Kyu Jin Choi

Korea Institute of Radiological & Medical Sciences, Sŏul, Seoul, South Korea

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Publications (23)75.42 Total impact

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    ABSTRACT: X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is well known as an antagonist of XIAP-mediated caspase inhibition. Although XAF1 serves as a tumor-suppressor gene, the role of XAF1 in cellular senescence remains unclear. We found that XAF1 expression was increased by genotoxic agents, such as doxorubicin and ionizing radiation in pulmonary microvascular endothelial cells, consequently leading to premature senescence. Conversely, downregulation of XAF1 in premature senescent cells partially overcame endothelial cell senescence. p53 knockdown, but not p16 knockdown, abolished senescence phenotypes caused by XAF1 induction. XAF1 expression was transcriptionally regulated by Bromodomain 7 (BRD7). XAF1 induction with interferon-gamma (IFN-γ) treatment was abrogated by BRD7 knockdown, which resulted in blocking interferon-induced senescence. In lung cancer cells, XAF1 tumor suppressor activity was decreased by BRD7 knockdown, and inhibition of tumor growth by IFN-γ did not appear in BRD7-depleted xenograft tumors. These data suggest that XAF1 is involved in BRD7-associated senescence and plays an important role in the regulation of endothelial senescence through a p53-dependent pathway. Furthermore, regulation of the BRD7/XAF1 system might contribute to tissue or organismal aging and protection against cellular transformation.
    No preview · Article · Jan 2016 · Oncotarget
  • Kwang Seok Kim · Jong-Ik Heo · Kyu Jin Choi · Sangwoo Bae
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    ABSTRACT: X-linked inhibitor of apoptosis (XIAP) and Chk1 are potential molecular targets in radiotherapy. However, their molecular association in the regulation of radiation sensitivity has been rarely studied. Here, we show that XIAP modulates radiation sensitivity by regulating stability of Chk1 in lung cancer cells. Both Chk1 and XIAP are highly expressed in various lung cancer cells. Overexpression of XIAP increased cell survival following genotoxic treatments by preventing downregulation of Chk1. However, XIAP reversed Chk1-protective activity in the presence of XIAP-associated factor 1 (XAF1) by degrading Chk1 via ubiquitination-dependent proteasomal proteolysis. The XIAP-XAF1 complex-mediated Chk1 degradation also required CUL4A and DDB1. Chk1 or XIAP was associated with DDB1 and CUL4A. Depletion of CUL4A or DDB1 prevented the XIAP-XAF1-mediated Chk1 degradation suggesting involvement of a CUL4A/DDB1-based E3 ubiquitin ligase in the process or its collaboration with XIAP E3 ligase activity. Taken together, our findings show that XIAP plays a dual role in modulation of Chk1 stability and cell viability following IR. In the absence of XAF1, XIAP stabilizes Chk1 under IR with corresponding increase of cell viability. By contrast, when XAF1 is overexpressed, XIAP facilitates Chk1 degradation, which leads to enhancement of radiation sensitivity. This selective regulation of Chk1 stability by XIAP and XAF1 could be harnessed to devise a strategy to modulate radiation sensitivity in lung cancer cells.
    No preview · Article · Dec 2014 · Cancer biology & therapy
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    ABSTRACT: Purpose: Inhibition of growth in mammalian cells in response to damage or stress is known as cellular senescence. Increasing evidence suggests that double-strand breaks (DSB) commonly mediate cellular senescence. Recently, radiation exposure has been reported to induce premature senescence. Materials and methods: We investigated whether ionizing radiation (IR) at 4 Gy induces cellular senescence with DNA damage response in human umbilical vein endothelial cells (HUVEC). To determine alterations in gene expression on IR exposure, we have developed a DNA microarray analysis system that contains genes known to be involved in replicative senescence. Results: The damage by IR exposure is shown to result in a variety of senescence-like phenotypes such as changes in cell morphology, decrease in cell proliferation, increase in senescence- associated β-galactosidase (SA-β-gal) staining, and suppression of angiogenic activity. Moreover, the expression levels of several genes associated with cell cycle regulation are remarkably increased in IR-exposed endothelial cells. We found that IGFBP5 (insulin-like growth factor binding protein 5), PLAT (plasminogen activator), SNAI2 (snail homolog 2), JAG1 (jagged 1), SPRY4 (Sprouty homolog 4), and CD44 were upregulated, whereas CFB (complement factor B), VCAM1 (vascular cell adhesion molecule 1), AQP1 (aquaporin 1), LOXL1 (lysyl oxidase-like 1), and RBPMS (RNA-binding protein with multiple splicing) were down- regulated in both radiation-damaged and old cells. Conclusions: These results imply that the IR-induced phenotype may be enhanced by alterations in genes associated with senescence.
