44 results on '"Byun DS"'
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2. Classification of monthly tidal envelopes in mixed tide regimes.
- Author
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Byun DS, Hart DE, Kim S, and Ha J
- Abstract
Coastal inundation is increasing globally. Changes in tidal water levels contribute to flood risk alongside rain and sea storm events. Unlike the latter, temporal variations in tides may be predicted and their patterns analyzed many years in advance. This paper explains two novel methods for characterizing monthly scale patterns in tidal water level variation: one simple qualitative method with restricted applicability; and another more complex quantitative method with global applicability to areas characterized by mixed, mainly semidiurnal and mixed, mainly diurnal tide regimes (~ 65% of global oceans). We reveal that in some areas tidal high and low waters are balanced in near symmetrical patterns, while elsewhere tides are skewed towards upper or lower tidal height envelopes. Areas characterized by tidal patterns skewed towards upper envelopes are at heightened risk of extreme event inundations during certain periods each year, event scale risks that will increase with climate changes. Those skewed towards lower tidal envelopes are prone to frequent flooding and are potentially at greater risk of chronic inundation with ongoing mean sea level rise. Our findings and the novel tidal pattern classification approaches offered contribute to understanding the time varying nature of tidal contributions to coastal inundation risks., (© 2023. The Author(s).)
- Published
- 2023
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3. Intense atmospheric frontogenesis by air-sea coupling processes during the passage of Typhoon Lingling captured at Ieodo Ocean Research Station.
- Author
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Yang S, Moon IJ, Bae HJ, Kim BM, Byun DS, and Lee HY
- Abstract
The Ieodo Ocean Research Station (Ieodo ORS) is a fixed marine observation platform at the boundary of the Yellow and East China Seas. In 2019, a Category 4 Typhoon Lingling passed by the Ieodo ORS very closely. At that time, the Ieodo ORS observed Sea Surface Temperature (SST) cooling of 4.5 °C by vertical mixing and negative turbulent heat flux (i.e., the sum of sensible and latent heat fluxes) due to the SST cooling. In this study, uncoupled and coupled simulations were conducted to examine the role of air-sea interactions in changes in atmospheric frontogenesis around the typhoon passage. In the coupled simulation, SST cooling up to 6 °C occurred over the dangerous semicircle due to vertical mixing induced by wind stress. Strong wind stress also enhanced the SST gradient and, therefore, contributed to the formation of a steeper atmospheric frontal zone. Moreover, the comparison with reliable datasets supports the physical linkage between SST cooling and atmospheric frontogenesis by utilizing the meridional theta-e gradient and moisture convergence zone. Therefore, from the simulation results, we hope to improve our understanding of atmospheric frontogenesis by air-sea coupling processes in the future development of a coupled atmosphere-ocean modeling system., (© 2022. The Author(s).)
- Published
- 2022
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4. Characteristic concentrations and isotopic composition of airborne lead at urban, rural and remote sites in western Korea.
- Author
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Lee S, Shin D, Han C, Choi KS, Hur SD, Lee J, Byun DS, Kim YT, and Hong S
- Subjects
- China, Asia, Eastern, Isotopes analysis, Republic of Korea, Seasons, Air Pollutants analysis, Environmental Monitoring, Lead analysis
- Abstract
Anthropogenic Pb emitted from East Asia, particularly China, is often long-range transported to the east by the prevailing westerlies. To characterize the geographical properties of varying atmospheric Pb concentrations by transboundary and domestic source(s)-related Pb in Korea, closely adjacent to China, the Al and Pb concentrations and the stable Pb isotopic composition were determined in the total suspended particles (TSP) collected at urban (IC), rural (TA), and remote background (JJ) sites in western Korea from August 2015 to October 2016. The annual average Pb concentrations were significantly higher in urban and rural areas (IC, 16.2 ng m
-3 and TA, 11.1 ng m-3 ) than in remote area (JJ, 6.41 ng m-3 ), showing pronounced seasonal variations with relatively higher concentrations in winter and spring and lower concentrations in summer and autumn. Significantly high enrichment factors (EF) for Pb indicate that anthropogenic contributions are important for this toxic element in TSP. Coupling the Pb isotopic signatures with the air mass back trajectories identified the major potential source regions for individual samples. The results show that during winter, China was the dominant contributor, accounting for 92%, 82%, and 100% of the sampling periods at IC, TA, and JJ, respectively. The Chinese contribution decreased in summer and autumn, whereas the Korean contribution increased, according to the East Asian monsoon system. The Pb concentrations increased by 2.2 (IC), 1.2 (TA) and 1.4 (JJ) times when the Chinese contribution was dominant, compared to the Korea-dominant periods. The Pb isotopic systematics for the samples characterized by the dominant Korean contribution differed substantially between the three sites, implying that the relative importance of various domestic sources varied with geographical areas in western Korea., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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5. Characteristics of elemental and Pb isotopic compositions in aerosols (PM 10-2.5 ) at the Ieodo Ocean Research Station in the East China Sea.
- Author
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Lee S, Han C, Shin D, Hur SD, Jun SJ, Kim YT, Byun DS, and Hong S
- Subjects
- Air Pollution analysis, China, Asia, Eastern, Oceans and Seas, Particulate Matter analysis, Trace Elements analysis, Aerosols analysis, Air Pollutants analysis, Environmental Monitoring, Lead analysis
- Abstract
A total of 82 aerosol samples (PM
10-2.5 ) were collected from June 18, 2015 to October 1, 2016 at the remote sea site, the Ieodo Ocean Research Station (IORS), in the East China Sea. Samples were analyzed for 10 elements (Al, Fe, Cu, Zn, As, Mo, Cd, Sb, Tl, and Pb) as well as Pb isotopic composition to characterize temporal variations in elemental concentration levels, and to identify the potential source regions of atmospheric pollutants transported over the remote East China Sea. The results showed that the annual average element concentrations were lowest compared to those at different sites in East Asia, suggesting a very clean background area of IORS, with values ranging from 114 ng m-3 for Al to 0.045 ng m-3 for Tl. Concentrations averaged seasonally for all the elements revealed the highest levels occurring between winter and spring, and the lowest levels in summer. High enrichment factors (EF) of more than 100 for trace elements suggest that these elements originated mostly from anthropogenic sources. Coupling the Pb isotopic composition with a back trajectory analysis identified the potential source regions for each sample. Our approach identified China as a dominant contributor affecting atmospheric composition changes at IORS, the remote area of the East China Sea. As the largest anthropogenic emission source in East Asia, China contributed to almost 100% of the elemental concentration levels in winter and spring, ∼53% in summer and ∼63% in autumn. Because IORS's ambient air is sensitive to even slight changes in pollutant loading due to the significantly low pollution levels, long-term monitoring of air quality at IORS will provide invaluable information on the progress and efforts of atmospheric pollution management linked to emission controls in East Asian countries, especially China., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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6. Relationship between augmentation index and acute ischemic stroke subtype.
- Author
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Byun DS, Han SW, Park JH, Kim JY, Baik JS, and Park JH
- Subjects
- Aged, Aged, 80 and over, Analysis of Variance, Blood Pressure, Echocardiography, Female, Hemodynamics, Humans, Ischemic Attack, Transient classification, Ischemic Attack, Transient diagnosis, Magnetic Resonance Angiography, Male, Middle Aged, Risk Factors, Time Factors, Tomography, X-Ray Computed, Severity of Illness Index, Stroke classification, Stroke diagnosis
- Abstract
The aim of the present study was to explore the relationship between augmentation index (AIx) and vascular risk factors according to stroke subtypes. Patients were eligible for this study if they experienced their first ischemic stroke within the preceding 7 days and were 45 years of age or older. AIx was measured by applanation tonometry (SphygmoCor, AtCor Medical, Sydney, Australia) and ischemic stroke was classified according to the Trial of Org 10172 in the Acute Stroke Treatment (TOAST) classification system. A total of 189 patients were enrolled. The most frequent stroke subtype was lacune (76, 40.2%), followed by stroke of undetermined etiology, negative work-up (SUDn) (59, 31.2%), large artery atherosclerosis (LAA) (31, 16.4%), and cardioembolism (23, 12.2%). While there were no significant differences among the groups for hemodynamic indices, AIx at 75 beats per minute (AIx@75) was higher in lacune subtype (29.6%) than SUDn (28.4%), LAA (26.6%), and cardioembolism (24.8%) (p=0.064). The AIx@75 was significantly related to age (r=0.189), sex (r=0.252), peripheral systolic blood pressure (SBP) (r=0.189), peripheral diastolic blood pressure (DBP) (r=0.191), and peripheral mean arterial pressure (MAP) (r=0.327). Multiple linear regression analysis revealed that age, sex, peripheral SBP, peripheral DBP and peripheral MAP were significant (p<0.002). This study showed that arterial stiffness is increased in acute lacunar infarction. Considering the pathogenesis of lacunar infarction and the potential interconnected causes of arterial stiffness, our findings indicate that increased arterial stiffness in acute lacunar infarction may be related to the pathogenesis of lacunar infarction., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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7. Panophthalmoplegia and vision loss after cosmetic nasal dorsum injection.
- Author
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Kim SN, Byun DS, Park JH, Han SW, Baik JS, Kim JY, and Park JH
- Subjects
- Blindness pathology, Brain pathology, Female, Humans, Magnetic Resonance Imaging, Nose, Ocular Motility Disorders pathology, Optic Disk pathology, Retinal Artery Occlusion etiology, Retinal Artery Occlusion pathology, Blindness etiology, Cosmetic Techniques adverse effects, Hyaluronic Acid adverse effects, Ocular Motility Disorders etiology
- Abstract
We report a case of unilateral blindness and panophthalmoplegia after hyaluronic acid injection into the dorsum of the nose in a healthy young woman. Microspheres of hyaluronic acid are popular fillers for facial rejuvenation. While ocular side effects from injections in the nose and face have been reported following turbinate injection, rhinoplasty and infraorbital nerve block, ocular side effects from injection into the dorsum of the nose are extremely rare. We presume that the symptoms were due to obstruction of the branches of the ophthalmic artery. Under high injection pressure, the microspheres travelled to the ophthalmic artery and were propelled by the blood flow to the central retinal artery and the anterior and posterior long ciliary arteries, leading to her symptoms. Alternatively, there are several arterio-venous anastomotic channels in the nasal mucosa that aid heat exchange. These may have been the conduit for reflux of the filler into the arterial side of the regional circulation. Physicians must remain aware of serious complications during cosmetic injections to this region., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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8. Anti-inflammatory activities of an ethanol extract of Ecklonia stolonifera in lipopolysaccharide-stimulated RAW 264.7 murine macrophage cells.
