Kyu-Sun Lee - Academia.edu (original) (raw)
Papers by Kyu-Sun Lee
Reproduction, Fertility and Development, 2005
Histone acetylation plays an important role in the chromatin structure prior to zygotic gene expr... more Histone acetylation plays an important role in the chromatin structure prior to zygotic gene expression during early embryonic development. Successful animal clones indicate that differentiated somatic nuclei must be reprogrammed to some extent during pre-implantation development. However, the molecular mechanisms regarding epigenetic reprogramming of somatic nuclei in the early-stage embryos are poorly understood. To test this, the patterns of hyperacetylated histone H4 lysine 5 (AcH4K5) in the nuclear-transferred (NT) embryos were monitored, comparing in vitro fertilized (IVF) embryos and Trichostatin A (TSA)-NT embryos with TSA-treated cells. The intensity signals of AcH4K5 were observed in early-stage embryos and somatic cells (bovine ear skin fibroblasts composed of about 80% at G0/G1 stage) by immunofluorescence analysis with anti-AcH4K5 using image the analyzer system, SigmaScan-pro V5.01 (SPSS, Inc., Chicago, IL, USA). Our data were analyzed by analysis of variance (ANOVA) u...
Frontiers in cellular neuroscience, 2014
Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase d... more Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase domains and two helix-loop-helix Ca(2+)-binding domains called EF hands. Pioneering genetic studies in Drosophila first revealed a key function of Miro in regulating the axonal transport of mitochondria, during which Miro forms a multi-protein transport complex with Milton and Kinesin heavy chain (KHC) to link trafficking mitochondria with the microtubule (MT) cytoskeleton. Recent studies showed that through binding to the EF hands of Miro and causing conformational changes of Miro and alteration of protein-protein interactions within the transport complex, Ca(2+) can alter the engagement of mitochondria with the MT/kinesin network, offering one mechanism to match mitochondrial distribution with neuronal activity. Despite the importance of the Miro/Milton/Kinesin complex in regulating mitochondrial transport in metazoans, not all components of the transport complex are conserved in lower ...
Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Ab), ... more Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Ab), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of ER stress-mediated Ab neurotoxicity still remain unknown. Here, we show that treatment of Ab triggers the UPR in the SK-N-SH human neuroblastoma cells. Ab mediated UPR pathway accompanies the activation of protective pathways such as Grp78/ Bip and PERK-eIF2a pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Ab neurotoxicity through reducing the activation of eIF2a and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2a pathway, significantly increased the...
Reproduction Fertility and Development
European Journal of Cell Biology, 2008
Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against v... more Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against various insults. However, the molecular mechanism of this protective effect has not been identified. In this study, we examined the protective effects of KYNA against 1-methyl-4-phenylpyridinium (MPP(+)), the best-characterized toxin inducing pathological changes resembling Parkinson's disease (PD), using SH-SY5Y and SK-N-SH human neuroblastoma cells. Pre-treatment of KYNA attenuated MPP(+)-induced neuronal cell death in SH-SY5Y and SK-N-SH cells. MPP(+)-induced cell death was preceded by increases in Bax expression and mitochondrial dysfunction, such as collapse of mitochondrial membrane potential (DeltaPsi(m)), release of cytochrome c from mitochondria into the cytoplasm, and increases in caspase-9/-3 activities. KYNA effectively inhibited all of these mitochondrial apoptotic processes. Our results indicate that KYNA plays a protective role by down-regulating Bax expression and maintaining mitochondrial function in MPP(+)-induced neuronal cell death, and suggest that KYNA may have therapeutic potential in PD.
PLoS ONE, 2008
Germline-stem cells (GSCs) produce gametes and are thus true &amp... more Germline-stem cells (GSCs) produce gametes and are thus true "immortal stem cells". In Drosophila ovaries, GSCs divide asymmetrically to produce daughter GSCs and cystoblasts, and the latter differentiate into germline cysts. Here we show that the histone-lysine methyltransferase dSETDB1, located in pericentric heterochromatin, catalyzes H3-K9 trimethylation in GSCs and their immediate descendants. As germline cysts differentiate into egg chambers, the dSETDB1 function is gradually taken over by another H3-K9-specific methyltransferase, SU(VAR)3-9. Loss-of-function mutations in dsetdb1 or Su(var)3-9 abolish both H3K9me3 and heterochromatin protein-1 (HP1) signals from the anterior germarium and the developing egg chambers, respectively, and cause localization of H3K9me3 away from DNA-dense regions in most posterior germarium cells. These results indicate that dSETDB1 and SU(VAR)3-9 act together with distinct roles during oogenesis, with dsetdb1 being of particular importance due to its GSC-specific function and more severe mutant phenotype.