    No preview · Article · Oct 2013 · International Journal of Radiation Biology
  • Kwang Seok Kim · Kyu Jin Choi · Sangwoo Bae
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    ABSTRACT: Interferon-gamma (IFNγ) is a cytokine with roles in immune responses as well as in tumor control. Interferon is often used in cancer treatment together with other therapies. Here we report a novel approach to enhancement of cancer cell killing by combined treatment of IFNγ with ionizing radiation. We found that IFNγ treatment alone in HeLa cells induced phosphorylation of Chk1 in a time- and dose-dependent manner, and resulted in cell arrest. Moreover IFNγ treatment was correlated with attenuation of Chk1 as the treatment shortened protein half-life of Chk1. As Chk1 is an essential cell cycle regulator for viability after DNA damage, attenuation of Chk1 by IFNγ pre-treatment in HeLa cells resulted in increased cell death following ionizing radiation about 2-folds than ionizing radiation treatment alone whereas IFNγ treatment alone had little effect on cell death. X-linked inhibitor of apoptosis-associated factor 1 (XAF1), an IFN-induced gene, seems to partly regulate IFNγ-induced Chk1 destabilization and radiation sensitivity because transient depletion of XAF1 by siRNA prevented IFNγ-induced Chk1 attenuation and partly protected cells from IFNγ-enhanced radiation cell killing. Therefore the results provide a novel rationale to combine IFNγ pretreatment and DNA-damaging anti-cancer drugs such as ionizing radiation to enhance cancer cell killing.
    No preview · Article · Sep 2012 · Cancer biology & therapy
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    ABSTRACT: Identification of genes that modulate radiation sensitivity provides important tools to study cellular responses to ionizing radiation. We combined DNA microarrays and viability assays to identify modulators of radiation sensitivity in A549 lung cancer cells. Up-regulated genes were selected from microarray experiments and RNA expression levels were confirmed by real-time RT-PCR analysis. Cell viability assays such as clonogenic assay, MTT and FACS analysis of cell death, identified the ELAVL4 gene as a novel modulator of radiation sensitivity. ELAVL4 expression was induced following ionizing irradiation. Depletion of the ELAVL4 gene increased radiation sensitivity of A549 cells as shown by decreased surviving cell fraction following irradiation in clonogenic assay. Enhanced radiation sensitivity of ELAVL4-depleted cells was attributable to decreased cell proliferation as well as increased apoptotic cell death following irradiation. Thus the endogenous function of ELAVL4 in relation to radiation sensitivity might be the regulation of cell proliferation and death. This approach to identification of modulators for radiation sensitivity has several advantages in terms of functional selectivity, stringency and time. Further analysis of the modulators should find potential use in the application of radiation biomarkers as well as modulators of cellular radiation responses.
    Preview · Article · Jul 2011 · Oncology Reports
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    ABSTRACT: The radiosensitizing activity of celastrol, a quinone methide triterpene was examined. We found that celastrol treatment of the NCI-H460 lung cancer cell line increased radiation-induced cell killing. The increased radiosensitivity was correlated with decreased levels of Hsp90 clients, such as EGFR, ErbB2 and survivin as well as with increased p53 expression. Celastrol inhibited the ATP-binding activity of Hsp90. Furthermore, celastrol treatment dissociated an Hsp90 client protein, EGFR, and this in turn resulted in degradation of the client protein. These results were not observed with another structurally similar triterpenoid, 6β-acetonyl-22β-hydroxytingenol (TG), suggesting that a specific structural feature of the triterpenoid is required for radiosensitization. Moreover celastrol treatment increased p53 levels by phosphorylating Ser15 and Ser20 residues as well as by inhibiting its proteasomal degradation. Celastrol may be considered an effective radiosensitizer acting as an inhibitor of Hsp90 and a p53 activator. The two activities could be applicable to a broad range of cancer cells with either wild-type or mutant p53 because either activity could be effective for the enhancement of radiation cell killing. Further analysis with other triterpenoids should identify the functional moiety of the structure and additional candidates for effective radiosensitizers, which can be used in combined radiotherapy.
    No preview · Article · Mar 2011 · International Journal of Molecular Medicine
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    ABSTRACT: Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-kappaB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-kappaB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/Mek/Erk pathway.
