ,Protein-Tyrosine Kinases ,Phosphoproteins ,Cell biology ,Fibronectins ,DNA-Binding Proteins ,Enzyme Activation ,medicine.anatomical_structure ,chemistry ,Amino Acid Substitution ,Receptor-CD3 Complex, Antigen, T-Cell ,Tyrosine ,Neural cell adhesion molecule ,Signal transduction ,Carrier Proteins ,Tyrosine kinase ,Signal Transduction ,Transcription Factors - Abstract
Stimulation of the CD3/TCR results within minutes in an increase in T cell adhesion mediated by β1 integrins. The biochemical pathways that control CD3-mediated increases in β1 integrin-mediated adhesion remain poorly characterized. In this study, the role of the tyrosine kinase ZAP-70 in the regulation of β1 integrin activity by the CD3/TCR was investigated. CD3 stimulation did not increase β1 integrin-mediated adhesion of the ZAP-70-deficient Jurkat T cell line, P116, to the β1 integrin ligand fibronectin. Reintroduction of wild-type ZAP-70, but not a kinase-inactive variant, K369R, corrected the adhesive defect observed in P116 T cells. In addition, the kinase-inactive ZAP-70 mutant inhibited CD3-induced adhesion of primary human T cell blasts. Interestingly, a ZAP-70 mutant with a tyrosine to phenylalanine substitution at position 319 (Y319F) restored the adhesive defect in P116 T cells, even though Y319F ZAP-70 failed to fully reconstitute CD3-initiated NF-AT-dependent transcription and tyrosine phosphorylation of the LAT adapter protein. Finally, expression of mutants of LAT and the SLP-76 adapter protein that modulate CD3-mediated activation of an NF-AT reporter gene failed to block CD3-induced increases in β1 integrin-mediated adhesion. These observations support a model in which the tyrosine kinase activity of ZAP-70 kinase is critical for regulation of β1 integrin activity by CD3/TCR. However, the signaling events downstream of ZAP-70 that regulate CD3/TCR-mediated activation of β1 integrin function exhibit key differences when compared with the signaling pathways that regulate transcriptional events initiated by CD3/TCR stimulation.
- Published
- 2000
39. Mutation of Tyr307 and Leu309 in the protein phosphatase 2A catalytic subunit favors association with the alpha 4 subunit which promotes dephosphorylation of elongation factor-2
- Author
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Angus C. Nairn, David L. Brautigan, Kohei Murata, and Heekyoung Chung
- Subjects
RFC5 ,Protein subunit ,Trimer ,Biology ,Transfection ,Biochemistry ,Dephosphorylation ,Bacterial Proteins ,Peptide Elongation Factor 2 ,Leucine ,Catalytic Domain ,Lectins ,Protein biosynthesis ,Phosphoprotein Phosphatases ,Animals ,Protein Phosphatase 2 ,Phosphorylation ,Anion Exchange Resins ,Protein phosphatase 2 ,Chromatography, Ion Exchange ,Peptide Elongation Factors ,Phosphoproteins ,Molecular biology ,Precipitin Tests ,Elongation factor ,Resins, Synthetic ,Hemagglutinins ,COS Cells ,Mutagenesis, Site-Directed ,Tyrosine ,Peptides ,Oligopeptides - Abstract
The cellular location and substrate specificity of the catalytic subunit (C) of protein phosphatase 2A (PP2A) depend on its interaction with A and B subunits. The distribution of epitope-tagged wild-type or mutated C subunits was studied by transient expression in COS-7 cells. Wild-type tagged C expressed at low levels formed ABC trimer and AC dimer like the endogenous C. Single mutations of C at the site of phosphorylation (Y307F) or carboxymethylation (L309Q) resulted in recovery of only AC dimer. Double mutation of both residues resulted in association of C with alpha 4 protein (alpha 4), a novel subunit of PP2A, instead of with A and B subunits. Thus, the distribution of C between ABC trimer, AC dimer, and alpha 4C complexes can be affected by modifications of the C-terminal residues. The alpha 4 protein is a homologue of the yeast Tap42 protein that functions downstream of the TOR protein to regulate protein synthesis. Transient overexpression of FLAG-alpha 4 resulted in increased dephosphorylation of elongation factor 2, but had no effect on phosphorylation of either p70S6 kinase or PHAS-I (eIF4E-BP). Signals that affect phosphorylation or methylation of the C subunit of PP2A may promote subunit exchange and direct phosphatase activity to specific intracellular substrates.