FEBS Letters, 2008
Mitochondrial dysfunction is a hallmark of beta-amyloid (Ab)-induced neuronal toxicity in Alzheim... more Mitochondrial dysfunction is a hallmark of beta-amyloid (Ab)-induced neuronal toxicity in AlzheimerÕs disease (AD). Epidemiological studies have indicated that alcohol consumption plays a role in the development of AD. Here we show that alcohol exposure has a synergistic effect on Ab-induced neuronal cell death. Ab-treated cultured neurons displayed spontaneous generation of reactive oxygen species (ROS), disruption of their mitochondrial membrane potential, induction of caspase-3 and p53 activities, and loss of cell viability. Alcohol exposure facilitated Ab-induced neuronal cell death. Our study shows that alcohol consumption enhances Ab-induced neuronal cell death by increasing ROS and mitochondrial dysfunction. Crown
Cancer Research, 2014
The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSC... more The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.
Reproduction, fertility, and development, 2014
While a critical role of autophagy in mammalian early embryogenesis has been demonstrated, few st... more While a critical role of autophagy in mammalian early embryogenesis has been demonstrated, few studies have been conducted regarding the role of autophagy in in vitro maturation (IVM) of immature oocytes. In the present study we investigated the effect of rapamycin, a chemical autophagy inducer, on the nuclear and cytoplasmic maturation of porcine oocytes. Rapamycin treatment led to increased expression of LC3-II, an autophagy marker. Compared with the control group, as well as the 5 and 10nM rapamycin treatment groups, the rate of MII oocyte production was higher in the 1nM rapamycin treatment group, indicating improvement in nuclear maturation. In the analyses of cytoplasmic maturation, we found that the level of p34(cdc2), a cytoplasmic maturation marker, and the monospermic fertilisation rate were higher in the 1nM rapamycin treatment group than in the other groups. Moreover, the beneficial effect of 1nM rapamycin on cytoplasmic maturation of MII oocytes was further evidenced by...
Journal of Cellular Biochemistry, 2008
As a nuclear phosphoprotein, proto-oncogene protein DEK is capable to changing chromatin structur... more As a nuclear phosphoprotein, proto-oncogene protein DEK is capable to changing chromatin structure. DEK was recently identified as an inhibitor of histone acetylation mediated by p300 and PCAF and to facilitate transcriptional repression. To elucidate the biological functions of DEK in vivo, we have constructed transgenic flies that overexpress the human DEK in the developing eye. Transgenic flies developed a severe rough eye phenotype, which is indicative of ectopically induced apoptosis. Genetic and biochemical analyses, including the rescue of the apoptotic phenotype by pan-caspase inhibitor protein p35 and caspase activity analyses, suggested that DEK induces apoptotic cell death through a caspases-9 and -3 dependent pathway. Using extracts from larval salivary glands, we have determined that the global histone acetylation levels of histone H3 Lys9 and H4 Lys5 were decreased upon DEK overexpression. Using chromatin immunoprecipitation assays, we have demonstrated that overexpression of DEK induced the histone H3 and H4 hypoacetylation of promoter of the antiapoptotic gene bcl-2. Co-expression of bcl-2 also rescued apoptosis and the reduced expression of bcl-2 gene was analyzed by real-time PCR. Our results indicate that acidic domain containing protein DEK might have a role in modulating both transcriptional regulation and apoptosis through HAT inhibitory activity.
Molecular & Cellular Proteomics, 2006
Cloned animals developed from somatic cell nuclear transfer (SCNT) embryos are useful resources f... more Cloned animals developed from somatic cell nuclear transfer (SCNT) embryos are useful resources for agricultural and medical applications. However, the birth rate in the cloned animals is very low, and the cloned animals that have survived show various developmental defects. In this report, we present the morphology and differentially regulated proteins in the extraembryonic tissue from SCNT embryos to understand the molecular nature of the tissue. We examined 26-day-old SCNT porcine embryos at which the sonogram can first detect pregnancy. The extraembryonic tissue from SCNT embryos was abnormally small compared with the control. In the proteomic analysis with the SCNT extraembryonic tissue, 39 proteins were identified as differentially regulated proteins. Among up-regulated proteins, Annexins and Hsp27 were found. They are closely related to the processes of apoptosis. Among down-regulated proteins, Peroxiredoxins and anaerobic glycolytic enzymes were identified. In the Western blot analysis, antioxidant enzymes and the antiapoptotic Bcl-2 protein were down-regulated, and caspases were up-regulated. In the terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay with the placenta from SCNT embryos, apoptotic trophoblasts were observed. These results demonstrate that a major reason for the low birth rate of cloned animals is due to abnormal apoptosis in the extraembryonic tissue during early pregnancy.