- Author
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Lee MS, Kwon MS, Choi JW, Shin T, No HK, Choi JS, Byun DS, Kim JI, and Kim HR
- Subjects
- Animals, Anti-Inflammatory Agents isolation & purification, Macrophages drug effects, Mice, NF-kappa B immunology, Anti-Inflammatory Agents pharmacology, Lipopolysaccharides immunology, Macrophages immunology, Phaeophyceae chemistry
- Abstract
Ecklonia stolonifera is a brown alga that was shown to have antioxidant, anti-inflammatory, tyrosinase inhibitory, and chemopreventive activities. However, the molecular mechanisms underlying its anti-inflammatory activity remain unclear. In this study, we investigated the molecular mechanism of the anti-inflammatory action of E. stolonifera ethanolic extracts (ESE) using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. ESE inhibited LPS-induced nitric oxide (IC(50) = 72 ± 1.9 μg/mL) and prostaglandin E(2) (IC(50) = 98 ± 5.3 μg/mL) production in a dose-dependent manner and suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 cells. ESE also reduced the production of pro-inflammatory cytokines in LPS-stimulated RAW 264.7 cells. LPS-induced nuclear factor-κB (NF-κB) transcriptional activity and NF-κB translocation into the nucleus were significantly inhibited by ESE treatment through the prevention of the degradation of inhibitor κB-α. Moreover, ESE inhibited the activation of Akt, ERK, JNK1/2, and p38 MAPK in LPS-stimulated RAW 264.7 cells. The main components with anti-inflammatory activity in ESE were identified as phlorofucofuroeckol A and B based on the inhibition of NO production. Our results indicate that ESE can be considered as a potential source of therapeutic agents for inflammatory diseases.
- Published
- 2012
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9. Dioxinodehydroeckol inhibits melanin synthesis through PI3K/Akt signalling pathway in α-melanocyte-stimulating hormone-treated B16F10 cells.
- Author
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Lee MS, Yoon HD, Kim JI, Choi JS, Byun DS, and Kim HR
- Subjects
- Animals, Cell Line, Tumor, Dioxins isolation & purification, Melanins biosynthesis, Mice, Phaeophyceae chemistry, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, alpha-MSH, Dioxins pharmacology, Melanins antagonists & inhibitors
- Abstract
Antimelanogenic activity has previously been reported in ethyl acetate fraction of Ecklonia stolonifera. In this study, using the isolated dioxinodehydroeckol from the fraction, we sought to investigate an antimelanogenic signalling pathway in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 melanoma cells. Treatment with dioxinodehydroeckol inhibited the cellular melanin contents and expression of melanogenesis-related proteins, including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related proteins TRP-1 and TRP-2. Moreover, dioxinodehydroeckol stimulated phosphorylation of Akt in a dose-dependent manner without affecting phosphorylation of ERK. These data suggest that dioxinodehydroeckol reduces melanin synthesis through the MITF regulation dependent upon PI3K/Akt signalling pathway., (© 2012 John Wiley & Sons A/S.)
- Published
- 2012
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10. Isolation and identification of phlorotannins from Ecklonia stolonifera with antioxidant and hepatoprotective properties in tacrine-treated HepG2 cells.
- Author
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Lee MS, Shin T, Utsuki T, Choi JS, Byun DS, and Kim HR
- Subjects
- Antioxidants pharmacology, Dioxins chemistry, Dioxins isolation & purification, Dioxins pharmacology, Hep G2 Cells, Humans, Mitochondria metabolism, Protective Agents pharmacology, Reactive Oxygen Species metabolism, Tacrine pharmacology, Tannins pharmacology, Antioxidants chemistry, Antioxidants isolation & purification, Phaeophyceae chemistry, Protective Agents chemistry, Protective Agents isolation & purification, Tannins chemistry, Tannins isolation & purification
- Abstract
Four kinds of phlorotannins having antioxidant activity were isolated from the ethyl acetate fraction of Ecklonia stolonifera ethanolic extract. The structures of the phlorotannins were determined on the basis of spectroscopic evidence, including 1D and 2D nuclear magnetic resonance. The isolated phlorotannins showed potential radical-scavenging activities against 2,2-diphenyl-1-picrylhydrazyl and suppressed the intracellular reactive oxygen species in tacrine-treated HepG2 cells. Among them, eckol and 2-phloroeckol showed hepatoprotective activity in tacrine-treated HepG2 cells; however, phlorofucofuroeckol B and 6,6'-bieckol did not show the activity, even though having high antioxidant activity. Both eckol and 2-phloroeckol inhibited the expression of Fas-mediated cell-death proteins, including tBid, caspase-3, and poly(ADP-ribose) polymerase, and suppressed the release of cytochrome c from mitochondria to cytosol in a dose-dependent manner in tacrine-treated HepG2 cells. These results suggest that eckol and 2-phloroeckol are the principal hepatoprotective constituents of the ethyl acetate fraction of E. stolonifera ethanolic extract.
- Published
- 2012
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11. 6-Methoxyluteolin from Chrysanthemum zawadskii var. latilobum suppresses histamine release and calcium influx via down-regulation of FcεRI α chain expression.
- Author
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Shim SY, Park JR, and Byun DS
- Subjects
- Anti-Allergic Agents isolation & purification, Cell Line, Humans, Hypersensitivity drug therapy, Hypersensitivity genetics, Immunoglobulin E immunology, Luteolin isolation & purification, Mast Cells drug effects, Mast Cells immunology, Plant Extracts isolation & purification, Receptors, IgE immunology, Anti-Allergic Agents pharmacology, Calcium immunology, Chrysanthemum chemistry, Down-Regulation drug effects, Histamine Release drug effects, Hypersensitivity immunology, Luteolin pharmacology, Plant Extracts pharmacology, Receptors, IgE genetics
- Abstract
Mast cells and basophils are important effector cells in immunoglobulin-E (IgE)-mediated allergic reactions. Using the human basophilic KU812F cells, we assessed the inhibitory effects of 6-methoxyluteolin, isolated from Chrysanthemum zawadskii, in the FcεRI-mediated allergic reaction. We determined that 6-methoxyluteolin inhibited anti-FcεRI α chain antibody (CRA-1)-induced histamine release, as well as elevation of intracellular calcium concentration [Ca2+]i in a dose-dependent manner. Moreover, the inhibitory effects of 6-methoxyluteolin on the cell surface expression and the mRNA level of the FcεRI α chain were determined by flow cytometric analysis and reverse transcription-polymerase chain reaction (RTPCR), respectively. Therefore, these results show that 6- methoxyluteolin is a potent inhibitor of histamine release and calcium influx via down-regulation of the FcεRI α chain.
- Published
- 2012
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12. Villin expression is frequently lost in poorly differentiated colon cancer.
- Author
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Arango D, Al-Obaidi S, Williams DS, Dopeso H, Mazzolini R, Corner G, Byun DS, Carr AA, Murone C, Tögel L, Zeps N, Aaltonen LA, Iacopetta B, and Mariadason JM
- Subjects
- Animals, Biomarkers, Tumor genetics, Cell Differentiation physiology, Cell Membrane metabolism, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, DNA Methylation genetics, DNA, Neoplasm genetics, Down-Regulation, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Homeodomain Proteins metabolism, Humans, Kaplan-Meier Estimate, Mice, Mice, SCID, Microfilament Proteins genetics, Microsatellite Instability, Microsatellite Repeats, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasm Transplantation, Oligonucleotide Array Sequence Analysis methods, Prognosis, Promoter Regions, Genetic genetics, Real-Time Polymerase Chain Reaction methods, Tumor Cells, Cultured, Biomarkers, Tumor metabolism, Colorectal Neoplasms metabolism, Microfilament Proteins metabolism
- Abstract
Colorectal cancers (CRCs) are classified as having microsatellite instability (MSI) or chromosomal instability (CIN); herein termed microsatellite stable (MSS). MSI colon cancers frequently display a poorly differentiated histology for which the molecular basis is not well understood. Gene expression and immunohistochemical profiling of MSS and MSI CRC cell lines and tumors revealed significant down-regulation of the intestinal-specific cytoskeletal protein villin in MSI colon cancer, with complete absence in 62% and 17% of MSI cell lines and tumors, respectively. Investigation of 577 CRCs linked loss of villin expression to poorly differentiated histology in MSI and MSS tumors. Furthermore, mislocalization of villin from the membrane was prognostic for poorer outcome in MSS patients. Loss of villin expression was not due to coding sequence mutations, epigenetic inactivation, or promoter mutation. Conversely, in transient transfection assays villin promoter activity reflected endogenous villin expression, suggesting transcriptional control. A screen of gut-specific transcription factors revealed a significant correlation between expression of villin and the homeobox transcription factor Cdx-1. Cdx-1 overexpression induced villin promoter activity, Cdx-1 knockdown down-regulated endogenous villin expression, and deletion of a key Cdx-binding site within the villin promoter attenuated promoter activity. Loss of Cdx-1 expression in CRC lines was associated with Cdx-1 promoter methylation. These findings demonstrate that loss of villin expression due to Cdx-1 loss is a feature of poorly differentiated CRCs., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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13. Phlorofucofuroeckol A inhibits the LPS-stimulated iNOS and COX-2 expressions in macrophages via inhibition of NF-κB, Akt, and p38 MAPK.
- Author
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Kim AR, Lee MS, Shin TS, Hua H, Jang BC, Choi JS, Byun DS, Utsuki T, Ingram D, and Kim HR
- Subjects
- Animals, Cell Line, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Cytokines metabolism, Lipopolysaccharides pharmacology, Macrophages drug effects, Macrophages metabolism, Mice, NF-kappa B metabolism, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Proto-Oncogene Proteins c-akt metabolism, RNA, Messenger antagonists & inhibitors, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor AP-1 metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Anti-Inflammatory Agents pharmacology, Benzofurans pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Dioxins pharmacology, Nitric Oxide Synthase Type II antagonists & inhibitors
- Abstract
We have recently reported that phlorofucofuroeckol A isolated from the edible brown algae Ecklonia stolonifera showed potential antioxidative and anti-inflammatory properties in macrophage stimulated by LPS treatments. In this study, we further investigated the pharmacological characteristic of phlorofucofuroeckol A in regulations of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 through regulatory and signaling pathways using LPS-treated RAW 264.7 cells. Treatment with 20 μM of phlorofucofuroeckol A significantly decreased levels of iNOS and COX-2 mRNA induced by LPS stimulation. As results, levels of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were significantly reduced by treatments of phlorofucofuroeckol A in LPS-stimulated RAW 264.7 cells. Phlorofucofuroeckol A inhibited promoter activities of inflammatory-mediators (iNOS and COX-2) and transcriptional factors (nuclear factor-κB, NF-κB, and AP-1) in LPS-treated RAW 264.7 cells. Moreover, phlorofucofuroeckol A inhibited activation of Akt and p38 MAPK in LPS-treated RAW 264.7 cells. These results indicate that the phlorofucofuroeckol A regulates iNOS and COX-2 expressions through the NF-κB-dependent transcriptional control associated with inhibition of multiple signaling proteins, suggesting potential candidates of phloroglucinol derivatives for treatments of inflammatory diseases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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14. Intestinal epithelial-specific PTEN inactivation results in tumor formation.
