• Mycobiology
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• v.38 no.1
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• pp.26-32
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• 2010

The cyclic AMP (cAMP) pathway plays a major role in growth, sexual differentiation, and virulence factor synthesis of pathogenic fungi. In Cryptococcus neoformans, perturbation of the cAMP pathway, such as a deletion in the gene encoding adenylyl cyclase (CAC1), causes defects in the production of virulence factors, including capsule and melanin production, as well as mating. Previously, we performed a comparative transcriptome analysis of the Ras- and cAMP- pathway mutants, which revealed 163 potential cAMP-regulated genes (38 genes at a 2-fold cutoff). The present study characterized the role of one of the cAMP pathway-dependent genes (serotype A identification number CNAG_ 06576.2). The expression patterns were confirmed by Northern blot analysis and the gene was designated cAMP-regulated gene 1 (CAR1). Interestingly, deletion of CAR1 did not affect biosynthesis of any virulence factors and the mating process, unlike the cAMP-signaling deficient cac1$\Delta$ mutant. Furthermore, the car1$\Delta$ mutant exhibited wild-type levels of the stress-response phenotype against diverse environmental cues, indicating that Car1, albeit regulated by the cAMP-pathway, is not essential to confer a cAMP-dependent phenotype in C. neoformans.

• BMB Reports
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• v.35 no.3
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• pp.251-254
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• 2002

The genetic factors that contribute to the development of coronary artery disease (CAD) are poorly understood. It is likely that multiple genes that act independently or synergistically contribute to the development of CAD and the outcome. Recently, an insertion/deletion (I/D) polymorphism of the human angiotensin I-converting enzyme (ACE) gene, a major component of the renin-angiotensin system (RAS), was identified. The association of the ACE gene D allele with essential hypertension and CAD has been reported in the African-American, Chinese, and Japanese populations. However, other studies have failed to detect such an association. It has been suggested that these inconsistencies may be due to the difference in backgrounds of the population characteristics. In the present study, we investigated the I/D polymorphism of the ACE gene in 103 subjects of both sexes, consisting of 59 normal controls and 44 patients with hypertension. The allele and genotype frequency were significantly different between the hypertensive and control groups (p < 0.01). Among the three ACE I/D variants, the DD genotype was associated with the highest value of the mean systolic blood pressure [SBP] and mean diastolic blood pressure [DBP] (p = < 0.05) in men, but not in women. In the overall population, the mean SBP and DBP was highest in DD subjects, intermediate in I/D subjects, and the least in II subjects.

• BMB Reports
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• v.53 no.11
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• pp.576-581
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• 2020

Dimethylation of the histone H3 protein at lysine residue 9 (H3K9) is mediated by euchromatin histone methyltransferase II (EHMT2) and results in transcriptional repression of target genes. Recently, chemical inhibition of EHMT2 was shown to induce various physiological outcomes, including endoplasmic reticulum stress-associated genes transcription in cancer cells. To identify genes that are transcriptionally repressed by EHMT2 during apoptosis, and cell stress responses, we screened genes that are upregulated by BIX-01294, a chemical inhibitor of EHMT2. RNA sequencing analyses revealed 77 genes that were upregulated by BIX-01294 in all four hepatic cell carcinoma (HCC) cell lines. These included genes that have been implicated in apoptosis, the unfolded protein response (UPR), and others. Among these genes, the one encoding the stress-response protein Ras-related GTPase C (RRAGC) was upregulated in all BIX-01294-treated HCC cell lines. We confirmed the regulatory roles of EHMT2 in RRAGC expression in HCC cell lines using proteomic analyses, chromatin immune precipitation (ChIP) assay, and small guide RNA-mediated loss-of-function experiments. Upregulation of RRAGC was limited by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), suggesting that ROS are involved in EHMT2-mediated transcriptional regulation of stress-response genes in HCC cells. Finally, combined treatment of cells with BIX-01294 and 5-Aza-cytidine induced greater upregulation of RRAGC protein expression. These findings suggest that EHMT2 suppresses expression of the RRAGC gene in a ROS-dependent manner and imply that EHMT2 is a key regulator of stress-responsive gene expression in liver cancer cells.

