Publications (18)110.91 Total impact
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Article: Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.
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ABSTRACT: BACKGROUND: Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. METHODS: Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. RESULTS: In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10(-8); OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. CONCLUSIONS: Our findings provide new insights into the genetic architecture underlying OF in East Asians.Journal of Medical Genetics 01/2013; · 6.36 Impact Factor -
Article: Gene-based copy number variation study reveals a microdeletion at 12q24 that influences height in the Korean population.
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ABSTRACT: Height is a classic polygenic trait with high heritability (h(2)=0.8). Recent genome-wide association studies have revealed many independent loci associated with human height. In addition, although many studies have reported an association between copy number variation (CNV) and complex diseases, few have explored the relationship between CNV and height. Recent studies reported that single nucleotide polymorphisms (SNPs) are highly correlated with common CNVs, suggesting that it is warranted to survey CNVs to identify additional genetic factors affecting heritable traits such as height. This study tested the hypothesis that there would be CNV regions (CNVRs) associated with height nearby genes from the GWASs known to affect height. We identified regions containing >1% copy number deletion frequency from 3,667 population-based cohort samples using the Illumina HumanOmni1-Quad BeadChip. Among the identified CNVRs, we selected 15 candidate regions that were located within 1Mb of 283 previously reported genes. To assess the effect of these CNVRs on height, statistical analyses were conducted with samples from a case group of 370 taller (upper 10%) individuals and a control group of 1,828 individuals (lower 50%). We found that a newly identified 17.7kb deletion at chromosomal position 12q24.33, approximately 171.6kb downstream of GPR133, significantly correlated with height; this finding was validated using quantitative PCR. These results suggest that CNVs are potentially important in determining height and may contribute to height variation in human populations.Genomics 11/2012; · 3.02 Impact Factor -
Article: Association between the ABO locus and hematological traits in Korean.
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ABSTRACT: Recently, genome-wide association studies identified a pleiotropic gene locus, ABO, as being significantly associated with hematological traits. To confirm the effects of ABO on hematological traits, we examined the link between the ABO locus and hematological traits in Korean population-based cohorts. Six tagging SNPs for ABO were analyzed with regard to their effects on hematological traits [white blood cell count (WBC), red blood cell count (RBC), platelet (Plat), mean corpuscular volume (MCV), and mean corpuscular haemoglobin concentration (MCHC)]. Linear regression analyses were performed, controlling for recruitment center, sex, and age as covariates. Of the 6 tagging SNPs, 3 (rs2073823, rs8176720, and rs495828) and 3 (rs2073823, rs8176717, and rs687289) were significantly associated with RBC and MCV, respectively (Bonferroni correction p-value criteria < 0.05/6 = 0.008). rs2073823 and a reported SNP (rs8176746), as well as rs495828 and a reported SNP (rs651007), showed perfect linkage disequilibrium status (r2s = 0.99). Of the remaining 3 SNPs (rs8176720, rs8176717 and rs687289), rs8176717 generated an independent signal with moderate p-value (= 0.045) when it was adjusted for by rs2073823 (the most significant SNP). We also identified a copy number variation (CNV) that was tagged by the SNP rs8176717, the minor allele of which correlated with the deletion allele of CNV. Our haplotype analysis indicated that the haplotype that contained the CNV deletion was significantly associated with MCV (β ± se = 0.363 ± 0.118, p =2.09 × 10-3). Our findings confirm that ABO is one of the genetic factors that are associated with hematological traits in the Korean population. This result is notable, because GWASs fail to evaluate the link between a CNV and phenotype traits.BMC Genetics 09/2012; 13:78. · 2.47 Impact Factor -
Article: Effect of genetic predisposition on blood lipid traits using cumulative risk assessment in the korean population.
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ABSTRACT: Dyslipidemia, mainly characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, is an important etiological factor in the development of cardiovascular disease (CVD). Considering the relationship between childhood obesity and CVD risk, it would be worthwhile to evaluate whether previously identified lipid-related variants in adult subjects are associated with lipid variations in a childhood obesity study (n = 482). In an association analysis for 16 genome-wide association study (GWAS)-based candidate loci, we confirmed significant associations of a genetic predisposition to lipoprotein concentrations in a childhood obesity study. Having two loci (rs10503669 at LPL and rs16940212 at LIPC) that showed the strongest association with blood levels of TG and HDL-C, we calculated a genetic risk score (GRS), representing the sum of the risk alleles. It has been observed that increasing GRS is significantly associated with decreased HDL-C (effect size, -1.13 ± 0.07) compared to single nucleotide polymorphism combinations without two risk variants. In addition, a positive correlation was observed between allelic dosage score and risk allele (rs10503669 at LPL) on high TG levels (effect size, 10.89 ± 0.84). These two loci yielded consistent associations in our previous meta-analysis. Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C) overlap to a large extent in childhood as well as in adulthood. Post-GWAS functional characterization of these variants is further required to elucidate their pathophysiological roles and biological mechanisms.Genomics & informatics. 06/2012; 10(2):99-105. -
Article: A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study.