Bioelectromagnetics, 2008
Mobile phones are widely used in the modern world. However, biological effects of electromagnetic... more Mobile phones are widely used in the modern world. However, biological effects of electromagnetic radiation produced by mobile phones are largely unknown. In this report, we show biological effects of the mobile phone 835 MHz electromagnetic field (EMF) in the Drosophila model system. When flies were exposed to the specific absorption rate (SAR) 1.6 W/kg, which is the proposed exposure limit by the American National Standards Institute (ANSI), more than 90% of the flies were viable even after the 30 h exposure. However, in the SAR 4.0 W/kg strong EMF exposure, viability dropped from the 12 h exposure. These EMF exposures triggered stress response and increased the production of reactive oxygen species. The EMF exposures also activated extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling, but not p38 kinase signaling. Interestingly, SAR 1.6 W/kg activated mainly ERK signaling and expression of an anti-apoptotic gene, whereas SAR 4.0 W/kg strongly activated JNK signaling and expression of apoptotic genes. In addition, SAR 4.0 W/kg amplified the number of apoptotic cells in the fly brain. These findings demonstrate that the exposure limit on electromagnetic radiation proposed by ANSI triggered ERK-survival signaling but the strong electromagnetic radiation activated JNK-apoptotic signaling in Drosophila.
Pesticide Biochemistry and Physiology, 2008
This study was designed to determine the minimum effective concentration of paraquat that modulat... more This study was designed to determine the minimum effective concentration of paraquat that modulated the expression of PKD-related genes in Drosophila. We first studied the viability of Drosophila and then tested the expression of the PKD-related genes-Parkin, UCH, and tau-in various concentrations of paraquat in the water sucked by Drosophila. The lowest effective concentration of paraquat was approximately 20 lM and the gene expression was induced at paraquat doses between 20 mM and 20 lM.
Biology of Reproduction, 2014
The stress produced by the coupling of reactive oxygen species (ROS) and endoplasmic reticulum (E... more The stress produced by the coupling of reactive oxygen species (ROS) and endoplasmic reticulum (ER) has been explored extensively, but little is known regarding their roles in the early development of mammalian embryos. Here, we demonstrated that the early development of in vitro-produced (IVP) bovine embryos was governed by the cooperative action between ROS and ER stress. Compared with the tension produced by 5% O2, 20% O2 significantly decreased the blastocyst formation rate and cell survival, which was accompanied by increases in ROS and in levels of sXBP-1 transcript, which is an ER stress indicator. In addition, treatment with glutathione (GSH), a ROS scavenger, decreased ROS levels, which resulted in increased blastocyst formation and cell survival rates. Importantly, levels of sXBP-1 and ER stress-associated transcripts were reduced by GSH treatment in developing bovine embryos. Consistent with this observation, tauroursodeoxycholate (TUDCA), an ER stress inhibitor, improved blastocyst developmental rate, trophectoderm proportion, and cell survival. Moreover, ROS and sXBP-1 transcript levels were markedly decreased by supplementation with TUDCA, suggesting a possible mechanism governing the mutual regulation between ROS and ER stress. Interestingly, knockdown of XBP-1 transcripts resulted in both elevation of ROS and decrease of antioxidant transcripts, which ultimately reduced in vitro developmental competence of bovine embryos. Based on these results, in vitro developmental competence of IVP bovine embryos was highly dependent on the coupled response between oxidative and ER stresses. These results increase our understanding of the mechanism(s) governing early embryonic development and may improve strategies for the generation of IVP embryos with high developmental competence.
Molecules and Cells, 2012
In Drosophila, broad complex, tramtrack, bric à brac (BTB)/ poxvirus and zinc finger (POZ) transc... more In Drosophila, broad complex, tramtrack, bric à brac (BTB)/ poxvirus and zinc finger (POZ) transcription factors are essential regulators of development. We searched the Drosophila genome for BTB/POZ-ZF domains and discovered an unknown Drosophila gene, dPLZF, which encodes an orthologue of human PLZF. We then characterized the biological function of the dPLZF via genetic interaction analysis. Ectopic expression of dPLZF in the wing induced extra vein formation during wing development in Drosophila. Genetic interactions between dPLZF and Ras or extracellular signal-regulated kinase (ERK) significantly enhanced the formation of vein cells. On the other hand, loss-of-function mutations in dPLZF resulted in a dramatic suppression of the extra and ectopic vein formation induced by elevated Ras/ERK signaling. Moreover, dPLZF activity upregulated the expression of rhomboid (rho) and spitz, which perform crucial functions in vein cell formation in the developing wing. These results indicate that dPLZF is a transcription factor controlled by the Ras/ERK signaling pathway, which is a prominent regulator of vein cell formation during wing development in Drosophila.