- Published
- 1999
40. Protein phosphatase 2A suppresses MAP kinase signalling and ectopic protein expression
- Author
-
Heekyoung Chung and David L. Brautigan
- Subjects
Gene Expression ,Mitogen-activated protein kinase kinase ,Biology ,Transactivation ,Mice ,Phosphoprotein Phosphatases ,Animals ,Humans ,c-Raf ,Protein Phosphatase 2 ,RNA, Messenger ,Kinase activity ,Cell Line, Transformed ,MAP kinase kinase kinase ,Protein phosphatase 1 ,Cell Biology ,Protein phosphatase 2 ,3T3 Cells ,Molecular biology ,Recombinant Proteins ,Enzyme Activation ,Protein Biosynthesis ,COS Cells ,Calcium-Calmodulin-Dependent Protein Kinases ,Ectopic expression ,HeLa Cells ,Signal Transduction - Abstract
Signalling by MAP kinase was examined in COS-7 cells by transiently expressing a transcription reporter system plus epitope-tagged protein phosphatase 2A catalytic subunit [(HA)3-PP2Ac]. Transactivation of a luciferase gene by GAL4-Elk-1 in serum-stimulated cells was reduced 20-fold by co-expression of wild type (HA)3-PP2Ac. This reduction of MAP kinase signalling required specific type-2A phosphatase activity, because the effects were not mimicked by co-expression of either a mutated, inactive (HA)3-PP2Ac or wild-type PP1Cdelta. Expression of (HA)3-PP2Ac was severely restricted by its own activity because 3-fold more inactive (HA)3-PP2Ac was produced. In a different assay the kinase activity of FLAG-ERK2 was 4-fold lower when co-transfected with (HA)3-PP2Ac, compared to controls. Unexpectedly, mRNA of the reporter constructs were nearly eliminated by even low level expression of (HA)3-PP2Ac in either COS7 or HEK293 cells. The results show that PP2A activity is strictly regulated and can be a limiting factor in ectopic expression of various proteins.
- Published
- 1999
41. Application of SELDI-TOF mass spectrometry for the identification of differentially expressed proteins by formaldehyde exposure
- Author
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Byung-Don Han, Gu Kong, Hyeon-Yeong Kim, Heekyoung Chung, Young-mi Jung, and Byung-Hoon Lee
- Subjects
Chromatography ,Chemistry ,Seldi tof ,Identification (biology) ,General Medicine ,Toxicology ,Mass spectrometry ,FORMALDEHYDE EXPOSURE - Published
- 2006
42. Comprehensive analysis of differential gene expression profiles on d-galactosamine-induced acute mouse liver injury and regeneration
- Author
-
Mingoo Kim, Ju Han Kim, Kiseok Jang, Hyun-Jun Kim, Jungeun Yang, Heekyoung Chung, Yong-Sung Lee, and Gu Kong
- Subjects
Liver injury ,Chemistry ,Regeneration (biology) ,Gene expression ,medicine ,D galactosamine ,General Medicine ,Toxicology ,medicine.disease ,Molecular biology - Published
- 2006
43. SPARC-based VLIW testbed
- Author
-
J.-W. Ahn, Soo-Mook Moon, Jungkeun Park, SangMin Shim, and Heekyoung Chung
- Subjects
Speedup ,Computer science ,Testbed ,Speculative execution ,Parallel computing ,computer.software_genre ,Theoretical Computer Science ,law.invention ,Instruction set ,Microprocessor ,Computational Theory and Mathematics ,Hardware and Architecture ,law ,Very long instruction word ,Systems design ,Compiler ,Hardware_CONTROLSTRUCTURESANDMICROPROGRAMMING ,computer - Abstract
The performance of very long instruction word (VLIW) microprocessors depends on the close co-operation between the compiler and the architecture. To design a high-performance VLIW a testbed is required that allows detailed co-evaluation of both compilation techniques and architectural features. The paper introduces a new VLIW testbed based on the SPARC instruction set architecture, which includes an aggressive scheduling compiler and a fast VLIW simulator. The compiler takes gcc-generated optimised SPARC code as input and generates parallelised VLIW code, targeting advanced VLIW architectures. The