- Author
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Byun DS, Ahmed N, Nasser S, Shin J, Al-Obaidi S, Goel S, Corner GA, Wilson AJ, Flanagan DJ, Williams DS, Augenlicht LH, Vincan E, and Mariadason JM
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Adenoma genetics, Adenoma pathology, Animals, Epithelial Cells pathology, Intestinal Neoplasms genetics, Intestinal Neoplasms pathology, Intestine, Small pathology, Mice, Mice, Knockout, PTEN Phosphohydrolase genetics, Phosphorylation, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction genetics, Wnt Proteins genetics, Wnt Proteins metabolism, beta Catenin genetics, beta Catenin metabolism, Adenocarcinoma metabolism, Adenoma metabolism, Epithelial Cells metabolism, Intestinal Neoplasms metabolism, Intestine, Small metabolism, PTEN Phosphohydrolase metabolism
- Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN(Lox/Lox) mice with villin(Cre) mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN(Lox/Lox)/villin(Cre) mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.
- Published
- 2011
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15. Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction.
- Author
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Wilson AJ, Chueh AC, Tögel L, Corner GA, Ahmed N, Goel S, Byun DS, Nasser S, Houston MA, Jhawer M, Smartt HJ, Murray LB, Nicholas C, Heerdt BG, Arango D, Augenlicht LH, and Mariadason JM
- Subjects
- Apoptosis genetics, Apoptosis physiology, Binding Sites, Butyrates pharmacology, Caco-2 Cells, Colonic Neoplasms enzymology, Colonic Neoplasms pathology, Dactinomycin pharmacology, HCT116 Cells, HT29 Cells, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Promoter Regions, Genetic, Sp1 Transcription Factor metabolism, Sp3 Transcription Factor metabolism, Transcriptional Activation, Apoptosis drug effects, Colonic Neoplasms drug therapy, Colonic Neoplasms genetics, Gene Expression Regulation, Neoplastic drug effects, Genes, Immediate-Early drug effects, Histone Deacetylase Inhibitors pharmacology, Sp1 Transcription Factor genetics, Sp3 Transcription Factor genetics
- Abstract
Histone deacetylase inhibitors (HDACi) induce growth arrest and apoptosis in colon cancer cells and are being considered for colon cancer therapy. The underlying mechanism of action of these effects is poorly defined with both transcription-dependent and -independent mechanisms implicated. We screened a panel of 30 colon cancer cell lines for sensitivity to HDACi-induced apoptosis and correlated the differences with gene expression patterns induced by HDACi in the five most sensitive and resistant lines. A robust and reproducible transcriptional response involving coordinate induction of multiple immediate-early (fos, jun, egr1, egr3, atf3, arc, nr4a1) and stress response genes (Ndrg4, Mt1B, Mt1E, Mt1F, Mt1H) was selectively induced in HDACi sensitive cells. Notably, a significant percentage of these genes were basally repressed in colon tumors. Bioinformatics analysis revealed that the promoter regions of the HDACi-induced genes were enriched for KLF4/Sp1/Sp3 transcription factor binding sites. Altering KLF4 levels failed to modulate apoptosis or transcriptional responses to HDACi treatment. In contrast, HDACi preferentially stimulated the activity of Spl/Sp3 and blocking their action attenuated both the transcriptional and apoptotic responses to HDACi treatment. Our findings link HDACi-induced apoptosis to activation of a Spl/Sp3-mediated response that involves derepression of a transcriptional network basally repressed in colon cancer.
- Published
- 2010
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16. Inhibitory effects of phloroglucinol derivatives isolated from Ecklonia stolonifera on Fc(epsilon)RI expression.
- Author
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Shim SY, Choi JS, and Byun DS
- Subjects
- Basophils cytology, Basophils physiology, Calcium immunology, Cell Degranulation drug effects, Cell Line, Cell Survival drug effects, Histamine immunology, Humans, Phloroglucinol analogs & derivatives, RNA, Messenger metabolism, Receptors, IgE analysis, Gene Expression drug effects, Laminaria chemistry, Phloroglucinol isolation & purification, Phloroglucinol pharmacology, Receptors, IgE genetics, Receptors, IgE immunology
- Abstract
Two bioactive phloroglucinol derivatives, dioxinodehydroeckol (DHE) and phlorofucofuroeckol A (PFF-A) were isolated from edible marine brown alga, Ecklonia stolonifera, and evaluated for effects on cell surface Fc(epsilon)RI expression in KU812F cells. DHE and PFF-A were found to reduce the cell surface expression, and total cellular protein and mRNA levels for the Fc(epsilon)RI alpha chain. Moreover, both compounds exerted inhibitory effects against the elevation of intracellular calcium concentration [Ca(2+)](i) and histamine release from anti-Fc(epsilon)RI alpha chain antibody (CRA-1)-stimulated cells. These inhibitory effects were stronger for PFF-A than for DHE. These results show that two phloroglucinol derivatives, DHE and PFF-A, may exert anti-allergic effects via the inhibition of Fc(epsilon)RI expression, calcium influx, and degranulation in basophils, and contributes to the pharmacological activities of marine brown alga, including E. stolonifera.
- Published
- 2009
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17. Isolation and identification of phlorotannins from Ecklonia stolonifera with antioxidant and anti-inflammatory properties.
- Author
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Kim AR, Shin TS, Lee MS, Park JY, Park KE, Yoon NY, Kim JS, Choi JS, Jang BC, Byun DS, Park NK, and Kim HR
- Subjects
- Animals, Benzofurans analysis, Benzofurans pharmacology, Cell Line, Chemical Fractionation, Cyclooxygenase 2 Inhibitors pharmacology, Dioxins analysis, Dioxins pharmacology, Enzyme Inhibitors pharmacology, Free Radical Scavengers pharmacology, Macrophages, Mice, Nitric Oxide Synthase Type II antagonists & inhibitors, Tannins isolation & purification, Tannins pharmacology, Anti-Inflammatory Agents pharmacology, Antioxidants pharmacology, Phaeophyceae chemistry, Tannins analysis
- Abstract
Bioactivity-guided fractionation of Ecklonia stolonifera was used to determine the chemical identity of bioactive constituents, with potent antioxidant activities. The structures of the phlorotannins were determined on the basis of spectroscopic analysis, including NMR and mass spectrometry analysis. The antioxidant activities of the isolated compounds were evaluated by free radical scavenging activities in both in vitro and cellular systems. The anti-inflammatory effects of the isolated compounds were evaluated by determining their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophage cells. The results indicated that phlorofucofuroeckol A, dieckol, and dioxinodehydroeckol showed potential radical scavenging activities against 2,2-diphenyl-1-picrylhydrazyl. Among them, phlorofucofuroeckol A and dieckol significantly suppressed the intracellular reactive oxygen species level assayed by 2',7'-dichlorofluorescein diacetate assay in LPS-induced RAW 264.7 cells. Phlorofucofuroeckol A significantly inhibited the LPS-induced production of NO and PGE(2) through the down-regulation of inducible nitric oxide synthase and cyclooxygenase 2 protein expressions. In conclusion, these results suggest that phlorofucofuroeckol A has a potential for functional foods with antioxidant and anti-inflammatory activities.
- Published
- 2009
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18. Kaempferol isolated from Nelumbo nucifera stamens negatively regulates FcepsilonRI expression in human basophilic KU812F cells.
- Author
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Shim SY, Choi JS, and Byun DS
- Subjects
- Calcium metabolism, Cells, Cultured, Dose-Response Relationship, Drug, Gene Expression, Histamine Release drug effects, Humans, Molecular Structure, Plant Extracts pharmacology, Basophils drug effects, Kaempferols pharmacology, Nelumbo chemistry, Receptors, IgE metabolism
- Abstract
Mast cells and basophils perform important functions as pivotal effector cells in IgE-mediated allergic reactions. KU812F cells, a human basophilic cell line isolated originally from chronic myelocytic leukemia, express a high affinity receptor of IgE, FcepsilonRI. Kaempferol was extracted and isolated from a methanolic extract of flavonoid-rich Nelumbo nucifera stamens. In the present study, the inhibitory effects of kaempferol on FcepsilonRI expression in human basophilic KU812F cells was examined. Flow cytometric analysis revealed that FcepsilonRI expression on the cell surface was suppressed in a concentration-dependent manner when the cells were cultured with kaempferol. Moreover, RTPCR analysis showed that the mRNA levels for FcepsilonRI alpha- and gamma-chains were reduced as the result of kaempferol treatment in a concentration-dependent manner. Kaempferol showed its suppressive effects on intracellular Ca2+ concentration and histamine release from anti-FcepsilonRI alpha- chain antibody-stimulated cells in a concentration-dependent manner. These observations indicate that kaempferol may exert antiallergic effect via downregulation of FcepsilonRI expression and degranulation.
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- 2009
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19. Proteomic changes during intestinal cell maturation in vivo.
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Chang J, Chance MR, Nicholas C, Ahmed N, Guilmeau S, Flandez M, Wang D, Byun DS, Nasser S, Albanese JM, Corner GA, Heerdt BG, Wilson AJ, Augenlicht LH, and Mariadason JM
- Subjects
- Animals, Coloring Agents, Electrophoresis, Gel, Two-Dimensional, Endoplasmic Reticulum Chaperone BiP, Enzymes chemistry, Enzymes genetics, Enzymes isolation & purification, Gene Expression Regulation, Intestinal Mucosa chemistry, Intestinal Mucosa cytology, Intestine, Small chemistry, Intestine, Small cytology, Lipids physiology, Mice, Proteins chemistry, Proteins genetics, Proteins isolation & purification, Rats, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Steroids metabolism, Intestinal Mucosa physiology, Intestine, Small physiology, Proteomics
- Abstract
Intestinal epithelial cells undergo progressive cell maturation as they migrate along the crypt-villus axis. To determine molecular signatures that define this process, proteins differentially expressed between the crypt and villus were identified by 2D-DIGE and MALDI-MS. Forty-six differentially expressed proteins were identified, several of which were validated by immunohistochemistry. Proteins upregulated in the villus were enriched for those involved in brush border assembly and lipid uptake, established features of differentiated intestinal epithelial cells. Multiple proteins involved in glycolysis were also upregulated in the villus, suggesting increased glycolysis is a feature of intestinal cell differentiation. Conversely, proteins involved in nucleotide metabolism, and protein processing and folding were increased in the crypt, consistent with functions associated with cell proliferation. Three novel paneth cell markers, AGR2, HSPA5 and RRBP1 were also identified. Notably, significant correlation was observed between overall proteomic changes and corresponding gene expression changes along the crypt-villus axis, indicating intestinal cell maturation is primarily regulated at the transcriptional level. This proteomic profiling analysis identified several novel proteins and functional processes differentially induced during intestinal cell maturation in vivo. Integration of proteomic, immunohistochemical, and parallel gene expression datasets demonstrate the coordinated manner in which intestinal cell maturation is regulated.