Journal of Molecular Endocrinology, 2013
Endoplasmic reticulum (ER) stress generally occurs in secretory cell types. It has been reported ... more Endoplasmic reticulum (ER) stress generally occurs in secretory cell types. It has been reported that Leydig cells, which produce testosterone in response to human chorionic gonadotropin (hCG), express key steroidogenic enzymes for the regulation of testosterone synthesis. In this study, we analyzed whether hCG induces ER stress via three unfolded protein response (UPR) pathways in mouse Leydig tumor (mLTC-1) cells and the testis. Treatment with hCG induced ER stress in mLTC-1 cells via the ATF6, IRE1a/XBP1, and eIF2a/GADD34/ATF4 UPR pathways, and transient expression of 50 kDa protein activating transcription factor 6 (p50ATF6) reduced the expression level of steroidogenic 3b-hydroxysteroid dehydrogenase O5-O4-isomerase (3b-HSD) enzyme. In an in vivo model, high-level hCG treatment induced expression of p50ATF6 while that of steroidogenic enzymes, especially 3b-HSD, 17a-hydroxylase/C17-20 lyase (CYP17), and 17b-hydrozysteroid dehydrogenase (17b-HSD), was reduced. Expression levels of steroidogenic enzymes were restored by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Furthermore, lentivirus-mediated transient expression of p50ATF6 reduced the expression level of 3b-HSD in the testis. Protein expression levels of phospho-JNK, CHOP, and cleaved caspases-12 and -3 as markers of ER stress-mediated apoptosis markedly increased in response to high-level hCG treatment in mLTC-1 cells and the testis. Based on transmission electron microscopy and H&E staining of the testis, it was shown that abnormal ER morphology and destruction of Key Words " Leydig cells " Steroidogenic enzyme expression " Activating transaction factor 6 " ER stress " Testosterone Journal of Molecular Endocrinology Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 151-166 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 153 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 154 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 155 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 156 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 157 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 158 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 159 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 160 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 161 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 162 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 163 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 164 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 165 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 166
Background: Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been... more Background: Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been widely used as a spice and herbal medicine in Asia. It has been suggested to have many biological activities, such as antioxidative, antiinflammatory, anticancer, chemopreventive, and antineurodegenerative properties. We evaluated the impact of curcumin on life span, fecundity, feeding rate, oxidative stress, locomotion, and gene expression in two different wild-type Drosophila melanogaster strains, Canton-S and Ives, under two different experimental conditions. Results: We report that curcumin extended the life span of two different strains of D. melanogaster, an effect that was accompanied by protection against oxidative stress, improvement in locomotion, and chemopreventive effects. Life span extension was gender and genotype specific. Curcumin also modulated the expression of several aging-related genes, including mth, thor, InR, and JNK. Conclusions: The observed positive effects of curcumin on life span and health span in two different D. melanogaster strains demonstrate a potential applicability of curcumin treatment in mammals. The ability of curcumin to mitigate the expression levels of age-associated genes in young flies suggests that the action of curcumin on these genes is a cause, rather than an effect, of its life span-extending effects.
BMC Molecular Biology, 2011
Background: The unfolded protein response (UPR) is an evolutionary conserved adaptive reaction fo... more Background: The unfolded protein response (UPR) is an evolutionary conserved adaptive reaction for increasing cell survival under endoplasmic reticulum (ER) stress conditions. X-box-binding protein-1 (Xbp1) is a key transcription factor of UPR that activates genes involved in protein folding, secretion, and degradation to restore ER function. The UPR induced by ER stress was extensively studied in diseases linked to protein misfolding and aggregations. However, in the porcine system, genes in the UPR pathway were not investigated. In this study, we isolated and characterized the porcine Xbp1 (pXbp1) gene in ER stress using porcine embryonic fibroblast (PEF) cells and porcine organs. ER stress was induced by the treatment of tunicamycin and cell viability was investigated by the MTT assay. For cloning and analyzing the expression pattern of pXbp1, RT-PCR analysis and Western blot were used. Knock-down of pXbp1 was performed by the siRNA-mediated gene silencing.
Developmental & Comparative Immunology, 2012
Innate immunity plays an important role in combating microbial infection in animals. During bacte... more Innate immunity plays an important role in combating microbial infection in animals. During bacterial infection in Drosophila melanogaster gut, Dual oxidase (Duox) generates reactive oxygen species (ROS) to fight against the infected microbes. Concurrently, antioxidant systems eliminate residual ROS and protect the hosts. Here we found that Drosophila melanogaster Peroxiredoxin V (dPrxV) is an immune-related antioxidant enzyme which maintains intestinal redox homeostasis. dPrxV was highly expressed in gut and induced by the oral infection of Erwinia carotovora carotovora. dPrxV expression was increased by the gut-specific Duox overexpression but decreased by Duox inhibition. Moreover, dPrxV expression was mediated by the JNK/FOXO signaling and dPrxV mutant reduced survival after gut infection. These results suggest that JNK/FOXO mediated dPrxV expression plays a critical role in Drosophila melanogaster gut during bacterial infection in protecting the host gut epithelial cells from oxidative damage.
