• The Journal of Internal Korean Medicine
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• v.25 no.4
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• pp.274-288
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• 2004

Objectives : This study was designed to evaluate the effect on cytotoxicity of Bojungikki-tang(BIT) in human lung cancer H460 cells. Methods : BIT-induced cell death was confirmed as apoptosis characterized by chromatin condensation and increase of the $sub-G_1$, DNA content. It was tested whether the water extract of BIT affects the cell cycle regulators such as, p2l/Cipl, p27/Kipl, cyclin $B_1$. Results : The data showed that treatment of BIT decreased the viability of H460 cells in a dose-dependent manner. p2l/Cip1 is gradually decreased by the addition of the cells with BIT extract. Interestingly, p27/Kip1 is not detected for 24 hr after the addition of BIT extract, however, after 24 hr, p27/Kipl markedly increased. In addition, cyclin $B_1$, decreased in a time dependent manner after the addition of the water extract. The activation of caspase -3 protease was further confirmed by degradation of procaspase-8 protease andpoly(ADP-ribose) polymerase(P ARP) by BIT in H460 cells. Moreover, BIT induced the increase of Bak expression. Conclusion : These results suggest that the extract of BIT exerts anticancer effects to induce the death of human lung cancer H460 cells via down regulation of cell cycle regulators such as p2l/Cip1, and cyclin B1 or up regulation of cell cycle regulators such as p27/Kip1. Moerover results suggest that BIT induces an apoptosis in H460 cells via activation of intrinsic caspase cascades.

• Molecules and Cells
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• v.24 no.3
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• pp.409-415
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• 2007

The retinoblastoma (Rb) gene is one of the most important genes in cell cycle regulation and tumorigenesis. Homozygosity for a germ-line Rb mutation results in embryonic lethality and evokes developmental defects associated with inappropriate S-phase entry and high levels of apoptosis. Although Rb has been extensively studied, more target genes need to be identified and characterized to unravel the precise mechanism of Rb function. In order to identify Rb-regulated genes, we analyzed the gene expression profile of Rb-deficient mouse embryo fibroblasts (MEFs), and identified an unknown gene, RbEST47, that is transcriptionally upregulated in Rb-deficient MEFs. This gene is conserved from fruitfly to human. It is expressed in brain, lung, kidney, and testis, and is located on mouse chromosome 2. This region is syntenic to human chromosome 9q34.3, which frequently exhibits loss of heterozygosity in neoplastic diseases. RbEST47 was considerably down-regulated in immortalized cells, and showed cell cycle-dependent expression, suggesting important roles in S and/or G2.

• Journal of Life Science
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• v.11 no.4
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• pp.362-370
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• 2001

Regulation of cell proliferation is a complex process involving the regulated expression and /or modification of discrete gene products. which control transition between different stages of the cycle. The purpose of this short review is to provide an overview of somatic cell cycle events and their controls. Cycline have appeared as major positive regulators in this network, because their association to the cyclin-dependent kinases(Cdks) allows the subsequent activation on the Cdk/cyclin complexes and their catalatic activity. In mammalian cells, early to mid G1 progression and late G1 progression leading to S phase entry are directed by D-type cyclins-Cdk4, 6 and cyclin E-Cdk 2 both of which can phosphorylate the retinoblastoma protein (pRB). pRB is a transcriptional repressor which, in its unphosphorylated state, binds to members of the E2F transcription factor family and blocks E2F-dependent transcription of genes controlling the G1 to S phase transition an subsequent DNA synthesis. Cyclin A is produced in late G1 and expressed during S and G2 phae, and expression of B-type cyclins is typically maximal during the G2 to M phase transition and it controls the passage through M phase. They primarily associate with the activate Cdk2, and Cdc2, respectively. On the other hand, the Cdk inhibitors negatively control the activity of C아/cyclin complex by coordinating internal and/or external signals and impending proliferation at several key checkpoints. These current and further findings will provide novel approaches to understanding and treating major diseases.