    Preview · Article · Aug 2010 · Cell Research
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    ABSTRACT: The diffusion of I3− in volatile and non-volatile electrolytes is investigated to confirm the effects on the performance of dye-sensitized solar cells (DSSCs). The ionic diffusion is controlled by using electrolyte mediums with diverse viscosities including acetonitrile, 3-methoxy-propionitrile, diethylene glycol dimethyl ether, and poly(ethylene glycol dimethyl ether) with three different molecular weights and varying I3− concentrations. The diffusion flux in each electrolyte is characterized by scanning electrochemical microscopy. By measuring incident photon to current conversion efficiency, electrochemical impedance spectroscopy, and photovoltaic performance, the optimum diffusion flux of I3− is suggested for the best efficiency of DSSCs.
    No preview · Article · Jun 2010 · Journal of Photochemistry and Photobiology A Chemistry
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    ABSTRACT: A band-offset-based unified-RAM (URAM) cell fabricated on a Si/Si<sub>1-y</sub>C<sub>y</sub> substrate is presented for the fusion of a nonvolatile memory (NVM) and a capacitorless 1T-DRAM. An oxide/nitride/oxide (O/N/O) gate dielectric and a floating-body are combined in a FinFET structure to perform URAM operation in a single transistor. The O/N/O layer is utilized as a charge trap layer for NVM, and the floating-body is used as an excess hole storage node for capacitorless 1T-DRAM. The introduction of a pseudomorphic SiC-based heteroepitaxial layer into the Si substrate provides band offset in a valence band. The FinFET fabricated on the energy-band-engineered Si<sub>1-y</sub>C<sub>y</sub> substrate allows hole accumulation in the channel for 1T-DRAM. The band-engineered URAM yields a cost-effective process that is compatible with a conventional body-tied FinFET SONOS. The fabricated URAM shows highly reliable NVM and high-speed 1T-DRAM operations in a single memory cell.
    Full-text · Article · May 2009 · IEEE Transactions on Electron Devices
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    ABSTRACT: A novel fusion memory is proposed as a new paradigm of silicon based memory technology. An O/N/O gate dielectric and a floating body are combined with a FinFET, and the non-volatile memory (NVM) and high speed capacitorless 1T-DRAM are performed in a single transistor. A nitride trap layer is used as an electron storage node for NVM, and hetero-epitaxially grown Si/Si<sub>1-x</sub>Ge<sub>x</sub> energy band engineered bulk substrates allow excess hole storage for 1T-DRAM. Highly reliable 1T-DRAM and NVM are demonstrated.
    Full-text · Conference Paper · Jan 2009
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    ABSTRACT: The expression of glutathione-S-transferase (GST) fusion protein is extensively utilized in the study of protein-protein interactions. In the commonly used purification method, the overexpressed GST fusion protein is bound to the glutathione (GSH)-coupled resins via affinity chromatography, and then eluted by an excessive quantity of reduced GSH. However, this technique has certain limitations, such as low product purity, retention of GSH in the sample, as well as relatively high cost. To overcome these limitations, in this study, elution buffer containing 2% formic acid was utilized rather than GSH to elute the GST-fusion protein, and thereafter the acidic samples were neutralized using collecting buffer. By using this method, highly purified GST-cyclophilin A (CypA) fusion protein was obtained, without affecting the structural and functional characteristics such as PPIase and chaperone activities. Moreover, the procedure is also cost-effective, due to the low cost of formic acid as compared with GSH.
    Full-text · Article · Jan 2009 · Indian journal of biochemistry & biophysics
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    ABSTRACT: A pair of poly(ethylene glycol) oligomers with terminal groups capable of providing amine–acid interactions are used in dye-sensitized solar cells (DSSCs) as an electrolyte that can be easily solidified at room temperature. In spite of its solidity, the oligomer electrolyte has high ionic diffusion and good permeability into the nanopores of a TiO2 electrode. The electron diffusion coefficient and lifetime in a photoelectrode are largely affected by the adsorptive interaction between cations and the TiO2 surface. The energy-conversion efficiency of DSSCs using the oligomer electrolyte is greater than 4.5%. Long-term storage at room temperature demonstrates that the stability of the oligomer electrolyte system is superior to that of a volatile solvent electrolyte.
    Full-text · Article · Sep 2008 · Journal of Power Sources
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    ABSTRACT: A FinFET-based unified-RAM (URAM) using the band offset of Si/SiC is demonstrated for the fusion of a non-volatile memory (NVM) and capacitorless 1T-DRAM operation. An oxide/nitride/oxide (O/N/O) gate dielectric and a floating body caused by the band offset are combined in a bulk FinFET to allow two memory operations in a single transistor. The device is fabricated on an epitaxially grown Si/SiC substrate and its process is fully compatible with a conventional bulk FinFET SONOS. Highly reliable NVM and high speed 1T-DRAM operation are confirmed in a single URAM cell.