Reproduction, Fertility and Development, 2005
Histone acetylation plays an important role in the chromatin structure prior to zygotic gene expr... more Histone acetylation plays an important role in the chromatin structure prior to zygotic gene expression during early embryonic development. Successful animal clones indicate that differentiated somatic nuclei must be reprogrammed to some extent during pre-implantation development. However, the molecular mechanisms regarding epigenetic reprogramming of somatic nuclei in the early-stage embryos are poorly understood. To test this, the patterns of hyperacetylated histone H4 lysine 5 (AcH4K5) in the nuclear-transferred (NT) embryos were monitored, comparing in vitro fertilized (IVF) embryos and Trichostatin A (TSA)-NT embryos with TSA-treated cells. The intensity signals of AcH4K5 were observed in early-stage embryos and somatic cells (bovine ear skin fibroblasts composed of about 80% at G0/G1 stage) by immunofluorescence analysis with anti-AcH4K5 using image the analyzer system, SigmaScan-pro V5.01 (SPSS, Inc., Chicago, IL, USA). Our data were analyzed by analysis of variance (ANOVA) u...
Frontiers in cellular neuroscience, 2014
Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase d... more Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase domains and two helix-loop-helix Ca(2+)-binding domains called EF hands. Pioneering genetic studies in Drosophila first revealed a key function of Miro in regulating the axonal transport of mitochondria, during which Miro forms a multi-protein transport complex with Milton and Kinesin heavy chain (KHC) to link trafficking mitochondria with the microtubule (MT) cytoskeleton. Recent studies showed that through binding to the EF hands of Miro and causing conformational changes of Miro and alteration of protein-protein interactions within the transport complex, Ca(2+) can alter the engagement of mitochondria with the MT/kinesin network, offering one mechanism to match mitochondrial distribution with neuronal activity. Despite the importance of the Miro/Milton/Kinesin complex in regulating mitochondrial transport in metazoans, not all components of the transport complex are conserved in lower ...
Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Ab), ... more Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Ab), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of ER stress-mediated Ab neurotoxicity still remain unknown. Here, we show that treatment of Ab triggers the UPR in the SK-N-SH human neuroblastoma cells. Ab mediated UPR pathway accompanies the activation of protective pathways such as Grp78/ Bip and PERK-eIF2a pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Ab neurotoxicity through reducing the activation of eIF2a and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2a pathway, significantly increased the...
Reproduction Fertility and Development
European Journal of Cell Biology, 2008
Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against v... more Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against various insults. However, the molecular mechanism of this protective effect has not been identified. In this study, we examined the protective effects of KYNA against 1-methyl-4-phenylpyridinium (MPP(+)), the best-characterized toxin inducing pathological changes resembling Parkinson's disease (PD), using SH-SY5Y and SK-N-SH human neuroblastoma cells. Pre-treatment of KYNA attenuated MPP(+)-induced neuronal cell death in SH-SY5Y and SK-N-SH cells. MPP(+)-induced cell death was preceded by increases in Bax expression and mitochondrial dysfunction, such as collapse of mitochondrial membrane potential (DeltaPsi(m)), release of cytochrome c from mitochondria into the cytoplasm, and increases in caspase-9/-3 activities. KYNA effectively inhibited all of these mitochondrial apoptotic processes. Our results indicate that KYNA plays a protective role by down-regulating Bax expression and maintaining mitochondrial function in MPP(+)-induced neuronal cell death, and suggest that KYNA may have therapeutic potential in PD.
PLoS ONE, 2008
Germline-stem cells (GSCs) produce gametes and are thus true &amp... more Germline-stem cells (GSCs) produce gametes and are thus true "immortal stem cells". In Drosophila ovaries, GSCs divide asymmetrically to produce daughter GSCs and cystoblasts, and the latter differentiate into germline cysts. Here we show that the histone-lysine methyltransferase dSETDB1, located in pericentric heterochromatin, catalyzes H3-K9 trimethylation in GSCs and their immediate descendants. As germline cysts differentiate into egg chambers, the dSETDB1 function is gradually taken over by another H3-K9-specific methyltransferase, SU(VAR)3-9. Loss-of-function mutations in dsetdb1 or Su(var)3-9 abolish both H3K9me3 and heterochromatin protein-1 (HP1) signals from the anterior germarium and the developing egg chambers, respectively, and cause localization of H3K9me3 away from DNA-dense regions in most posterior germarium cells. These results indicate that dSETDB1 and SU(VAR)3-9 act together with distinct roles during oogenesis, with dsetdb1 being of particular importance due to its GSC-specific function and more severe mutant phenotype.