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- 2008
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20. NF-kappaB activates transcription of the RNA-binding factor HuR, via PI3K-AKT signaling, to promote gastric tumorigenesis.
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Kang MJ, Ryu BK, Lee MG, Han J, Lee JH, Ha TK, Byun DS, Chae KS, Lee BH, Chun HS, Lee KY, Kim HJ, and Chi SG
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- Cell Line, Tumor, Cell Proliferation, ELAV Proteins, ELAV-Like Protein 1, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases genetics, Polymerase Chain Reaction, Proto-Oncogene Proteins c-akt genetics, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Antigens, Surface genetics, NF-kappa B genetics, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, RNA, Neoplasm genetics, RNA-Binding Proteins genetics, Stomach Neoplasms genetics, Transcription, Genetic
- Abstract
Background & Aims: HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis., Methods: HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor kappaB (NF-kappaB) signaling., Results: Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G(1) to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-kappaB activity. AKT activation increased p65/RelA binding to a putative NF-kappaB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR., Conclusions: HuR is a direct transcription target of NF-kappaB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.
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- 2008
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21. Expression of selenium-binding protein 1 characterizes intestinal cell maturation and predicts survival for patients with colorectal cancer.
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Li T, Yang W, Li M, Byun DS, Tong C, Nasser S, Zhuang M, Arango D, Mariadason JM, and Augenlicht LH
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- Adult, Aged, Aged, 80 and over, Cell Line, Tumor, Colonic Neoplasms genetics, Colorectal Neoplasms pathology, Humans, Intestinal Mucosa pathology, Intestinal Mucosa physiopathology, Intestines pathology, Middle Aged, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Prognosis, RNA, Small Interfering genetics, Rectal Neoplasms genetics, Selenium-Binding Proteins metabolism, Survivors, Colorectal Neoplasms genetics, Intestines physiopathology, Selenium-Binding Proteins genetics
- Abstract
To identify candidate genes involved in the development of colorectal cancer, we used cDNA microarrays to analyze gene expression differences between human colorectal tumors and paired adjacent normal mucosa. We identified approximately 3.5-fold significant downregulation of selenium-binding protein 1 (SBP1) in colorectal tumors compared to normal mucosa (p = 0.003). Importantly, stage III colorectal cancer patients with low tumor-SBP1 expression had significantly shorter disease-free and overall survival as compared with those patients with high tumor-SBP1 expression (p = 0.04 and 0.03, respectively). We further characterized the role of SBP1 in colorectal cancer in vivo and in vitro. In normal tissue, SBP1 was maximally expressed in terminally differentiated epithelial cells on the luminal surface of crypts in the large intestine. Consistent with this in vivo localization, SBP1 was upregulated during in vitro colonic cell differentiation along the absorptive (Caco-2) and secretory (HT29 Clones 16E and 19A) cell lineages. Downregulation (approximately 50%) of SBP1 expression by small interfering RNA in colonic cancer cells was associated with reduced expression of another epithelial differentiation marker, carcinoembryonic antigen (CEA), although PCNA and p21(WAF1/cip1 )expression were not altered. These data demonstrate that higher expression of SBP1 is associated with differentiation of the normal colonic epithelia and may be a positive prognostic factor for survival in stage III colorectal carcinoma.
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- 2008
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22. HDAC4 promotes growth of colon cancer cells via repression of p21.
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Wilson AJ, Byun DS, Nasser S, Murray LB, Ayyanar K, Arango D, Figueroa M, Melnick A, Kao GD, Augenlicht LH, and Mariadason JM
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- Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Down-Regulation, Humans, Male, Mice, Mice, SCID, Models, Biological, Neoplasm Transplantation, RNA, Small Interfering metabolism, Cyclin-Dependent Kinase Inhibitor p21 antagonists & inhibitors, Gene Expression Regulation, Neoplastic, Histone Deacetylases physiology, Repressor Proteins physiology
- Abstract
The class II Histone deacetylase (HDAC), HDAC4, is expressed in a tissue-specific manner, and it represses differentiation of specific cell types. We demonstrate here that HDAC4 is expressed in the proliferative zone in small intestine and colon and that its expression is down-regulated during intestinal differentiation in vivo and in vitro. Subcellular localization studies demonstrated HDAC4 expression was predominantly nuclear in proliferating HCT116 cells and relocalized to the cytoplasm after cell cycle arrest. Down-regulating HDAC4 expression by small interfering RNA (siRNA) in HCT116 cells induced growth inhibition and apoptosis in vitro, reduced xenograft tumor growth, and increased p21 transcription. Conversely, overexpression of HDAC4 repressed p21 promoter activity. p21 was likely a direct target of HDAC4, because HDAC4 down-regulation increased p21 mRNA when protein synthesis was inhibited by cycloheximide. The importance of p21 repression in HDAC4-mediated growth promotion was demonstrated by the failure of HDAC4 down-regulation to induce growth arrest in HCT116 p21-null cells. HDAC4 down-regulation failed to induce p21 when Sp1 was functionally inhibited by mithramycin or siRNA-mediated down-regulation. HDAC4 expression overlapped with that of Sp1, and a physical interaction was demonstrated by coimmunoprecipitation. Chromatin immunoprecipitation (ChIP) and sequential ChIP analyses demonstrated Sp1-dependent binding of HDAC4 to the proximal p21 promoter, likely directed through the HDAC4-HDAC3-N-CoR/SMRT corepressor complex. Consistent with increased transcription, HDAC4 or SMRT down-regulation resulted in increased histone H3 acetylation at the proximal p21 promoter locus. These studies identify HDAC4 as a novel regulator of colon cell proliferation through repression of p21.
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- 2008
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23. Frequent epigenetic inactivation of hSRBC in gastric cancer and its implication in attenuated p53 response to stresses.
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Lee JH, Byun DS, Lee MG, Ryu BK, Kang MJ, Chae KS, Lee KY, Kim HJ, Park H, and Chi SG
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- Adenocarcinoma genetics, Adenoma genetics, Apoptosis, Blotting, Northern, Cell Line, Tumor, CpG Islands genetics, DNA Methylation, Down-Regulation, Flow Cytometry, Fluorescent Antibody Technique, Hamartoma genetics, Humans, Immunoblotting, In Situ Nick-End Labeling, Intracellular Signaling Peptides and Proteins metabolism, Neoplastic Stem Cells, Polyps genetics, Promoter Regions, Genetic genetics, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins metabolism, Gene Silencing, Intracellular Signaling Peptides and Proteins genetics, Stomach Neoplasms genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins genetics
- Abstract
hSRBC is a putative tumor suppressor located at 11p15.4, at which frequent genomic loss has been observed in several human malignancies. To explore the candidacy of hSRBC as a suppressor of gastric tumorigenesis, we analyzed the expression and mutation status of hSRBC in gastric tissues and cell lines. hSRBC transcript was expressed in all normal and benign tumor tissues examined, but undetectable or very low in 73% (11/15) cancer cell lines and 41% (46/111) primary tumors. Loss or reduction of hSRBC expression was tumor-specific and correlated with stage and grade of tumors. While allelic loss or somatic mutations of the gene were infrequent, its expression was restored in tumor cells by 5-aza-2'-deoxycytidine treatment and aberrant hypermethylation of 23 CpG sites in the promoter region showed a tight association with altered expression. Transient or stable expression of hSRBC led to a G(1) cell cycle arrest and apoptosis of tumor cells, and strongly suppresses colony forming ability and xenograft tumor growth. In addition, hSRBC elevated apoptotic sensitivity of tumor cells to genotoxic agents, such as 5-FU, etoposide and ultraviolet. Interestingly, hSRBC increased the protein stability of p53 and expression of p53 target genes, such as p21(Waf1), PUMA and NOXA, while hSRBC-mediated cell cycle arrest and apoptosis were abolished by blockade of p53 function. Our findings suggest that hSRBC is a novel tumor suppressor whose epigenetic inactivation contributes to the malignant progression of gastric tumors, in part, through attenuated p53 response to stresses., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2008
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24. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab.
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Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, and Mariadason JM
- Subjects
- Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Cetuximab, Class I Phosphatidylinositol 3-Kinases, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Epidermal Growth Factor pharmacology, ErbB Receptors biosynthesis, ErbB Receptors genetics, ErbB Receptors metabolism, Erlotinib Hydrochloride, G1 Phase drug effects, Gene Dosage, Genes, ras, HCT116 Cells, Humans, MAP Kinase Signaling System, Proto-Oncogene Proteins B-raf genetics, Quinazolines pharmacology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Resting Phase, Cell Cycle drug effects, ras Proteins genetics, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Mutation, PTEN Phosphohydrolase biosynthesis, Phosphatidylinositol 3-Kinases genetics
- Abstract
Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G(0)-G(1) arrest without inducing apoptosis. Notably, cetuximab-sensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines (14 +/- 5.0% versus 38.5 +/- 6.4% growth inhibition, mean +/- SE; P = 0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10.8 +/- 4.3% versus 38.8 +/- 5.9% growth inhibition, respectively; P = 0.002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy.
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- 2008
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25. Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses.