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ABSTRACT: Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent. To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls. In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14). This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.Breast cancer research: BCR 03/2012; 14(2):R56. · 5.24 Impact Factor -
Article: BioSMACK: a linux live CD for genome-wide association analyses.
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ABSTRACT: Recent advances in high-throughput genotyping technologies have enabled us to conduct a genome-wide association study (GWAS) on a large cohort. However, analyzing millions of single nucleotide polymorphisms (SNPs) is still a difficult task for researchers conducting a GWAS. Several difficulties such as compatibilities and dependencies are often encountered by researchers using analytical tools, during the installation of software. This is a huge obstacle to any research institute without computing facilities and specialists. Therefore, a proper research environment is an urgent need for researchers working on GWAS. We developed BioSMACK to provide a research environment for GWAS that requires no configuration and is easy to use. BioSMACK is based on the Ubuntu Live CD that offers a complete Linux-based operating system environment without installation. Moreover, we provide users with a GWAS manual consisting of a series of guidelines for GWAS and useful examples. BioSMACK is freely available at http://ksnp.cdc. go.kr/biosmack.BMB reports 01/2012; 45(1):44-6. · 1.72 Impact Factor -
Article: Microarray-based mutation detection and phenotypic characterization in Korean patients with retinitis pigmentosa.
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ABSTRACT: To evaluate microarray-based genotyping technology for the detection of mutations responsible for retinitis pigmentosa (RP) and to perform phenotypic characterization of patients with pathogenic mutations. DNA from 336 patients with RP and 360 controls was analyzed using the GoldenGate assay with microbeads containing 95 previously reported disease-associated mutations from 28 RP genes. Mutations identified by microarray-based genotyping were confirmed by direct sequencing. Segregation analysis and phenotypic characterization were performed in patients with mutations. The disease severity was assessed by visual acuity, electroretinography, optical coherence tomography, and kinetic perimetry. Ten RP-related mutations of five RP genes (PRP3 pre-mRNA processing factor 3 homolog [PRPF3], rhodopsin [RHO], phosphodiesterase 6B [PDE6B], peripherin 2 [PRPH2], and retinitis pigmentosa 1 [RP1]) were identified in 26 of the 336 patients (7.7%) and in six of the 360 controls (1.7%). The p.H557Y mutation in PDE6B, which was homozygous in four patients and heterozygous in nine patients, was the most frequent mutation (2.5%). Mutation segregation was assessed in four families. Among the patients with missense mutations, the most severe phenotype occurred in patients with p.D984G in RP1; less severe phenotypes occurred in patients with p.R135W in RHO; a relatively moderate phenotype occurred in patients with p.T494M in PRPF3, p.H557Y in PDE6B, or p.W316G in PRPH2; and a mild phenotype was seen in a patient with p.D190N in RHO. The results reveal that the GoldenGate assay may not be an efficient method for molecular diagnosis in RP patients with rare mutations, although it has proven to be reliable and efficient for high-throughput genotyping of single-nucleotide polymorphisms. The clinical features varied according to the mutations. Continuous effort to identify novel RP genes and mutations in a population is needed to improve the efficiency and accuracy of the genetic diagnosis of RP.Molecular vision 01/2012; 18:2398-410. · 2.20 Impact Factor -
Article: Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.