compiler can generate high-performance VLIW code, especially for non-numerical integer programs. The VLIW code is translated into a dedicated C program for fast and simple compiled simulation which generates detailed data for performance. The authors have performed a comprehensive empirical study on the testbed for both large-resource and small-resource machines. The result shows that as much as a geometric mean of fourfold speedup is obtainable on nontrivial integer benchmarks without using branch probability when performing speculative code motion. Also analysed are the characteristics of the useful and useless ALU operations in each cycle to see how the speedup is obtained. The analysis indicates that around half of the useful ALUs execute speculative instructions whose original paths are taken (thus being "hit"), yet a substantial number of ALUs are also wasted owing to useless speculative execution or copy execution.
- Published
- 1998
44. A Newly Identified CG301269 Improves Lipid and Glucose Metabolism Without Body Weight Gain Through Activation of Peroxisome Proliferator-Activated Receptor α and γ.
- Author
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Hyun Woo Jeong, Joo-Won Lee, Woo Sik Kim, Sung Sik Choe, Kyung-Hee Kim, Ho Seon Park, Hyun Jung Shin, Gha Young Lee, Dongkyu Shin, Hanjae Lee, Jun Hee Lee, Eun Bok Choi, Hyeon Kyu Lee, Heekyoung Chung, Seung Bum Park, Kyong Soo Park, Hyo-Soo Kim, Seonggu Ro, and Jae Bum Kim
- Subjects
PEROXISOMES ,CELL receptors ,METABOLIC disorders ,BIOLOGICAL assay ,FATTY acids ,OXIDATION ,GENES ,LABORATORY mice - Abstract
OBJECTIVE--Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS--Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS--CG301269 selectively stimulated the transcriptional activities of PPARa and PPAR7. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyper-lipidemia in vivo, hi db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS--We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
45. Induction of Neuronal Vascular Endothelial Growth Factor Expression by cAMP in the Dentate Gyrus of the Hippocampus Is Required for Antidepressant-Like Behaviors.
- Author
-
Jeong-Sik Lee, Deok-Jin Jang, Nuribalhae Lee, Hyoung-Gon Ko, Hyoung Kim, Yong-Seok Kim, Byungwoo Kim, Junehee Son, Sung Hyun Kim, Heekyoung Chung, Mun-Yong Lee, Woon Ryoung Kim, Woong Sun, Min Zhuo, Ted Abel, Bong-Kiun Kaang, and Hyeon Son
- Subjects
VASCULAR endothelial growth factors ,DENTATE gyrus ,HIPPOCAMPUS (Brain) ,ANTIDEPRESSANTS ,NEURONS ,LIGANDS (Biochemistry) - Abstract
The cAMP cascade and vascular endothelial growth factor (VEGF) are critical modulators of depression. Here we have tested whether the antidepressive effect of the cAMP cascade is mediated by VEGF in the adult hippocampus. We used a conditional genetic system in which the Aplysia octopamine receptor (Ap oa
1 ), a Gs -coupled receptor, is transgenically expressed in the forebrain neurons of mice. Chronic activation of the heterologous Ap oa1 by its natural ligand evoked antidepressant-like behaviors, accompanied by enhanced phosphorylation of cAMP response element-binding protein and transcription of VEGF in hippocampal dentate gyrus (DG) neurons. Selective knockdown of VEGF in these cells during the period of cAMP elevation inhibited the antidepressant-like behaviors. These findings reveal a molecular interaction between the cAMP cascade and VEGF expression, and the pronounced behavioral consequences of this interaction shed light on the mechanism underlying neuronal VEGF functions in antidepression. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
46. Time- and Dose-based Gene Expression Profiles Produced by a Bile-duct--damaging Chemical, 4,4'-methylene Dianiline, in Mouse Liver in an Acute Phase.