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Chung SK, Lee MG, Ryu BK, Lee JH, Han J, Byun DS, Chae KS, Lee KY, Jang JY, Kim HJ, and Chi SG
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- Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Apoptosis Regulatory Proteins, Cell Line, Tumor, Cell Survival, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, CpG Islands genetics, DNA Methylation, Down-Regulation, Gene Expression, Gene Silencing, Genetic Variation, Humans, Intracellular Signaling Peptides and Proteins, Loss of Heterozygosity, Molecular Sequence Data, Neoplasm Proteins genetics, Neoplasm Staging, Promoter Regions, Genetic, Stimulation, Chemical, Transcription, Genetic, Apoptosis, Colorectal Neoplasms physiopathology, Neoplasm Proteins metabolism
- Abstract
Background & Aims: X-linked inhibitor of apoptosis protein-associated factor 1 (XAF1) is a candidate tumor suppressor located at the chromosome 17p13 region, but the molecular basis underlying its inactivation in human tumors and growth-inhibiting function has not been well defined. We explored the candidacy of XAF1 as a suppressor in colorectal tumorigenesis., Methods: XAF1 expression was characterized by polymerase chain reaction-based cloning, isoform-specific polymerase chain reaction, ribonuclease protection, and immunoblot assays. Allelic loss of the gene was evaluated by loss of heterozygosity (LOH) assay, and promoter CG dinucleotide (CpG) site methylation was determined using bisulfite sequencing. The effect of XAF1 on tumor growth was examined using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, colony formation, and viability assays., Results: Expression of 5 XAF1 variants including 2 novel transcripts was down-regulated concomitantly in 11 of 20 (55%) cell lines and 26 of 65 (40%) primary tumors. XAF1 reduction was tumor-specific and showed a correlation with advanced stage and high grade of tumor. LOH of the gene was found in 12 of 33 (36%) tumors. Promoter CpG site methylation was observed frequently in both cell lines and tumor tissues including many LOH tumors, suggesting that biallelic inactivation of XAF1 might be common in colorectal cancers. XAF1 expression suppressed tumor cell growth and enhanced cellular response to various apoptotic stimuli, such as 5-fluorouracil, etoposide, H(2)O(2), gamma-irradiation, ultraviolet, and tumor necrosis factor-alpha, whereas knockdown of its expression protected cells from the stresses., Conclusions: Genetic and epigenetic alteration of XAF1 is a common event in colorectal tumorigenesis and contributes to the malignant tumor progression by providing survival advantages for tumor cells under various stress conditions.
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- 2007
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26. Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses.
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Lee MG, Huh JS, Chung SK, Lee JH, Byun DS, Ryu BK, Kang MJ, Chae KS, Lee SJ, Lee CH, Kim JI, Chang SG, and Chi SG
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- Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Kidney Neoplasms enzymology, Kidney Neoplasms genetics, Male, Prostatic Neoplasms enzymology, Prostatic Neoplasms genetics, Reverse Transcriptase Polymerase Chain Reaction, Urinary Bladder Neoplasms enzymology, Urinary Bladder Neoplasms genetics, Urogenital Neoplasms enzymology, DNA Methylation, Dinucleoside Phosphates genetics, Neoplasm Proteins genetics, Promoter Regions, Genetic, Tumor Suppressor Protein p53 genetics, Urogenital Neoplasms genetics
- Abstract
XIAP-associated factor 1 (XAF1) is a new candidate tumor suppressor, which has been known to exert proapoptotic effects by interfering with the caspase-inhibiting activity of XIAP. To explore the XAF1's candidacy for a suppressor in urogenital tumorigenesis, we investigated the XAF1 status in a series of cancer cell lines and primary tumors derived from the bladder, kidney and prostate. Expression of XAF1 transcript was undetectable or extremely low in 60% (3/5) of bladder, 66% (10/15) of kidney, and 100% (3/3) prostate cancer cell lines. Abnormal reduction of XAF1 was also found in 33% (18/55) of primary bladder and 40% (8/20) of primary kidney tumors, and showed a correlation with advanced stage and high grade of bladder tumor. Hypermethylation at 14 CpG sites in the 5' proximal region of the XAF1 promoter was highly prevalent in cancers versus adjacent normal or benign tissues and tightly associated with reduced gene expression. XAF1 expression enhanced the apoptotic response of tumor cells to chemotherapeutic agents, such as etoposide or 5-FU. While XAF1 expression did not influence the subcellular distribution or expression of XIAP, it elevated the protein stability of p53 and its target gene expression. Moreover, the apoptosis-sensitizing and growth suppression function of XAF1 was markedly impeded by blockade of p53 function. Collectively, our study demonstrates that epigenetic alteration of XAF1 is frequent in human urogenital cancers and may contribute to the malignant progression of tumors by rendering tumor cells a survival advantage partially through the attenuated p53 response to apoptotic stresses.
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- 2006
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27. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer.
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Wilson AJ, Byun DS, Popova N, Murray LB, L'Italien K, Sowa Y, Arango D, Velcich A, Augenlicht LH, and Mariadason JM
- Subjects
- Apoptosis, Caco-2 Cells, Cell Differentiation, Cell Proliferation, Colon cytology, Colonic Neoplasms, Cyclin-Dependent Kinase Inhibitor p21 genetics, Down-Regulation, Gene Expression Regulation, Enzymologic, Gene Silencing, HCT116 Cells, Histone Deacetylase Inhibitors, Humans, Time Factors, Up-Regulation, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Histone Deacetylases metabolism
- Abstract
Inhibitors of histone deacetylases (HDACs) induce growth arrest, differentiation, and apoptosis of colon cancer cell lines in vitro and have demonstrated anti-cancer efficacy in clinical trials. Whereas a role for HDAC1 and -2 in mediating components of the HDAC inhibitor response has been reported, the role of HDAC3 is unknown. Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638(N/+) mice. HDAC3 was also maximally expressed in proliferating crypt cells in normal intestine. Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increased apoptosis. Similar effects were observed for HDAC2 and, to a lesser extent, for HDAC1. HDAC3 silencing also selectively induced expression of alkaline phosphatase, a marker of colon cell maturation. Concurrent with its effect on cell growth, overexpression of HDAC3 and other Class I HDACs inhibited basal and butyrate-induced p21 transcription in a Sp1/Sp3-dependent manner, whereas silencing of HDAC3 stimulated p21 promoter activity and expression. However, the magnitude of the effects elicited by silencing of individual Class I HDACs was significantly less than that induced by HDAC inhibitors. These findings identify HDAC3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression. These findings also demonstrate that multiple Class I HDACs are involved in repressing p21 and suggest that the growth-inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.
- Published
- 2006
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28. Tyrosinase inhibitors isolated from the edible brown alga Ecklonia stolonifera.
- Author
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Kang HS, Kim HR, Byun DS, Son BW, Nam TJ, and Choi JS
- Subjects
- Enzyme Inhibitors chemistry, Monophenol Monooxygenase metabolism, Phaeophyceae isolation & purification, Enzyme Inhibitors isolation & purification, Enzyme Inhibitors pharmacology, Laminaria isolation & purification, Monophenol Monooxygenase antagonists & inhibitors
- Abstract
Extracts from seventeen seaweeds were determined for tyrosinase inhibitory activity using mushroom tyrosinase with L-tyrosine as a substrate. Only one of them, Ecklonia stolonifera OKAMURA (Laminariaceae) belonging to brown algae, showed high tyrosinase inhibitory activity. Bioassay-guided fractionation of the active ethyl acetate (EtOAc) soluble fraction from the methanolic extract of E. stolonifera, led us to the isolation of phloroglucinol derivatives [phloroglucinol (1), eckstolonol (2), eckol (3), phlorofucofuroeckol A (4), and dieckol (5)]. Compounds 1 approximately 5 were found to inhibit the oxidation of L-tyrosine catalyzed by mushroom tyrosinase with IC50 values of 92.8, 126, 33.2, 177, and 2.16 microg/mL, respectively. It was compared with those of kojic acid and arbutin, well-known tyrosinase inhibitors, with IC50 values of 6.32 and 112 microg/ mL, respectively. The inhibitory kinetics analyzed from Lineweaver-Burk plots, showed compounds 1 and 2 to be competitive inhibitors with Ki of 2.3x10(-4) and 3.1x10(-4) M, and compounds 3 approximately 5 to be noncompetitive inhibitors with Ki of 1.9x10(-5), 1.4x10(-3) and 1.5x10(-5) M, respectively. This work showed that phloroglucinol derivatives, natural compounds found in brown algae, could be involved in the control of pigmentation in plants and other organisms through inhibition of tyrosinase activity using L-tyrosine as a substrate.
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- 2004
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29. Purification and characterization of arylsulfatase from Sphingomonas sp. AS6330.
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Kim JH, Byun DS, Godber JS, Choi JS, Choi WC, and Kim HR
- Subjects
- Agar metabolism, Arylsulfatases chemistry, Biotransformation, Carrageenan metabolism, Chromatography, Gel, Chromatography, Ion Exchange, Enzyme Stability, Hydrogen-Ion Concentration, Industrial Microbiology methods, Molecular Weight, Nitrobenzenes metabolism, Polysaccharides metabolism, Sepharose metabolism, Substrate Specificity, Temperature, Arylsulfatases isolation & purification, Arylsulfatases metabolism, Sepharose analogs & derivatives, Sphingomonas enzymology
- Abstract
Arylsulfatase was purified from Sphingomonas sp. AS6330 through ionic exchange, hydrophobic- and gel-chromatographies. The purity increased 12,800-fold with approximately 19.1% yield against cell homogenate. The enzyme was a monomeric protein with apparent molecular weight of 62 kDa as determined by sodium dodecylsulfate-polyacrylamide gel electrophoresis, and 41 kDa as determined by gel filtration. The enzyme had optimum reaction conditions for hydrolysis of sulfate ester bonds in agar and p-nitrophenyl sulfate (NPS) at pH 7.0 and 45 degrees C, with a specific activity of 3.93 and 97.2 U, respectively. The enzyme showed higher activity towards agar than other sulfated marine polysaccharides such as porphyran, fucoidan and carrageenan. The K(m) and V(max) of the enzyme for hydrolysis of NPS were 54.9 microM and 113 mM/min, respectively. With reaction of 200 g agar with 100 U arylsulfatase for 8 h at 45 degrees C, gel strength increased 2.44-fold, and 97.7% of the sulfate in the agar was hydrolyzed.
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- 2004
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30. Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas.