    Full-text · Conference Paper · Jul 2008
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    ABSTRACT: We reported previously that endogenous reactive oxygen species (ROS) function as myogenic signaling molecules. It has also been determined that excess ROS induce electrophile-response element (EpRE)-driven gene expression via activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nonetheless, the relationship between the metabolism of ROS (eg, H(2)O(2)) through glutathione (GSH) up-regulation, GSH-dependent reduction of H(2)O(2), and Nrf2-dependent gene regulation is not well established. Therefore, we attempted to determine whether H(2)O(2) controls the intracellular GSH redox state via the Nrf2-glutamate-cysteine ligase (GCL)/glutathione reductase (GR)-GSH signaling pathway. In our experiments, enhanced H(2)O(2) generation was accompanied by an increase in both total GSH levels and the GSH/GSSG ratio during muscle differentiation. Both GCL and GR transcriptional expression levels were markedly increased during muscle differentiation but reduced by catalase treatment. Nrf2 protein expression and nuclear translocation increased during myogenesis. The inhibition of GCL, GR, and Nrf2 both by inhibitors and by RNA interference blocked muscle differentiation. Phosphatidylinositol 3-kinase regulated the expression of the GCL C (a catalytic subunit) and GR genes via the induction of Nrf2 nuclear translocation and expression. In conclusion, endogenous H(2)O(2) generated during muscle differentiation not only functions as a signaling molecule, but also regulates the GSH redox state via activation of the Nrf2-GCL/GR-GSH signaling pathway downstream of phosphatidylinositol 3-kinase.
    Preview · Article · Jul 2008 · American Journal Of Pathology
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    ABSTRACT: This study measures the diffusion coefficients of I− and I3− in oligomer electrolytes as a function of the molecular weight of oligomers and investigates their effect on the performance of dye-sensitized solar cells (DSSCs). The high-diffusion coefficients of ions in an oligomer electrolyte with a lower molecular weight can help to promote the redox mechanism in DSSCs and thereby increase the short-circuit current density. They can also cause a decrease in the open-circuit voltage since a high-diffusion coefficient of I3− is capable of reducing the lifetime of electrons in TiO2 electrodes. To offset these effects, N-methyl-benzimidazole is added to the oligomer electrolytes, thereby improving the open-circuit voltage and fill factor and, consequently, the overall energy-conversion efficiency, which increases to over 5%. A further test involving storage at a high temperature of 75 °C demonstrates that DSSCs employing the oligomer electrolytes show excellent thermal stability over 200 h.
    Full-text · Article · Nov 2007 · Journal of Power Sources
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    ABSTRACT: Role of c-Src in muscle differentiation has been controversial. Here, we investigated if c-Src positively or negatively regulates muscle differentiation, using H9c2 and C2C12 cell lines. Inhibition of c-Src by treatment with PP1 and SU6656, pharmacologic inhibitors of Src family kinases, or by expression of a dominant negative c-Src, all induced muscle differentiation in proliferation medium (PM). In differentiating cells in differentiation medium (DM), c-Src activity gradually decreased and reached basal level 3 days after induction of differentiation. Inhibition of c-Src suppressed Raf/MEK/ERK pathway but activated p38 MAPK. Inhibition of p38 MAPK did not affect c-Src activity in PM. However, it reactivated Raf/MEK/ERK pathway in c-Src-inhibited cells regardless of PM or DM. Concomitant inhibition of c-Src and p38 MAPK activities blocked muscle differentiation in both media. In conclusion, suppression of c-Src activity stimulates muscle differentiation by activating p38 MAPK uni-directionally.