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ABSTRACT: To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.Nature Genetics 09/2011; 43(10):990-5. · 35.53 Impact Factor -
Article: Genome-wide Survey of Copy Number Variants Associated with Blood Pressure and Body Mass Index in a Korean Population
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ABSTRACT: Hypertension is the major factor of most death and high blood pressure (BP) can lead to stroke, myocardial in-farction and cardiac failure. Moreover, hypertension is strongly correlated with body mass index (BMI). Al-though the exact causes of hypertension are still un-clear, some of genetic loci were discovered from ge-nome-wide association study (GWAS). Therefore, it is essential to study genetic variation for finding more ge-netic factor affecting hypertension. The purpose of our study is to conduct a CNV association study for hyper-tension-related traits, BP and BMI, in Korean individuals. We identified 2,206 CNV regions from 3,274 commun-ity-based Korean participants using the Affymetrix Ge-nome-Wide Human SNP Array 6.0 platform and per-formed a logistic regression analysis of CNVs with two hypertension-related traits, BP and BMI. Moreover, the 4,692 participants in an independent cohort were se-lected for respective replication analyses. GWAS of CNV identified two loci encompassing previously known hy-pertension-related genes: LPA (lipoprotein) on 6q26, and JAK2 (Janus kinase 2) on 9p24, with suggestive p-val-ues (0.0334 for LPA and 0.0305 for JAK2). These two positive findings, however, were not evaluated in the replication stage. Our result confirmed the conclusion of CNV study from the WTCCC suggesting weak associa-tion with common diseases. This is the first study of CNV association study with BP and BMI in Korean pop-ulation and it provides a state of CNV association study with common human diseases using SNP array.Genomics & Informatics. 09/2011; -
Article: Data-driven approach to detect common copy-number variations and frequency profiles in a population-based Korean cohort.
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ABSTRACT: To date, hundreds of thousands of copy-number variation (CNV) data have been reported using various platforms. The proportion of Asians in these data is, however, relatively small as compared with that of other ethnic groups, such as Caucasians and Yorubas. Because of limitations in platform resolution and the high noise level in signal intensity, in most CNV studies (particularly those using single nucleotide polymorphism arrays), the average number of CNVs in an individual is less than the number of known CNVs. In this study, we ascertained reliable, common CNV regions (CNVRs) and identified actual frequency rates in the Korean population to provide more CNV information. We performed two-stage analyses for detecting structural variations with two platforms. We discovered 576 common CNVRs (88 CNV segments on average in an individual), and 87% (501 of 576) of these CNVRs overlapped by ≥1 bp with previously validated CNV events. Interestingly, from the frequency analysis of CNV profiles, 52 of 576 CNVRs had a frequency rate of <1% in the 8842 individuals. Compared with other common CNV studies, this study found six common CNVRs that were not reported in previous CNV studies. In conclusion, we propose the data-driven detection approach to discover common CNVRs including those of unreported in the previous Korean CNV study while minimizing false positives. Through our approach, we successfully discovered more common CNVRs than previous Korean CNV study and conducted frequency analysis. These results will be a valuable resource for the effective level of CNVs in the Korean population.European journal of human genetics: EJHG 07/2011; 19(11):1167-72. · 3.56 Impact Factor -
Article: A Genome-wide Association Study Identification of a New Genetic Locus with Susceptibility to Osteoporotic Fracture in the Korean Population
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ABSTRACT: Osteoporotic fracture (OF), along with bone mineral den-sity (BMD), is an important diagnostic parameter and a clinical predictive risk factor in the assessment of osteo-porosis in the elderly population. However, a genome-wide association study (GWAS) on OF has not yet been clarified sufficiently. To identify OF-associated genetic variants and candidate genes, we conducted a GWAS in a population-based cohort (Korean Association Resource [KARE], n=1,427 [case: 288 and control: 1139]) and per-formed a de novo replication study in hospital-based in-dividuals (Asan and Catholic Medical Center [ACMC], n=1,082 [case: 272 and control: 810]). In a combined meta-analysis, a newly identified genetic locus in an in-tergenic region at 10p11.2 (near genes FZD8 and ANKRD30A) showed the most significant association (odd ratio [OR] = 2.00, 95% confidence interval [CI] = 1.47∼2.74, p=1.27×10 −5) in the same direction. We provide the first evidence for a common genetic variant influencing OF and genetic information for further inves-tigation in bone metabolism.Genomics & Informatics. 07/2011; 9:52-58. -
Article: Identification of genome-wide copy number variations and a family-based association study of Avellino corneal dystrophy.