FEBS Letters, 2008
Mitochondrial dysfunction is a hallmark of beta-amyloid (Ab)-induced neuronal toxicity in Alzheim... more Mitochondrial dysfunction is a hallmark of beta-amyloid (Ab)-induced neuronal toxicity in AlzheimerÕs disease (AD). Epidemiological studies have indicated that alcohol consumption plays a role in the development of AD. Here we show that alcohol exposure has a synergistic effect on Ab-induced neuronal cell death. Ab-treated cultured neurons displayed spontaneous generation of reactive oxygen species (ROS), disruption of their mitochondrial membrane potential, induction of caspase-3 and p53 activities, and loss of cell viability. Alcohol exposure facilitated Ab-induced neuronal cell death. Our study shows that alcohol consumption enhances Ab-induced neuronal cell death by increasing ROS and mitochondrial dysfunction. Crown
Cancer Research, 2014
The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSC... more The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.
Reproduction, fertility, and development, 2014
While a critical role of autophagy in mammalian early embryogenesis has been demonstrated, few st... more While a critical role of autophagy in mammalian early embryogenesis has been demonstrated, few studies have been conducted regarding the role of autophagy in in vitro maturation (IVM) of immature oocytes. In the present study we investigated the effect of rapamycin, a chemical autophagy inducer, on the nuclear and cytoplasmic maturation of porcine oocytes. Rapamycin treatment led to increased expression of LC3-II, an autophagy marker. Compared with the control group, as well as the 5 and 10nM rapamycin treatment groups, the rate of MII oocyte production was higher in the 1nM rapamycin treatment group, indicating improvement in nuclear maturation. In the analyses of cytoplasmic maturation, we found that the level of p34(cdc2), a cytoplasmic maturation marker, and the monospermic fertilisation rate were higher in the 1nM rapamycin treatment group than in the other groups. Moreover, the beneficial effect of 1nM rapamycin on cytoplasmic maturation of MII oocytes was further evidenced by...
Journal of Cellular Biochemistry, 2008
As a nuclear phosphoprotein, proto-oncogene protein DEK is capable to changing chromatin structur... more As a nuclear phosphoprotein, proto-oncogene protein DEK is capable to changing chromatin structure. DEK was recently identified as an inhibitor of histone acetylation mediated by p300 and PCAF and to facilitate transcriptional repression. To elucidate the biological functions of DEK in vivo, we have constructed transgenic flies that overexpress the human DEK in the developing eye. Transgenic flies developed a severe rough eye phenotype, which is indicative of ectopically induced apoptosis. Genetic and biochemical analyses, including the rescue of the apoptotic phenotype by pan-caspase inhibitor protein p35 and caspase activity analyses, suggested that DEK induces apoptotic cell death through a caspases-9 and -3 dependent pathway. Using extracts from larval salivary glands, we have determined that the global histone acetylation levels of histone H3 Lys9 and H4 Lys5 were decreased upon DEK overexpression. Using chromatin immunoprecipitation assays, we have demonstrated that overexpression of DEK induced the histone H3 and H4 hypoacetylation of promoter of the antiapoptotic gene bcl-2. Co-expression of bcl-2 also rescued apoptosis and the reduced expression of bcl-2 gene was analyzed by real-time PCR. Our results indicate that acidic domain containing protein DEK might have a role in modulating both transcriptional regulation and apoptosis through HAT inhibitory activity.
Molecular & Cellular Proteomics, 2006
Cloned animals developed from somatic cell nuclear transfer (SCNT) embryos are useful resources f... more Cloned animals developed from somatic cell nuclear transfer (SCNT) embryos are useful resources for agricultural and medical applications. However, the birth rate in the cloned animals is very low, and the cloned animals that have survived show various developmental defects. In this report, we present the morphology and differentially regulated proteins in the extraembryonic tissue from SCNT embryos to understand the molecular nature of the tissue. We examined 26-day-old SCNT porcine embryos at which the sonogram can first detect pregnancy. The extraembryonic tissue from SCNT embryos was abnormally small compared with the control. In the proteomic analysis with the SCNT extraembryonic tissue, 39 proteins were identified as differentially regulated proteins. Among up-regulated proteins, Annexins and Hsp27 were found. They are closely related to the processes of apoptosis. Among down-regulated proteins, Peroxiredoxins and anaerobic glycolytic enzymes were identified. In the Western blot analysis, antioxidant enzymes and the antiapoptotic Bcl-2 protein were down-regulated, and caspases were up-regulated. In the terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay with the placenta from SCNT embryos, apoptotic trophoblasts were observed. These results demonstrate that a major reason for the low birth rate of cloned animals is due to abnormal apoptosis in the extraembryonic tissue during early pregnancy.