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Byun DS, Cho K, Ryu BK, Lee MG, Kang MJ, Kim HR, and Chi SG
- Subjects
- Adaptor Proteins, Signal Transducing, Adenocarcinoma metabolism, Alleles, Apoptosis Regulatory Proteins, Carrier Proteins biosynthesis, Carrier Proteins genetics, Cell Line, Tumor, Down-Regulation, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Silencing, High-Temperature Requirement A Serine Peptidase 2, Humans, Intracellular Signaling Peptides and Proteins, Mitochondrial Proteins biosynthesis, Mitochondrial Proteins genetics, Mutation, Neoplasm Proteins biosynthesis, Promoter Regions, Genetic, RNA, Messenger biosynthesis, RNA, Messenger genetics, Serine Endopeptidases biosynthesis, Serine Endopeptidases genetics, Stomach Neoplasms metabolism, Tumor Suppressor Protein p53 genetics, Adenocarcinoma genetics, Chromosomes, Human, Pair 17 genetics, DNA Methylation, Genes, Tumor Suppressor, Neoplasm Proteins genetics, Stomach Neoplasms genetics
- Abstract
X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects by interfering with the activities of caspases. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. To explore the candidacy of XAF1, Smac/DIABLO, and HtrA2 as a tumor suppressor in gastric tumorigenesis, we investigated the expression and mutation status of the genes in 123 gastric tissues and 15 cancer cell lines. Whereas Smac/DIABLO and HtrA2 transcripts were normally expressed in all cancer specimens we examined, XAF1 transcript was not expressed or present at extremely low levels in 40% (6 of 15) of cancer cell lines and in 23% (20 of 87) of primary carcinomas. Abnormal reduction of XAF1 expression showed a strong correlation with stage and grade of tumors, and a tumor-specific down-regulation of XAF1 was observed in 45% (9 of 20) of matched sets. Unlike XAF1, XIAP expression exhibited no detectable alteration in cancers. Whereas loss of heterozygosity within the XAF1 region or somatic mutations of the gene was not detected, expression of XAF1 transcript was reactivated in all nonexpressor cell lines after 5-aza-2-deoxycytidine treatment. The 5' upstream region of the XAF1 gene encompasses no gastric cell-rich region that rigorously satisfies the formal criteria for CpG islands. However, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Moreover, transcriptional silencing of XAF1 was tightly associated with hypermethylation of seven CpGs located in the 5' proximal region (nucleotides -23 to -234). Additionally, loss or abnormal reduction of XAF1 expression was found to inversely correlate with p53 mutations, suggesting that epigenetic inactivation of XAF1 and mutational alteration of p53 might be mutually exclusive events in gastric tumorigenesis. Collectively, our study suggests that epigenetic silencing of XAF1 by aberrant promoter methylation may contribute to the malignant progression of human gastric tumors.
- Published
- 2003
31. Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways.
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Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, and Chi SG
- Subjects
- Apoptosis, Humans, JNK Mitogen-Activated Protein Kinases, Male, RNA, Messenger analysis, Smad2 Protein, Transcription Factor AP-1 physiology, Transforming Growth Factor beta1, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases, DNA-Binding Proteins physiology, Interleukin-6 genetics, Mitogen-Activated Protein Kinases physiology, NF-kappa B physiology, Prostatic Neoplasms etiology, Trans-Activators physiology, Transforming Growth Factor beta pharmacology
- Abstract
Transforming growth factor (TGF)-beta1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-beta1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-beta1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-beta1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-beta1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-kappaB (NF-kappaB), JNK, and Ras. TGF-beta1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by TGF-beta1 was accompanied by nuclear translocation of NF-kappaB, which was blocked by the p38 inhibitors SB202190 and SB203580 or by IkappaBalphaDeltaN transfection, indicating the crucial role for the p38-NF-kappaB signaling in TGF-beta1 induction of IL-6. TGF-beta1 activated c-Jun phosphorylation, and IL-6 induction by TGF-beta1 was severely impeded by DN-c-Jun and DN-JNK or AP-1 inhibitor curcumin, showing that the JNK-c-Jun-AP-1 signaling plays a pivotal role in TGF-beta1 stimulation of IL-6. It was also found that the Ras-Raf-MEK1 cascade is activated by TGF-beta1 and participates in the TGF-beta1 induction of IL-6 in an AP-1-dependent manner. Cotransfection assays demonstrated that TGF-beta1 stimulation of IL-6 results from the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK-c-Jun-AP-1, or Ras-Raf-MEK1 cascades. In addition, a time course IL-6 decay revealed that mRNA stability of IL-6 is modestly increased by TGF-beta1, indicating that TGF-beta1 also regulates IL-6 at the post-transcriptional level. Intriguingly, IL-6 inactivation restored the sensitivity to TGF-beta1-mediated growth arrest and apoptosis, suggesting that elevated IL-6 in advanced prostate tumors might act as a resistance factor against TGF-beta1. Collectively, our data demonstrate that IL-6 expression is stimulated by tumor-producing TGF-beta1 in human prostate cancer cells through multiple signaling pathways including Smad2, p38, JNK, and Ras, and enhanced expression of IL-6 could contribute to the oncogenic switch of TGF-beta1 role for prostate tumorigenesis, in part by counteracting its growth suppression function.
- Published
- 2003
- Full Text
- View/download PDF
32. Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma.
- Author
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Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, Kim HJ, and Chi SG
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Adenoma metabolism, Adenoma pathology, DNA Methylation, DNA Mutational Analysis, DNA Primers chemistry, DNA, Neoplasm analysis, Gene Amplification, Gene Silencing, Hamartoma genetics, Hamartoma metabolism, Hamartoma pathology, Humans, Loss of Heterozygosity, Male, Mutation, Neoplasm Staging, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases metabolism, Phosphoric Monoester Hydrolases metabolism, Phosphorylation, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Promoter Regions, Genetic, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Pseudogenes genetics, RNA, Messenger metabolism, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Tumor Cells, Cultured, Tumor Suppressor Proteins metabolism, Adenocarcinoma genetics, Adenoma genetics, Phosphatidylinositol 3-Kinases genetics, Phosphoric Monoester Hydrolases genetics, Protein Serine-Threonine Kinases, Stomach Neoplasms genetics, Tumor Suppressor Proteins genetics
- Abstract
Mutational alterations of PTEN and PIK3CA, which negatively and positively regulate PI3-kinase activity, respectively, have been observed in many types of human cancer. To explore the implication of PTEN and PIK3CA mutations in gastric tumorigenesis, we characterized the expression and mutation status of the genes in 126 gastric tissues and 15 cell lines. Expression of PTEN transcript was abnormally low in 5 of 15 (33%) cell lines and 20 of 55 (36%) primary carcinomas, whereas 0 of 71 noncancerous tissues including 16 benign tumors showed altered expression. Allelotyping analysis using an intragenic polymorphism (IVS4+109) revealed that 14 of 30 (47%) informative cases carried LOH of the gene, which is closely linked to low expression. The LOH rate was significantly higher in advanced tumors [12 of 19 (63%)] compared to early-stage tumors [2 of 11 (18%)] and more frequent in poorly differentiated tumors [9 of 13 (69%)] than well- or moderately differentiated tumors [5 of 17 (29%)]. Interestingly, however, none of the LOH tumors carried mutational disruption of the remaining allele, suggesting haploinsufficiency of PTEN in gastric tumorigenesis. Methylation studies revealed that PTEN pseudogene, but not PTEN, is methylated in cell lines and primary tumors, indicating that PTEN is not a target of epigenetic silencing in gastric cancers and that the pseudogene should be considered more carefully in methylation analysis of the PTEN promoter. Genomic amplification of PIK3CA was found in 9 of 15 (60%) cell lines and 20 of 55 (36.4%) primary tumors but in no noncancerous tissues. Furthermore, PIK3CA amplification was predominantly detected in tumors with no PTEN alterations, suggesting that mutations of PTEN and PIK3CA are mutually exclusive events in gastric tumorigenesis. Amplification of PIK3CA was strongly associated with increased expression of PIK3CA transcript and elevated levels of phospho-AKT. Collectively, our data reveal that 13 of 15 (87%) gastric cell lines and 31 of 55 (56%) primary carcinomas harbored either amplification of PIK3CA or abnormal reduction of PTEN. Mutually exclusive alterations of PTEN and PIK3CA also suggest that mutations of either gene could activate the PI3-kinase/AKT signaling pathway, which is directly linked to the malignant progression of gastric tumor cells., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
33. Further isolation of antioxidative (+)-1-hydroxypinoresinol-1-O-beta-D-glucoside from the rhizome of Salvia miltiorrhiza that acts on peroxynitrite, total ROS and 1,1-diphenyl-2-picrylhydrazyl radical.
- Author
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Kang HS, Chung HY, Byun DS, and Choi JS
- Subjects
- Antioxidants chemistry, Antioxidants isolation & purification, Antioxidants pharmacology, Biphenyl Compounds, Glucosides chemistry, Glucosides isolation & purification, Plant Extracts chemistry, Plant Extracts isolation & purification, Plant Extracts metabolism, Rhizome chemistry, Rhizome metabolism, Salvia miltiorrhiza chemistry, Glucosides metabolism, Peroxynitrous Acid metabolism, Picrates metabolism, Reactive Oxygen Species metabolism, Salvia miltiorrhiza metabolism
- Abstract
A furanofuranoid lignan glycoside, with radical scavenging on peroxynitrite, total reactive oxygen species (ROS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, was isolated from the rhizome of Salvia miltiorrhiza and characterized as (+)-1-hydroxypinoresinol-1-O-beta-D-glucoside based on spectroscopic evidence. The compound exhibited peroxynitrite, total ROS and DPPH radical scavenging activities with IC50 values of 3.23 +/- 0.04, 2.26 +/- 0.07 and 32.3 +/- 0.13 microM, respectively. Penicillamine, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and L-ascorbic acid, acting as positive controls, showed radical scavenging activities with IC50 values of 6.72 +/- 0.25, 1.43 +/- 0.04 and 11.4 +/- 0.07 microM, respectively.
- Published
- 2003
- Full Text
- View/download PDF
34. Expression and mutation analyses of MKK4, a candidate tumour suppressor gene encoded by chromosome 17p, in human gastric adenocarcinoma.
- Author
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Chae KS, Ryu BK, Lee MG, Byun DS, and Chi SG
- Subjects
- Adenocarcinoma metabolism, Amino Acid Sequence, Base Sequence, Blotting, Western, Gene Expression, Humans, Loss of Heterozygosity, Mitogen-Activated Protein Kinase Kinases metabolism, Polymorphism, Single-Stranded Conformational, Pseudogenes genetics, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms metabolism, Tumor Cells, Cultured, Adenocarcinoma genetics, Chromosomes, Human, Pair 17 genetics, Genes, Tumor Suppressor physiology, MAP Kinase Kinase 4, Mitogen-Activated Protein Kinase Kinases genetics, Mutation genetics, Stomach Neoplasms genetics
- Abstract
Homozygous deletion or somatic mutations of mitogen-activated protein kinase kinase 4 (MKK4), a candidate tumour suppressor gene located at 17p11, have been observed in many types of human tumours. To explore the likelihood that MKK4 acts as a suppressor in gastric tumorigenesis, we examined the expression and mutation status of MKK4 in 144 gastric tissues and cell line specimens. Expression of the MKK4 transcript was easily detectable in all normal and benign tumour tissues and none of 102 primary carcinomas and cell lines showed an abnormal reduction in MKK4 expression. Expression levels of MKK4 transcript showed no cancer-specific reduction in 43 matched sets and did not correlate with stage, grade and histopathological types of the tumours. Western blot analysis also revealed that MKK4 protein expression in carcinoma tissues and cell lines is comparable to non-cancerous tissues. A significant loss of heterozygosity (LOH) was detected at telomeric markers of the MKK4, locus. However, no allelic deletion of the MKK4 gene or at the centromeric loci was identified. Moreover, no evidences for somatic mutations leading to amino acid substitutions or frameshifts of MKK4 were identified in the carcinoma tissues and cell lines, whereas a substantial fraction of the same set showed allelic loss or mutations of the TP53 gene located at 17p13, suggesting that LOH at telomeric loci or the TP53 locus might not extend into the MKK4 gene in gastric cancers. In this study, we also report the identification of a highly conserved MKK4 processed pseudogene, which shares 95% homology with the coding region of the functional MKK4 transcript. Collectively, our data demonstrate that genomic deletion or somatic mutation of MKK4 is infrequent in gastric cancers, suggesting that MKK4 might not be a critical target of genetic inactivation in gastric tumorigenesis.