• Molecules and Cells
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• v.42 no.7
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• pp.557-567
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• 2019

TSPAN12, a member of the tetraspanin family, has been highly connected with the pathogenesis of cancer. Its biological function, however, especially in ovarian cancer (OC), has not been well elucidated. In this study, The Cancer Genome Atlas (TCGA) dataset analysis revealed that upregulation of TSPAN12 gene expression was significantly correlated with patient survival, suggesting that TSPAN12 might be a potential prognostic marker for OC. Further exploration showed that TSPAN12 overexpression accelerated proliferation and colony formation of OVCAR3 and SKOV3 OC cells. Knockdown of TSPAN12 expression in A2780 and SKOV3 cells decreased both proliferation and colony formation. Western blot analysis showed that several cyclins and cyclin-dependent kinases (CDK) (e.g., Cyclin A2, Cyclin D1, Cyclin E2, CDK2, and CDK4) were significantly involved in the regulation of cell cycle downstream of TSPAN12. Moreover, TSPAN12 accelerated mitotic progression by controlling cell cycle. Thus, our data demonstrated that TSPAN12 could be a novel molecular target for the treatment of OC.

• Reproductive and Developmental Biology
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• v.32 no.2
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• pp.105-110
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• 2008

The endogenous retrovirus-like elements (HERVs) found on several human chromosomes are somehow involved in gene regulation, especially during the transcription level. HERV-H, located on chromosome Xp22, may regulate gastrin-releasing peptide receptor (GRPR) in connection with diverse diseases. By suppression subtractive hybridization screen on SV40-immortalized lung fibroblast (WI-38 VA-13), we discovered that expression of HERV-HX2, a clustered HERV-H sequence on chromosome X, was upregulated in immortalized lung cells, compared to that of normal cells. Expression of HERV-HX2 was then analyzed in various cell lines, including normal somatic cells, cancer cells, SV40-immortalized cells, and undifferentiated and differentiated human embryonic stem cells. Expression of HERV-HX2 was specifically upregulated in continuously-dividing cells, such as cancer cells and SV40-immortalized cells. Especially, HERV-HX2 in HeLa cells was highly upregulated during the S phase of the cell cycle. Similar results were obtained in hES cells, in which undifferentiated cells expressed more HERV-HX2 mRNA than differentiated hES cells, including neural precursor and endothelial progenitor cells. Taken together, our results suggest that HERV-HX2 is upregulated in cancer cells and undifferentiated hES cells, whereas downregulated as differentiation progress. Therefore, we assume that HERV-HX2 may playa role on proliferation of cancer cells as well as differentiation of hES cells in the transcriptional level.

• Proceedings of the Korean Society for Bioinformatics Conference
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• 2005.09a
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• pp.191-196
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• 2005

Genetic networks are a key to unraveling dynamic properties of biological processes and regulation of genes plays an essential role in dynamic behavior of the genetic networks. A popular characterization of regulation of the gene is a kinetic model. However, many kinetic parameters in the genetic regulation have not been available. To overcome this difficulty, in this report, state-space approach to modeling gene regulation is presented. Second-order systems are used to characterize gene regulation. Interpretation of coefficients in the second order systems as resistance, capacitance and inductance is studied. The mathematical methods for transient response analysis of gene regulation to external perturbation are investigated. Criterion for classifying gene into three categories: underdamped, overdamped and critical damped is discussed. The proposed models are applied to yeast cell cycle gene expression data.

• Biomedical Science Letters
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• v.16 no.2
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• pp.71-74
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• 2010

Cell proliferation is governed by precise and orderly process the regulation of which involves many different proteins. The key enzyme for cell growth and arrest is cyclin dependent kinases (cdks). In human cells, several cdks orchestrate four distinct cell cycle phases (M, $G_1$, S and $G_2$ ) and they sequentially operate in an order of cdc1, cdk4, cdk6 and cdk2. The regulatory components of cdks consist of cyclins and two family of cdk inhibitors, INK4 (inhibitors of cdk4) and KIP (kinase inhibitor protein). $G_1$ regulatory molecules for cdk mainly respond to environmental cues of mitogenic and anti-mitogenic stimuli and therefore influence activities of $G_1$ cdks, namely, cdk4/6 and cdk2. $G_1$ inhibitors include $p21^{CIP}$ and $p27^{KIP1}$. Between them, $p27^{KIP1}$ has attracted attentions of many researchers because of its characteristic regulatory features and diverse functions. Besides, the role of $p27^{KIP1}$ in cancer development warrants further studies in the future. Therefore, this review will focus on the recent findings and especially on the complexity of regulatory mechanisms of $p27^{KIP1}$.