Bioelectromagnetics, 2008
Mobile phones are widely used in the modern world. However, biological effects of electromagnetic... more Mobile phones are widely used in the modern world. However, biological effects of electromagnetic radiation produced by mobile phones are largely unknown. In this report, we show biological effects of the mobile phone 835 MHz electromagnetic field (EMF) in the Drosophila model system. When flies were exposed to the specific absorption rate (SAR) 1.6 W/kg, which is the proposed exposure limit by the American National Standards Institute (ANSI), more than 90% of the flies were viable even after the 30 h exposure. However, in the SAR 4.0 W/kg strong EMF exposure, viability dropped from the 12 h exposure. These EMF exposures triggered stress response and increased the production of reactive oxygen species. The EMF exposures also activated extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling, but not p38 kinase signaling. Interestingly, SAR 1.6 W/kg activated mainly ERK signaling and expression of an anti-apoptotic gene, whereas SAR 4.0 W/kg strongly activated JNK signaling and expression of apoptotic genes. In addition, SAR 4.0 W/kg amplified the number of apoptotic cells in the fly brain. These findings demonstrate that the exposure limit on electromagnetic radiation proposed by ANSI triggered ERK-survival signaling but the strong electromagnetic radiation activated JNK-apoptotic signaling in Drosophila.
Pesticide Biochemistry and Physiology, 2008
This study was designed to determine the minimum effective concentration of paraquat that modulat... more This study was designed to determine the minimum effective concentration of paraquat that modulated the expression of PKD-related genes in Drosophila. We first studied the viability of Drosophila and then tested the expression of the PKD-related genes-Parkin, UCH, and tau-in various concentrations of paraquat in the water sucked by Drosophila. The lowest effective concentration of paraquat was approximately 20 lM and the gene expression was induced at paraquat doses between 20 mM and 20 lM.
Biology of Reproduction, 2014
The stress produced by the coupling of reactive oxygen species (ROS) and endoplasmic reticulum (E... more The stress produced by the coupling of reactive oxygen species (ROS) and endoplasmic reticulum (ER) has been explored extensively, but little is known regarding their roles in the early development of mammalian embryos. Here, we demonstrated that the early development of in vitro-produced (IVP) bovine embryos was governed by the cooperative action between ROS and ER stress. Compared with the tension produced by 5% O2, 20% O2 significantly decreased the blastocyst formation rate and cell survival, which was accompanied by increases in ROS and in levels of sXBP-1 transcript, which is an ER stress indicator. In addition, treatment with glutathione (GSH), a ROS scavenger, decreased ROS levels, which resulted in increased blastocyst formation and cell survival rates. Importantly, levels of sXBP-1 and ER stress-associated transcripts were reduced by GSH treatment in developing bovine embryos. Consistent with this observation, tauroursodeoxycholate (TUDCA), an ER stress inhibitor, improved blastocyst developmental rate, trophectoderm proportion, and cell survival. Moreover, ROS and sXBP-1 transcript levels were markedly decreased by supplementation with TUDCA, suggesting a possible mechanism governing the mutual regulation between ROS and ER stress. Interestingly, knockdown of XBP-1 transcripts resulted in both elevation of ROS and decrease of antioxidant transcripts, which ultimately reduced in vitro developmental competence of bovine embryos. Based on these results, in vitro developmental competence of IVP bovine embryos was highly dependent on the coupled response between oxidative and ER stresses. These results increase our understanding of the mechanism(s) governing early embryonic development and may improve strategies for the generation of IVP embryos with high developmental competence.
Molecules and Cells, 2012
In Drosophila, broad complex, tramtrack, bric à brac (BTB)/ poxvirus and zinc finger (POZ) transc... more In Drosophila, broad complex, tramtrack, bric à brac (BTB)/ poxvirus and zinc finger (POZ) transcription factors are essential regulators of development. We searched the Drosophila genome for BTB/POZ-ZF domains and discovered an unknown Drosophila gene, dPLZF, which encodes an orthologue of human PLZF. We then characterized the biological function of the dPLZF via genetic interaction analysis. Ectopic expression of dPLZF in the wing induced extra vein formation during wing development in Drosophila. Genetic interactions between dPLZF and Ras or extracellular signal-regulated kinase (ERK) significantly enhanced the formation of vein cells. On the other hand, loss-of-function mutations in dPLZF resulted in a dramatic suppression of the extra and ectopic vein formation induced by elevated Ras/ERK signaling. Moreover, dPLZF activity upregulated the expression of rhomboid (rho) and spitz, which perform crucial functions in vein cell formation in the developing wing. These results indicate that dPLZF is a transcription factor controlled by the Ras/ERK signaling pathway, which is a prominent regulator of vein cell formation during wing development in Drosophila.