- Author
-
SUN-BOM KWON, JOON-SUK PARK, JUNG-YEON YI, JAE-WONG HWANG, MINGOO KIM, MI-OCK LEE, BYUNG-HOON LEE, HYUNGLAE KIM, JU HAN KIM, HEEKYOUNG CHUNG, GU KONG, KYUNG-SUN KANG, and BYUNG-IL YOON
- Subjects
TOXICOLOGY ,THERAPEUTICS ,TOXICOGENOMICS ,LABORATORY mice ,DIAMINODIPHENYLMETHANE ,GENES - Abstract
A toxicogenomics study was performed in the mouse liver after treatment of a bile-duct-damaging chemical, 4,4'-methylene dianiline (MDA), across multiple doses and sampling times in an acute phase using the AB Expression Array System. Imprinting control region (ICR) mice were given a single oral administration of a low (10 mg/kg b.w.) or high (100 mg/kg b.w.) dose of MDA. Mice were sacrificed six, twenty-four, and seventy-two hours after treatment for serum chemistry, histopathology, and mRNA preparation from liver samples. Treatment with MDA increased liver-toxicity-related enzymes in blood and induced bile-duct cell injury, followed by regeneration. To explore potential biomarker gene profiles, the altered genes were categorized into four expression patterns depending on dose and time. Numerous functionally defined and unclassified genes in each category were up- or down-regulated throughout the period from cellular injury to the recovery phase, verified by RT-PCR. Many genes associated with liver toxicity and diseases belonged to one of these categories. The chemokine-mediated Th1 pathway was implicated in the inflammatory process. The genes associated with oxidative stress, apoptosis, and cell-cycle regulation were also dynamically responsive to MDA treatment. The Wnt/β-catenin signaling pathway was likely responsible for the reconstitution process of the MDA-injured liver. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
47. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers.
- Author
-
Ki-Seok Jang, Seung Sam Paik, Heekyoung Chung, Young-Ha Oh, and Gu Kong
- Subjects
METASTASIS ,ANTIGENS ,CARCINOGENESIS ,TUMORS ,BREAST cancer - Abstract
Metastasis associated antigen 1 (MTA1) is a recently identified candidate metastasis-associated gene that plays an important role in tumorigenesis and tumor aggressiveness, especially tumor invasiveness and metastasis. We analyzed the relationship between MTA1 expression and variable clinicopathological features and characterized its role in tumor angiogenesis in human breast cancers. Two hundred and sixty-three breast cancer cases that successfully underwent surgery at Hanyang University Hospital (Seoul, Korea) between January 1989 and December 1997 were enrolled. MTA1 expression was observed by immunohistochemical staining and correlated with intratumoral microvessel density (MVD) and other clinicopathological parameters. MTA1 overexpression correlated significantly with higher tumor grade (grades 1 and 2 vs grade 3, P = 0.009). However, MTA1 expression did not correlate with tumor stage, status of estrogen and progesterone receptors, or axillary lymph node metastasis. Interestingly, MTA1 expression was found to correlate significantly with tumor MVD ( P = 0.002). Survival analysis did not show a significant difference between MTA1 overexpression and poorer survival. In conclusion, MTA1 overexpression was found to be closely associated with higher tumor grade and increased tumor angiogenesis. These findings suggest MTA1 as a predictor of aggressive phenotype and a possible target molecule for anti-angiogenic drugs in breast cancer treatment. ( Cancer Sci 2006) [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
48. Mutation of Tyr307 nad Leu309 in the protein phosphatase 2A catalytic subunit favors association...
- Author
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Heekyoung Chung and Nairn, Angus C.