- Published
- 2002
- Full Text
- View/download PDF
35. Expression and mutation analyses of P53R2, a newly identified p53 target for DNA repair in human gastric carcinoma.
- Author
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Byun DS, Chae KS, Ryu BK, Lee MG, and Chi SG
- Subjects
- Adenocarcinoma pathology, Adenoma pathology, Antineoplastic Agents pharmacology, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Division, Cyclin-Dependent Kinase Inhibitor p21, Cyclins genetics, Cyclins metabolism, DNA Damage, DNA Mutational Analysis, DNA Primers chemistry, DNA, Neoplasm analysis, Doxorubicin pharmacology, Humans, Polymerase Chain Reaction, RNA, Messenger metabolism, Ribonucleotide Reductases metabolism, Stomach Neoplasms pathology, Transfection, Tumor Cells, Cultured, Adenocarcinoma genetics, Adenoma genetics, DNA Repair, Ribonucleotide Reductases genetics, Stomach Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
p53R2, a recently identified putative tumor suppressor located at 8q23.1, encodes a protein with striking similarity to a small subunit of ribonucleotide reductase. p53R2 is directly induced by wild-type p53 and involved in the p53 checkpoint for repair of damaged DNA, raising the possibility that mutational inactivation of p53R2 may contribute to the development and progression of human malignancies. To explore the p53R2's candidacy for a suppressor in gastric tumorigenesis, we examined the expression and mutation status of p53R2 in 166 gastric specimens including 90 primary adenocarcinomas and 15 cell lines. In response to genotoxic damages, p53R2 transcription was clearly activated in wild-type but not mutant-type p53-carrying cells while basal expression of p53R2 in undamaged cells showed no association with the mutational status of p53. Host cell reactivation assay revealed that p53R2 enhances DNA repair efficiency and plays a role in the p53-mediated repair of damaged DNA, whereas no significant effect of p53R2 on cell growth and apoptosis was detected in flow cytometry and [(3)H]thymidine incorporation assays. p53R2 transcript was expressed in all normal and tumor tissues and its expression levels were not significantly different between normal and malignant carcinoma tissues. p53R2 expression showed no correlation with stage, grade and histological types of tumors. Moreover, no tumor-specific reduction of p53R2 was detected in 30 matched sets. Mutational analysis of p53R2 in 105 carcinomas including 15 cell lines also failed to detect any evidences for genomic deletion or somatic mutations leading to amino acid substitutions or frameshift whereas 31% (28 of 90) of the same primary tumors showed p53 alterations. Whereas 82% (23 of 28) of the mutant p53-carrying primary tumors expressed abnormally low p21(Waf1), no association of p53R2 expression with the p53 status was recognized, suggesting that basal transcription of p53R2 is regulated through the p53-independent mechanism. Collectively, our study indicates that although p53R2 is induced in a p53-dependent manner and involved the p53-mediated DNA repair in gastric epithelial cells, it is not a critical target of genetic inactivation in gastric tumorigenesis., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
- Full Text
- View/download PDF
36. Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma.
- Author
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Byun DS, Lee MG, Chae KS, Ryu BG, and Chi SG
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Chromosomes, Human, Pair 3, CpG Islands, Disease Progression, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Mutation, Neoplasm Proteins biosynthesis, Neoplasm Staging, Promoter Regions, Genetic, Protein Isoforms, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Tumor Cells, Cultured, Adenocarcinoma genetics, DNA Methylation, Gene Silencing, Genes, Tumor Suppressor, Neoplasm Proteins genetics, Stomach Neoplasms genetics, Tumor Suppressor Proteins
- Abstract
Methylation associated inactivation of RASSF1, a putative tumor suppressor identified at 3p21.3, has been frequently observed in several human malignancies, including lung and breast cancers. To explore the penetrance of RASSF1 in gastric carcinogenesis, we performed expression and mutation analyses of 3 isotypes of RASSF1 (A, B, and C) in 150 gastric specimens, including 15 carcinoma cell lines. RASSF1A and RASSF1B transcripts were not expressed in 60% (9 of 15) and 33% (5 of 15) of gastric carcinoma cell lines, respectively, whereas RASSF1C was detectable in all cell lines. Bisulfite DNA sequencing analysis revealed that the CpG island in the RASSF1A promoter is hypermethylated in all RASSF1A-nonexpressing cell lines. In addition, both RASSF1A and RASSF1B were re-expressed by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Among 90 primary gastric adenocarcinomas examined, 41 (46%) and 19 (21%) expressed no or abnormally low levels of RASSF1A and RASSF1B, respectively, and 12 (13%) tumors showed no expression of both isoforms. Loss or abnormal down-regulation of RASSF1A correlated with tumor stage and grade but not with histological types of tumors. Methylation-specific PCR analysis demonstrated that 95% (39 of 41) of RASSF1A-nonexpressing primary tumors are methylated at the CpG sites in the promoter, whereas none of the adjacent noncancerous or normal tissues are methylated. No somatic mutations were detected in RASSF1 transcripts expressed in unmethylated tumors. However, 10 methylated tumors, including 4 cell lines, showed low genomic levels of RASSF1 and expressed no RASSF1A transcripts, suggesting that RASSF1A inactivation might be caused by both epigenetic and genetic mechanisms in a subset of gastric adenocarcinomas. In conclusion, our data indicate that epigenetic transcriptional silencing of RASSF1, especially RASSF1A isoform, is a frequent event in gastric tumorigenesis and might play an important role in the malignant progression of gastric adenocarcinomas.
- Published
- 2001
37. Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma.
- Author
-
Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, Kim JI, Chang SG, and Chi SG
- Subjects
- Adult, Base Sequence, Chromosomes, Human, Pair 3, CpG Islands genetics, DNA Methylation, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor genetics, Humans, Loss of Heterozygosity, Male, Middle Aged, Molecular Sequence Data, Neoplasm Proteins biosynthesis, Promoter Regions, Genetic, RNA, Messenger biosynthesis, RNA, Messenger genetics, Tumor Cells, Cultured, Urinary Bladder Neoplasms metabolism, Gene Silencing, Neoplasm Proteins genetics, Tumor Suppressor Proteins, Urinary Bladder Neoplasms genetics
- Abstract
Allelic deletion or transcriptional silencing of RASSF1, a putative tumor suppressor at 3p21.3, has been found in a considerable proportion of lung, breast, and ovarian cancers. In this study, we analyzed the expression and mutation status of three RASSF1 isoforms (-A, -B, and -C) in 55 primary bladder carcinomas and 10 bladder and prostate cancer cell lines. The RASSF1A transcript was not found in 80% (4 of 5) and 100% (4 of 4) of bladder and prostate cell lines, respectively. Compared with normal bladder tissues, loss or significant reduction of RASSF1A was identified in 62% (34 of 55) of primary bladder carcinomas and 10 (83%) of 12 matched sets showed tumor-specific alteration of RASSF1A expression. Moreover, loss or abnormal down-regulation of RASSF1A correlated with advanced tumor stage. RASSF1B was undetectable in 60% (3 of 5) of bladder cell lines and in 31% (17 of 55) of primary tumors, but none of these tumors showed altered expression exclusively in RASSF1B. RASSF1C transcript was detected in all cell lines and primary tumors we examined. Expression of RASSF1A and RASSF1B was reactivated in all nonexpressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Bisulfite DNA sequencing analysis revealed that aberrant hypermethylation at the CpG island in the RASSF1A promoter is strongly associated with the loss of RASSF1A expression in cell lines and uncultured primary tumors. Methylation-specific PCR and BstUI digestion analyses also demonstrated that 97% (33 of 34) of RASSF1A-nonexpressing primary tumors are methylated. Although somatic mutations were not identified in RASSF1 transcripts expressed in unmethylated tumors, 24% (9 of 37) of methylated cell lines and primary tumors showed detectable reductions in genomic levels of RASSF1, suggesting that RASSF1A inactivation might be caused by both epigenetic and genetic mechanisms in a subset of bladder tumors. Together, our data suggest that RASSF1A inactivation may play a critical role in the malignant progression of human bladder carcinomas.
- Published
- 2001
38. Toxoplasma gondii Hsp70 as a danger signal in toxoplasma gondii-infected mice.
- Author
-
Mun HS, Aosai F, Norose K, Chen M, Hata H, Tagawa YI, Iwakura Y, Byun DS, and Yano A
- Subjects
- Animals, HSP30 Heat-Shock Proteins, Heat-Shock Proteins genetics, Heat-Shock Proteins isolation & purification, Immunity, Innate, Interferon-gamma genetics, Interferon-gamma pharmacology, Macrophages, Peritoneal metabolism, Membrane Proteins genetics, Membrane Proteins isolation & purification, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide metabolism, Protozoan Proteins genetics, RNA, Messenger isolation & purification, RNA, Protozoan isolation & purification, Antigens, Protozoan, HSP70 Heat-Shock Proteins isolation & purification, Protozoan Proteins isolation & purification, Toxoplasmosis, Animal mortality
- Abstract
Toxoplasma gondii Hsp70, T gondii Hsp30/bag1, and surface antigen 1 messenger RNAs were shown to be useful in analyzing stage conversion of T gondii between bradyzoites and tachyzoites. The high-level expression of T gondii Hsp70 was correlated with mortality in interferon-gamma knockout mice infected with T gondii. Tgondii Hsp70 inhibited the induction of nitric oxide release by peritoneal macrophages of T gondii-infected mice. These findings identify T gondii Hsp70 as a danger signal during lethal, acute T gondii infection.