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ABSTRACT: To determine the association of identified copy number variations (CNVs) in whole genome with the risk of Avellino corneal dystrophy (ACD) in a Korean population. Case-control study. A total of 146 patients with ACD and 226 control subjects. A total of 193 trios were genotyped by the Illumina HumanHapCNV370-Duo BeadChip (370,404 markers) (Illumina, Inc., San Diego, CA). The intensity signal (log R ratio) and allelic intensity ratio (B allele frequency) of each marker in all individuals were obtained by Illumina BeadStudio software (Illumina, Inc.). To obtain authentic CNVs in this study, we performed a family-based CNV validation and family-based boundary mapping using the PennCNV algorithm, which incorporates multiple factors, including total log R ratio, B allele frequency, and family information, based on an integrated hidden Markov model. Statistical comparison and identification of CNVs between case and control using family information. We identified 27,267 individual trio CNVs with a median size of 16.2 kb, aggregated in 2245 CNV regions. Most of the identified trio CNVs in this study showed well-defined CNV boundaries and overlapped with those in the Database of Genomic Variants (DGV) (83.4% in number and 79.2% in length). With the common CNV regions (264 CNV regions >5%), we performed a family-based association test with the risk of ACD. Two CNV regions (chr6:29978470-29987783 and chr14:59896944-59916129) were significantly associated with the risk of ACD (P=0.05-0.003 and P=0.008, respectively). This study describes the first results of a genome-wide association analysis of individual CNVs with the risk of ACD and shows that 2 novel CNV loci may be involved in the risk of ACD. The author(s) have no proprietary or commercial interest in any materials discussed in this article.Ophthalmology 03/2010; 117(7):1306-12.e4. · 5.45 Impact Factor -
Article: Multilaboratory Assessment of Variations in Spectrophotometry-Based DNA Quantity and Purity Indexes
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ABSTRACT: Human genetic studies are using an increasing number of biobanked DNA samples, which require consistent measurements of DNA quantity and purity between multicenters or multilaboratories. In an attempt to stan-dardize DNA quantitation protocols, a DNA quantitation project was performed, in which 16 technicians from 11 laboratories participated in measuring optical density (A260, A280, A230) of multiple DNA samples (N ¼ 35) of known concentrations. We analyzed variations in the measurement of DNA quantity and purity and found that the mean interoperator coefficients of variation percentage for A260, A260/A280, and A260/A230 values among individuals were 21.9%, 7.4%, and 24.7%, respectively. In contrast, the mean intra-operator coefficients of variation percentage for A260, A260/A280, and A260/A230 values were 9.9%, 1.7%, and 8.3%, respectively. The variability in A260/A230 determination was much more sensitive to the method of DNA quantitation and the technical skill of the individual than those of A260 and A260/A280. In addition, a concentration of DNA of >100 ng/mL was found to reduce the variability of DNA quantity (A260) and purity (A260/A280 and A260/A230 ratios) indexes. This work emphasizes the need for standardization of DNA quantitation proto-cols for multicenter DNA work, as well as the importance of training and education of technicians at these centers.Biopreservation and Biobanking 01/2010; 4(8):187-192. · 1.29 Impact Factor -
Article: Genetic associations of common deletion polymorphisms in families with Avellino corneal dystrophy.
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ABSTRACT: Although the locations of many common deletion variants in the human genome are unknown, such deletions may be causative in rare disorders. Deletions can be mapped through the identification of Mendelian inconsistencies in pedigrees. Data for a total of 341,577 SNPs from an ACD family cohort (n=551) and 341,039 SNPs from a Korean-Vietnamese family cohort (n=554) were collected for a genome-wide association study using Illumina 370K-Duo Beadchips((R)). In the present study, a Mendelian inconsistency analysis of genotype data identified 1029 deletion variants in Korean and Korean-Vietnam family cohorts of 404 trios comprising 1105 individuals. Small-deletion copy number variations adjacent to 10 deletion variants were then validated by the real-time quantitative polymerase chain reaction. The expected copy numbers of each deletion variant were directly matched to its genotype cluster image. Deletion variants were also in strong linkage disequilibrium with nearby SNPs. To determine the overall contribution of the 1029 deletion variants, we analyzed case-control trio associations with the risk for Avellino corneal dystrophy. One SNP marker (rs885945) neighboring the gene encoding major histocompatibility complex class I F (HLA-F) was significantly associated with the risk of Avellino corneal dystrophy (P=0.0003). rs885945 showed high LD with SNPs within the HLA-F gene. Therefore, HLA-F may be a potential candidate gene for Avellino corneal dystrophy.Biochemical and Biophysical Research Communications 08/2009; 387(4):688-93. · 2.48 Impact Factor -
Article: A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits.
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ABSTRACT: To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 x 10(-9)) and 6q22 (rs12110693, P = 1.6 x 10(-9)), with the latter approximately 400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 x 10(-7)). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 x 10(-12)) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we identified two loci influencing bone mineral density at multiple sites. On chromosome 7q31, rs7776725 (within the FAM3C gene) was associated with bone density at the radius (P = 1.0 x 10(-11)), tibia (P = 1.6 x 10(-6)) and heel (P = 1.9 x 10(-10)). On chromosome 7p14, rs1721400 (mapping close to SFRP4, a frizzled protein gene) showed consistent associations at the same three sites (P = 2.2 x 10(-3), P = 1.4 x 10(-7) and P = 6.0 x 10(-4), respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.Nature Genetics 06/2009; 41(5):527-34. · 35.53 Impact Factor -
Article: Splicing factor ASF/SF2 and transcription factor PPAR-gamma cooperate to directly regulate transcription of uncoupling protein-3.