Journal of Molecular Endocrinology, 2013
Endoplasmic reticulum (ER) stress generally occurs in secretory cell types. It has been reported ... more Endoplasmic reticulum (ER) stress generally occurs in secretory cell types. It has been reported that Leydig cells, which produce testosterone in response to human chorionic gonadotropin (hCG), express key steroidogenic enzymes for the regulation of testosterone synthesis. In this study, we analyzed whether hCG induces ER stress via three unfolded protein response (UPR) pathways in mouse Leydig tumor (mLTC-1) cells and the testis. Treatment with hCG induced ER stress in mLTC-1 cells via the ATF6, IRE1a/XBP1, and eIF2a/GADD34/ATF4 UPR pathways, and transient expression of 50 kDa protein activating transcription factor 6 (p50ATF6) reduced the expression level of steroidogenic 3b-hydroxysteroid dehydrogenase O5-O4-isomerase (3b-HSD) enzyme. In an in vivo model, high-level hCG treatment induced expression of p50ATF6 while that of steroidogenic enzymes, especially 3b-HSD, 17a-hydroxylase/C17-20 lyase (CYP17), and 17b-hydrozysteroid dehydrogenase (17b-HSD), was reduced. Expression levels of steroidogenic enzymes were restored by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Furthermore, lentivirus-mediated transient expression of p50ATF6 reduced the expression level of 3b-HSD in the testis. Protein expression levels of phospho-JNK, CHOP, and cleaved caspases-12 and -3 as markers of ER stress-mediated apoptosis markedly increased in response to high-level hCG treatment in mLTC-1 cells and the testis. Based on transmission electron microscopy and H&E staining of the testis, it was shown that abnormal ER morphology and destruction of Key Words " Leydig cells " Steroidogenic enzyme expression " Activating transaction factor 6 " ER stress " Testosterone Journal of Molecular Endocrinology Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 151-166 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 153 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 154 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 155 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 156 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 157 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 158 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 159 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 160 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 161 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 162 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 163 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 164 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 165 Research S-J PARK, T-S KIM and others hCG-induced ER stress-mediated apoptosis 50:2 166
Background: Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been... more Background: Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been widely used as a spice and herbal medicine in Asia. It has been suggested to have many biological activities, such as antioxidative, antiinflammatory, anticancer, chemopreventive, and antineurodegenerative properties. We evaluated the impact of curcumin on life span, fecundity, feeding rate, oxidative stress, locomotion, and gene expression in two different wild-type Drosophila melanogaster strains, Canton-S and Ives, under two different experimental conditions. Results: We report that curcumin extended the life span of two different strains of D. melanogaster, an effect that was accompanied by protection against oxidative stress, improvement in locomotion, and chemopreventive effects. Life span extension was gender and genotype specific. Curcumin also modulated the expression of several aging-related genes, including mth, thor, InR, and JNK. Conclusions: The observed positive effects of curcumin on life span and health span in two different D. melanogaster strains demonstrate a potential applicability of curcumin treatment in mammals. The ability of curcumin to mitigate the expression levels of age-associated genes in young flies suggests that the action of curcumin on these genes is a cause, rather than an effect, of its life span-extending effects.
BMC Molecular Biology, 2011
Background: The unfolded protein response (UPR) is an evolutionary conserved adaptive reaction fo... more Background: The unfolded protein response (UPR) is an evolutionary conserved adaptive reaction for increasing cell survival under endoplasmic reticulum (ER) stress conditions. X-box-binding protein-1 (Xbp1) is a key transcription factor of UPR that activates genes involved in protein folding, secretion, and degradation to restore ER function. The UPR induced by ER stress was extensively studied in diseases linked to protein misfolding and aggregations. However, in the porcine system, genes in the UPR pathway were not investigated. In this study, we isolated and characterized the porcine Xbp1 (pXbp1) gene in ER stress using porcine embryonic fibroblast (PEF) cells and porcine organs. ER stress was induced by the treatment of tunicamycin and cell viability was investigated by the MTT assay. For cloning and analyzing the expression pattern of pXbp1, RT-PCR analysis and Western blot were used. Knock-down of pXbp1 was performed by the siRNA-mediated gene silencing.
Developmental & Comparative Immunology, 2012
Innate immunity plays an important role in combating microbial infection in animals. During bacte... more Innate immunity plays an important role in combating microbial infection in animals. During bacterial infection in Drosophila melanogaster gut, Dual oxidase (Duox) generates reactive oxygen species (ROS) to fight against the infected microbes. Concurrently, antioxidant systems eliminate residual ROS and protect the hosts. Here we found that Drosophila melanogaster Peroxiredoxin V (dPrxV) is an immune-related antioxidant enzyme which maintains intestinal redox homeostasis. dPrxV was highly expressed in gut and induced by the oral infection of Erwinia carotovora carotovora. dPrxV expression was increased by the gut-specific Duox overexpression but decreased by Duox inhibition. Moreover, dPrxV expression was mediated by the JNK/FOXO signaling and dPrxV mutant reduced survival after gut infection. These results suggest that JNK/FOXO mediated dPrxV expression plays a critical role in Drosophila melanogaster gut during bacterial infection in protecting the host gut epithelial cells from oxidative damage.