    No preview · Article · Oct 2007 · Archives of Biochemistry and Biophysics
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    ABSTRACT: Although the RhoA/Rho kinase (RhoA/ROK) pathway has been extensively investigated, its roles and downstream signaling pathways are still not well understood in myogenic processes. Therefore, we examined the effects of RhoA/ROK on myogenic processes and their signaling molecules using H9c2 and C2C12 cells. Increases in RhoA/ROK activities and serine phosphorylation levels of insulin receptor substrate (IRS)-1 (Ser307 and Ser636/639) and IRS-2 were found in proliferating myoblasts, whereas IRS-1/2 tyrosine phosphorylation and phosphatidylinositol (PI) 3-kinase activity increased during the differentiation process. ROK strongly bound to IRS-1/2 in proliferation medium but dissociated from them in differentiation medium (DM). ROK inactivation by a ROK inhibitor, Y27632, or a dominant-negative ROK, decreased IRS-1/2 serine phosphorylation with increases in IRS-1/2 tyrosine phosphorylation and PI 3-kinase activity, which led to muscle differentiation even in proliferation medium. Inhibition of ROK also enhanced differentiation in DM. ROK activation by a constitutive active ROK blocked muscle differentiation with the increased IRS-1/2 serine phosphorylation, followed by decreases in IRS-1/2 tyrosine phosphorylation and PI 3-kinase activity in DM. Interestingly, fibroblast growth factor-2 added to DM also blocked muscle differentiation through RhoA/ROK activation. Fibroblast growth factor-2 blockage of muscle differentiation was reversed by Y27632. Collectively, these results suggest that the RhoA/ROK pathway blocks muscle differentiation by phosphorylating IRS proteins at serine residues, resulting in the decreased IRS-1/2 tyrosine phosphorylation and PI 3-kinase activity. The absence of the inhibitory effects of RhoA/ROK in DM due to low concentrations of myogenic inhibitory growth factors seems to allow IRS-1/2 tyrosine phosphorylation, which stimulates muscle differentiation via transducing normal myogenic signaling.
    Preview · Article · Oct 2007 · Molecular Endocrinology
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    ABSTRACT: A GaAs defect-free epitaxial layer has been grown on Si via a Ge concentration graded SiGe on insulator (SGOI) for application in high channel-mobility metal-oxide-semiconductor field effect transistor. The SGOI layer, 42 nm thick, serves as the compliant and intermediate buffer to reduce the lattice and thermal expansion mismatches between Si and GaAs. A modified two-step Ge condensation technique achieves the surface Ge concentration in SGOI as high as 71%. It is also found that low-temperature migration enhanced epitaxy during the initial GaAs nucleation on the SGOI surface is critical to obtain a device quality GaAs layer by epitaxial growth.
    Full-text · Article · Sep 2007 · Journal of Applied Physics
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    ABSTRACT: Cyclophilin A (CypA) has been reported to be overexpressed in cancer cells, especially in solid tumors. To determine the role of CypA in tumorigenesis, we investigated the induction of CypA as well as the role it plays in cancer cells. Here, we have shown that induction of CypA is associated with hypoxia in a variety of cells, including DU145 human prostate cancer cell line. Our analysis of the CypA promoter clearly showed that CypA up-regulation is mediated by hypoxia-inducible factor-1alpha transcription factor. Interestingly, overexpression of CypA prevented hypoxia- and cisplatin-induced apoptosis, and this was associated with the suppression of reactive oxygen species generation and depolarization of mitochondrial membrane potential, whereas small interfering RNA-based CypA knockdown aggravated these factors. These results suggest that CypA is important in tumorigenesis, especially in tumor apoptosis.
    Preview · Article · May 2007 · Cancer Research
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    ABSTRACT: A novel fabrication technique to grow device quality GaAs on Si substrate is proposed using thin graded SiGe-on-insulator (SGOI) substrate. Combination of low-temperature GaAs molecular beam epitaxy (MBE) growth technique, low-temperature GaAs migration enhanced epitaxy (MEE) technique, and modified two-step Ge condensation technique has demonstrated successful growth of 10-nm GaAs layer grown on a tensile strained 42-nm graded SGOI layer.
    No preview · Article · Apr 2007 · ECS Transactions

Publication Stats

285 Citations
75.42 Total Impact Points

Institutions

  • 2010-2016
    • Korea Institute of Radiological & Medical Sciences
      Sŏul, Seoul, South Korea
    • Seoul National University
      • Department of Materials Science and Engineering
      Sŏul, Seoul, South Korea
  • 2013
    • National Cancer Center Korea
      QYK, Gyeonggi-do, South Korea
  • 2009
    • Korea Advanced Institute of Science and Technology
      • Department of Electrical Engineering
      Daiden, Daejeon, South Korea
  • 2005-2009
    • Kyung Hee University
      • • Institute for Medical Science
      • • Department of Medicine
      Sŏul, Seoul, South Korea
  • 2008
    • University of California, Merced
      • School of Natural Sciences
      Merced, California, United States
  • 2007-2008
    • Korea Institute of Science and Technology
      • Photo-electronic Hybrids Research Center
      Sŏul, Seoul, South Korea