• Journal of Microbiology and Biotechnology
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• v.23 no.11
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• pp.1586-1597
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• 2013

Energy-efficient metabolic responses were often noted in high-productive cultures. To better understand these metabolic responses, an investigation into the relationship between metabolic responses and energy regulation was conducted via a comparative analysis among cultures with different energy source supplies. Both glycolysis and glutaminolysis were studied through the kinetic analyses of major extracellular metabolites concerning the fast and slow cell growth stages, respectively, as well as the time-course profiles of intracellular metabolites. In three cultures showing distinct antibody productivities, the amino acid metabolism and energy state were further examined. Both the transition of lactate from production to consumption and steady intracellular pools of pyruvate and lactate were observed to be correlated with efficient energy regulation. In addition, an efficient utilization of amino acids as the replenishment for the TCA cycle was also found in the cultures with upregulated energy metabolism. It was further revealed that the inefficient energy regulation would cause low cell productivity based on the comparative analysis of cell growth and productivity in cultures having distinct energy regulation.

• Biomolecules & Therapeutics
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• v.30 no.6
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• pp.585-592
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• 2022

Treatment of triple-negative breast cancer (TNBC) has been limited due to the lack of molecular targets. In this study, we evaluated the cytotoxicity of hydroxyzine, a histamine H1 receptor antagonist in human triple-negative breast cancer BT-20 and HCC-70 cells. Hydroxyzine inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay showed that hydroxyzine induced apoptosis. The hydroxyzine-induced apoptosis was accompanied down-regulation of cyclins and CDKs, as well as the generation of reactive oxygen species (ROS) without cell cycle arrest. The effect of hydroxyzine on the induction of ROS and apoptosis on TNBC cells was prevented by pre-treatment with ROS scavengers, N-acetyl cysteine or Mito-TEMPO, a mitochondria-targeted antioxidant, indicating that an increase in the generation of ROS mediated the apoptosis induced by hydroxyzine. Western blot analysis showed that hydroxyzine-induced apoptosis was through down-regulation of the phosphorylation of JAK2 and STAT3 by hydroxyzine treatment. In addition, hydroxyzine induced the phosphorylation of JNK and p38 MAPK. Our results indicate that hydroxyzine induced apoptosis via mitochondrial superoxide generation and the suppression of JAK2/STAT3 signaling.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.2
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• pp.205-213
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• 2017

Quercetin, a plant-derived flavonoid found in fruits, vegetables and tea, has been known to possess bioactive properties such as anti-oxidant, anti-inflammatory and anti-cancer. In this study, anti-cancer effect of quercetin and its underlying mechanisms in triple-negative breast cancer cells was investigated. MTT assay showed that quercetin reduced breast cancer cell viability in a time and dose dependent manner. For this, quercetin not only increased cell apoptosis but also inhibited cell cycle progression. Moreover, quercetin increased FasL mRNA expression and p51, p21 and GADD45 signaling activities. We also observed that quercetin induced protein level, transcriptional activity and nuclear translocation of Foxo3a. Knockdown of Foxo3a caused significant reduction in the effect of quercetin on cell apoptosis and cell cycle arrest. In addition, treatment of JNK inhibitor (SP 600125) abolished quercetin-stimulated Foxo3a activity, suggesting JNK as a possible upstream signaling in regulation of Foxo3a activity. Knockdown of Foxo3a and inhibition of JNK activity reduced the signaling activities of p53, p21 and GADD45, triggered by quercetin. Taken together, our study suggests that quercetin induces apoptosis and cell cycle arrest via modification of Foxo3a signaling in triple-negative breast cancer cells.