- Published
- 2000
- Full Text
- View/download PDF
39. Development and characterization of a flavoring agent from oyster cooker effluent.
- Author
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Kim DS, Baek HH, Ahn CB, Byun DS, Jung KJ, Lee HG, Cadwallader KR, and Kim HR
- Subjects
- Animals, Gas Chromatography-Mass Spectrometry, Odorants analysis, Flavoring Agents analysis, Ostreidae chemistry
- Abstract
The general composition of concentrated oyster cooker effluent (OCE) was 80% moisture, 6.7% total nitrogen, 2.4% glycogen, and 8.5% ash. Optimum conditions for enzymatic hydrolysis of OCE were 50 degrees C, 2 h of reaction time, 0.1% amylase mixture (alpha-amylase plus glucoamylase), and 0.2% protease NP. Hydrolysis of OCE led to an increase in free amino acids, with taurine comprising approximately 20% of the total. Inosine monophosphate was predominant (456 mg/100 g) among nucleotides and related compounds. Enzyme hydrolysis increased extractable nitrogen by approximately 2-fold. Trimethylamine, trimethylamine oxide, and total creatinine levels were not affected by enzyme treatment. Predominant aroma-active components of enzyme-hydrolyzed OCE included 2-acetyl-1-pyrroline and 3-(methylthio)propanal. Results of this study may help alleviate the wastewater disposal problem currently caused by OCE.
- Published
- 2000
- Full Text
- View/download PDF
40. Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer.
- Author
-
Park BJ, Park JI, Byun DS, Park JH, and Chi SG
- Subjects
- Cell Cycle, Cell Division drug effects, DNA-Binding Proteins metabolism, Enzyme Activation, Enzyme Inhibitors pharmacology, Flavonoids pharmacology, Flow Cytometry, Humans, Male, Polymorphism, Single-Stranded Conformational, Prostatic Neoplasms enzymology, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Time Factors, Trans-Activators metabolism, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Genes, ras genetics, MAP Kinase Signaling System, Oncogene Protein p21(ras) metabolism, Prostatic Neoplasms metabolism, Transforming Growth Factor beta metabolism
- Abstract
Elevated expression of transforming growth factor (TGF)-beta1 has been implicated in prostate tumorigenesis despite its growth-inhibitory effect on normal epithelial and carcinoma cells of the prostate. In this study, we identified that G1-to-S transition of the cell cycle is stimulated by TGF-beta1 in the prostate cancer cell line TSU-Pr1. No mutation of signal mediators, including Smads, and induction of PAI-1 transcription indicated that the TGF-beta1 signaling cascade is functionally intact in this cell line. Whereas pharmacological inhibitors of various mitogenic signaling pathways showed no effects, blockade of the mitogen-activated protein kinase (MAPK) pathway by the MAPK kinase 1 inhibitor PD98059 restored the growth inhibitory role of TGF-beta1 in TSU-Pr1, which carries an oncogenic mutation in Ha-Ras (V12). Moreover, expression of antisense Ha-Ras or dominant negative Raf-1 abrogated the mitogenic effect of TGF-beta1 in TSU-Pr1, and the TGF-beta1 inhibition of DU145 was switched to stimulation by V12Ha-Ras transfection. Whereas the negative growth regulation by TGF-beta1 was completely inhibited by dominant negative Smad2, Smad3, or Smad4, its mitogenic effect was not affected, suggesting that this action is Smad-independent. Interestingly, whereas the TGF-beta1-mediated up-regulation of p15INK4B and p21WAF1 transcription was abolished in TSU-Pr1 and V12Ha-Ras-transfected DU145, inhibition of the Ras/MAPK pathway restored the TGF-beta1 induction of these genes. Taken together, our data suggest that prostate carcinomas with the Ras/MAPK pathway activation might have a selective growth advantage by autocrine TGF-beta1 production.
- Published
- 2000
41. Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma.
- Author
-
Kang MJ, Park BJ, Byun DS, Park JI, Kim HJ, Park JH, and Chi SG
- Subjects
- Adenocarcinoma pathology, Alleles, Azacitidine analogs & derivatives, Azacitidine pharmacology, Culture Media, Serum-Free pharmacology, Cyclin-Dependent Kinase Inhibitor p21, Cyclins genetics, DNA, Neoplasm analysis, DNA, Neoplasm genetics, Decitabine, Gene Expression Regulation, Neoplastic drug effects, Genes, Tumor Suppressor, HL-60 Cells, Humans, Mutation, Polymorphism, Single-Stranded Conformational, RNA, Messenger drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms pathology, Tumor Cells, Cultured, Tumor Protein p73, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins, U937 Cells, Adenocarcinoma genetics, DNA-Binding Proteins genetics, Genomic Imprinting, Nuclear Proteins genetics, Stomach Neoplasms genetics
- Abstract
The p73 gene located at 1p36.3 encodes for a protein with significant similarity to p53. To investigate the penetrance of p73 in gastric carcinogenesis, we analyzed the expression, allelotype, and mutation of p73 in five cell lines and 75 tissues. Although extremely low levels of p73 expression were observed in all noncancerous gastric tissues and four of five cell lines, a significant elevation of p73 was detected in 37 of 39 (94.9%) carcinoma tissues. Furthermore, a tumor-specific increase of p73 was identified in 14 of 16 (87.5%) matched sets. Allelotyping analysis using a StyI or BanI polymorphism revealed that 5 of 21 (23.8%) informative carcinomas, but none of 19 noncancerous cases, express p73 biallelically, suggesting the transcriptional activation of a silent allele in a subset of cancers. Whereas the transcription of an active allele was markedly induced by serum starvation or clump formation of the cells, treatment with 5-aza-2'deoxycytidine activated a silent allele with a subsequent up-regulation of an active allele, supporting the genomic imprinting and autoregulation of the gene. Allelic deletion or mutation of the gene was not found, and no association of p73 expression with the mutational status of p53 or expression of p21Waf1 was recognized. Taken together, this study argues that p73 is not a target of genetic alteration in gastric carcinogenesis and suggests that overexpression of p73 might be triggered by physiological stresses accompanied with outgrowth of tumors, such as hypoxia or nutrient deprivation.
- Published
- 2000
42. Modulation of antioxidant activities and immune response by food restriction in aging Fisher-344 rats.
- Author
-
Byun DS, Venkatraman JT, Yu BP, and Fernandes G
- Subjects
- Aging metabolism, Animals, Cholesterol analysis, Fatty Acids analysis, Interleukin-2 biosynthesis, Lymphocyte Activation, Male, Membrane Fluidity, Membrane Lipids chemistry, Rats, Rats, Inbred F344, Aging immunology, Antioxidants analysis, Diet, Reducing, Superoxide Dismutase metabolism
- Abstract
Food restriction delays the loss of several cellular immune functions, retards the onset of many diseases during aging and, consequently, extends life span significantly in laboratory rodents. The present study was undertaken to determine whether the age-associated loss in immune function is linked to changes in microsomal and mitochondrial membranes of spleens in Fischer-344 (F-344) male rats. In this study, we determined cytosolic superoxide dismutase activity (SOD), fluidity and cholesterol content in the splenic microsomal and mitochondrial membranes, and DNA synthesis and IL-2 production in spleen cells from young and old ad libitum-fed (AL) and food restricted (FR) rats. The results show that proliferative response to phytohemagglutinin (PHA) and concanavalin A (Con-A) was significantly higher in the spleen cells of 18-month- and 24-month-old FR rats, as compared to their age-matched AL controls. Cytosolic SOD activity in the 24-month-old AL rats decreased by 28% as compared to 6-month-old AL rats, whereas in FR old rats, the loss was only 12%, suggesting that food restriction prevents loss in cytosolic SOD activity in spleens. Our data are consistent with the notion that food restriction modulates loss in immune response of splenocytes by maintaining both cytosolic SOD activity and membrane fluidity during aging.
- Published
- 1995
- Full Text
- View/download PDF
43. Effect of cholestanol feeding on sterol concentrations in the serum, liver, and cerebellum of mice.
- Author
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Byun DS, Kasama T, Shimizu T, Yorifuji H, and Seyama Y
- Subjects
- Animals, Cerebellum ultrastructure, Chromatography, High Pressure Liquid, Diet, Liver pathology, Liver ultrastructure, Male, Mice, Microscopy, Electron, Sterols blood, Xanthomatosis etiology, Cerebellum metabolism, Cholestanols pharmacology, Liver metabolism, Sterols metabolism
- Abstract
In order to elucidate the mechanism of xanthoma formation in cerebrotendinous xanthomatosis, mice were fed for 32 weeks with a diet rich in 5 alpha-cholestan-3 beta-ol (cholestanol) (1%, w/w). The concentrations of sterols in the serum, liver, and cerebellum were determined using high performance liquid chromatography. In the cholestanol-fed mice, the cholestanol concentrations in the serum and liver reached maxima in the first 2 to 4 weeks; the levels were about 30- to 100-fold higher than in the control diet mice. The cholestanol concentrations declined thereafter, finally to 50-60% of the maxima. Cholesterol concentrations were slightly lower in the cholestanol-fed mice throughout the experiments than in the control diet mice. On the other hand, the levels of cholestanol in the cerebellum increased almost linearly in parallel to the feeding time, and no decline was observed. These results suggest that the capacity of the liver to remove or degrade cholestanol was increased by long-term intake of this compound, whereas the cerebellum had no such feed-back regulation. Histological examinations using an electron microscope revealed the enlargement of lysosomal granules in the liver of the cholestanol-fed mice.
- Published
- 1988
- Full Text
- View/download PDF
44. Quantitative analysis of sterols in serum by high-performance liquid chromatography. Application to the biochemical diagnosis of cerebrotendinous xanthomatosis.
- Author
-
Kasama T, Byun DS, and Seyama Y
- Subjects
- Benzoates, Chromatography, High Pressure Liquid, Gas Chromatography-Mass Spectrometry, Humans, Indicators and Reagents, Spectrophotometry, Ultraviolet, Xanthomatosis blood, Sterols blood, Xanthomatosis diagnosis
- Abstract
A method for the simultaneous determination of 5 alpha-cholestan-3 beta-ol and cholesterol in serum by high-performance liquid chromatography was developed. After addition of internal standard (5 beta-cholestan-3 alpha-ol) and saponification with ethanolic potassium hydroxide, the sterols were converted into their benzoyl derivatives, which were subjected to reversed-phase liquid chromatography with ultraviolet detection at 228 nm. Only 0.1 ml of serum was needed to give a reproducible result. This method has been used for the biochemical diagnosis of cerebrotendinous xanthomatosis, a hereditary disorder of cholesterol metabolism.
- Published
- 1987
- Full Text
- View/download PDF
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