- Subjects
- *
PHOSPHATASES , *TYROSINE - Abstract
Reveals that the mutation of Tyr307 and Leu309 in the protein phosphatase 2A catalytic subunit favors association with the alpha4 subunit which promotes dephosphorylation of elongation factor-2. Promotion of subunit exchange and direct phosphatase activity to specific intracellular substrates.
- Published
- 1999
- Full Text
- View/download PDF
49. BAF6Oa Interacts with p53 to Recruit the SWI/SNF Complex.
- Author
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Jaehak Oh, Sohn, Dong H., Myunggon Ko, Heekyoung Chung, Jeon, Sung H., and Seong, Rho H.
- Subjects
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TUMORS , *CHROMATIN , *CHROMOSOMES , *GENES , *APOPTOSIS - Abstract
To understand the tumor-suppressing mechanism of the SWI/SNF chromatin remodeling complex, we investigated its molecular relationship with p53. Using the pREP4-luc episomal reporter, we first demonstrated that p53 utilizes the chromatin remodeling activity of the SWI/SNF complex to initiate transcription from the chromatin-structured promoter. Among the components of the SWI/SNF complex, we identified BAF60a as a mediator of the interaction with p53 by the yeast two-hybrid assay. p53 directly interacted only with BAF60a, but not with other components of the SWI/SNF complex, such as BRG1, SRG3, SNF5, or BAF57. We found out that multiple residues at the amino acid 108 -150 region of BAF60a were involved in the interaction with the tetramerization domain of p53. The N-terminal fragment of BAF60a containing the p53-interacting region as well as small interfering RNA for baf60a inhibited the SWI/SNF complex-mediated transcriptional activity of p53. The uncoupling of p53 with the SWI/SNF complex resulted in the repression of both p53-dependent apoptosis and cell cycle arrest by the regulation of target genes. These results suggest that the SWI/SNF chromatin remodeling complex is involved in the suppression of tumors by the interaction with p53. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
50. SRG3 Interacts Directly with the Major Components of the SWI/SNF Chromatin Remodeling Complex and Protects Them from Proteasomal Degradation.
- Author
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Sohn, Dong H., Lee, Kyoo Y., Changjin Lee, Jaehak Oh, Heekyoung Chung, Jeon, Sung H., and Seong, Rho H.
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CHROMATIN , *CHROMOSOMES , *DROSOPHILA , *LEAVENING agents , *YEAST , *TRANSGENIC animals - Abstract
The mammalian SWI/SNF complex is an evolutionarily conserved ATP-dependent chromatin remodeling complex that consists of nine or more components. SRG3, a murine homologue of yeast SWI3, Drosophila MOIRA, and human BAF155, is a core component of the murine SWI/SNF complex required for the regulation of transcriptional processes associated with development, cellular differentiation, and proliferation. Here we report that SRG3 interacts directly with other components of the mammalian SWI/SNF complex such as SNF5, BRG1, and BAF60a. The SWIRM domain and the SANT domain were required for SRG3-SNF5 and SRG3-BRG1 interactions, respectively. In addition, SRG3 stabilized SNF5, BRG1, and BAF60a by attenuating their proteasomal degradation, suggesting its general role in the stabilization of the SWI/SNF complex. Such a stabilization effect of SRG3 was not only observed in the in vitro cell system, but also in cells isolated from SRG3 transgenic mice or knock-out mice haploinsufficient for the Srg3 gene. Taken together, these results suggest the critical role of SRG3 in the post-transcriptional stabilization of the major components of the SWI/SNF complex. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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