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ABSTRACT: The different isoforms of the uncoupling protein-3 (UCP3) are expressed in skeletal muscle and are up-regulated by splicing factors. Here, we report that UCP3 alternative splicing (alternative polyadenylation) is regulated by cooperation between the splicing factor ASF/SF2 and the transcription factor PPAR-gamma. We found that ASF/SF2 activates formation of long-form UCP3 (UCP3(L)) by inhibiting a cleavage and polyadenylation signal (AATAAA) located in its final intron that prematurely terminates message elongation. PPAR-gamma activates this process by directly interacting with ASF/SF2, providing the first example of a direct link between a transcription factor and alternative splicing. Activation of ASF/SF2 promotes formation of UCP3(L), whereas loss of ASF/SF2 decreases production of both UCP3(L) and short-form UCP3 (UCP3(S)). We suggest that the relative abundance of ASF/SF2 and PPAR-gamma determines the ratio of UCP3 isoforms.Biochemical and Biophysical Research Communications 01/2009; 378(4):877-82. · 2.48 Impact Factor -
Article: Association of TRAF2 with the short form of cellular FLICE-like inhibitory protein prevents TNFR1-mediated apoptosis.
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ABSTRACT: We have previously shown that c-FLIPL is a more potent inhibitor than c-FLIPS of Fas ligand-induced apoptosis and that c-FLIPL physically binds to Daxx, an alternative Fas-signaling adaptor. Here we examined whether c-FLIPS effectively inhibits TNFR1-mediated apoptosis and triggers JNK activation through its interaction with TRAF2. Some cancer cell lines, such as DU145, AGS, and PC3, have higher levels of c-FLIPS than other cell lines, such as SNU-719 and T24. The expression of c-FLIPS correlated with the susceptibility to TNFR1-mediated apoptosis. In contrast to DU145 and PC3, which are resistant to TNFR1-mediated apoptosis, T24 and SNU719 were sensitive to TNF-alpha treatment. To address the role of c-FLIPS in TNFR1-mediated apoptosis, we examined the molecular interaction between c-FLIPS and TRAF2. As expected, western blot analysis revealed that TRAF2 antibody immunoprecipitated a greater amount of c-FLIPS than c-FLIPL. Also, we measured the involvement of c-FLIPS in TNF-alpha-induced JNK activation and apoptosis by comparing these in TNF-alpha-resistant and TNF-alpha-sensitive cell lines. Treatment with TNF-alpha increased the phosphorylated JNK level in SNU719 and T24 cells, whereas DU145 and AGS cells were resistant to TNF-alpha-mediated apoptosis. We now report that the short form of c-FLIPS is a more efficient inhibitor of TNF-receptor 1-mediated apoptosis signaling than the long form of the protein.Journal of Molecular Signaling 02/2008; 3:2. -
Article: Modification of serine 392 is a critical event in the regulation of p53 nuclear export and stability.
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ABSTRACT: Although it has been shown that phosphorylations of p53 serine its residues are critical events for the regulation of their function, the specific biological effects of each of these phosphorylations, especially at serine 392, remain to be elucidated. Serine 392 has been proposed to play a role in the tetramerization of p53 and in the enhancement of its DNA-binding affinity. However, this is not consistent with other reports showing that substitution of serine 392 does not disrupt p53 function. These discrepancies suggest that modification of serine 392 may contribute to p53 activity through other transactivating pathways. In this study, we demonstrate that this C-terminal serine residue (p53-392S) in fact plays a critical role in the regulation of p53 stability such that substitution with alanine (p53-392A) strongly enhances p53 stability without disrupting mouse double minute 2 binding. Additionally, the p53-392A mutant is localized mainly in the nucleus, whereas both wild-type p53 and a glutamic acid mutant, p53-392E, are evenly distributed throughout the cytoplasm and nucleus. However, each of these p53 species had similar effects on both cell cycle inhibition and apoptosis, in response to either UV or adriamycin treatment. Moreover, p53-392A protein was resistant to E6-mediated degradation. Our results suggest that although serine 392 is not essential for the transactivation and nuclear import of p53, it exerts important effects upon p53 stability via the inhibition of its nuclear export mechanism.FEBS Letters 09/2004; 572(1-3):92-8. · 3.54 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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Korea Centers for Disease Control and Prevention
Taiden, Daejeon, South Korea
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2008–2009
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National Institute of Health, Korea
Cheongsong gun, North Gyeongsang, South Korea
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