• Toxicological Research
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• v.24 no.3
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• pp.201-206
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• 2008

Exposure to formaldehyde(FA) is closely associated with adverse health effects such as irritation, inflammation, and squamous cell carcinomas of the nasal cavities. Owing to its rapid metabolism and elimination, exposure to FA does not always result in an increased concentration in blood or urine of animals and humans. Therefore, the development of biomarkers for FA exposure is necessary for risk assessment. In the present study, the effects of FA were investigated on the expression of genes involved in the MAPK pathway in vitro and results confirmed in rats exposed to FA by inhalation. Treatment of Hs 680.Tr human tracheal epithelial cells with FA induced gene expression for PDGFA, TNFSF11, SHC1, and HRAS. HRAS expression was also increased in tracheas of rats exposed to FA. In addition, FA exposure induced the expression of RASSF4, a member of the Rasassociation domain family of Ras effectors, in rat tracheas. In conclusion, data showed FA-inducible expression of genes involved in the MAPK pathway occurred and increased expression of HRAS and RASSF4 was noted in rat tracheas subchronically exposed to FA by inhalation. These genes may serve as molecular targets of FA toxicity facilitating the understanding of the toxic mechanism.

• Proceedings of the Korean Nutrition Society Conference
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• 2002.05a
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• pp.29-41
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• 2002

While the sequencing of several genomes was underway, several advanced techniques in genetics, molecular biology and protein chemistry emerged. Within the nutritional sciences, while the focus on nutrition education, epidemiology and public health aspects remains essential; it is crucial to incorporate the new advances in gene and protein discovery in nutritional studies. Nutrition is a discipline that has always integrated social, biochemical and physiological sciences from the studies at the molecule level to studies at the population level. For this reason, nutritionists are in a prime position to readily incorporate the current genomics approaches in nutrition research, All the available analytical techniques can and should be used in modern nutritional sciences. These include genetics, genomics, proteomics and metabolomics which also require integration and use of bioinformatics and computational methods for data analysis and management. These applications will be briefly reviewed with a primary focus on what the genomics and genetics approaches offer to nutritionists. We will use one of our research focus areas to illustrate uses of some of these applications in obesity-hypertension research. Our central hypothesis is that adipose tissue is an endocrine organ that plays a major role in obesity and related hypertension. We are primarily studying the renin angiotensin system (RAS). We provide evidence from our own studies and others for the paracrine as well as endocrine role of adipocyte-derived angiotensin II in adipocyte gene expression, adiposity and blood pressure regulation. Both cell culture studies as well as knockout and transgenic mice models are used to test our hypothesis. Genomics and proteomics technologies are currently developed to complement our physiological and molecular studies on the RAS and for a fine analysis of this system and its function in health and disease.

• Proceedings of the Korean Nutrition Society Conference
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• 2002.06a
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• pp.598-603
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• 2002

While the sequencing of several genomes was underway, several advanced techniques in genetics, molecular biology and protein chemistry emerged. Within the notritional sciences, while the focus on nutrition education, epidemiology and public health aspects remains essential; it is crucial to incorporate the new advances in gene and protein discovery in nutritional studies. Nutrition is a discipline that has always integrated social, biochemical and physiological sciences from the studies at the molecule level to studies at the population level. for this reason, nutritionists are in a prime position to readily incorporate the current genomics approaches in nutrition research. All the available analytical techniques can and should be used in modem nutritional sciences. These include genetics, genomics, proteomics and metabolomics which also require integration and use of bioinformatics and computational methods for data analysis and management. These applications will be briefly reviewed with a primary focus on what the genomics and genetics approaches offer to nutritionists. We will use one of our research focus areas to illustrate uses of some of these applications in obesity-hypertension research. Our central hypothesis is that adipose tissue is an endocrine organ that plays a major role in obesity and related hypertension. We are primarily studying the renin angiotensin system (RAS). We provide evidence from our own studies and others for the paracrine as well as endocrine role of adipocyte-derived angiotensin II in adipocyte gene expression, adiposity and blood pressure regulation. Both cell culture studies as well as knockout and transgenic mice models are used to test our hypothesis. Genomics and proteomics technologies are currently developed to complement our physiological and molecular studies on the RAS and for a fine analysis of this system and its function in health and disease.

• Toxicological Research
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• v.25 no.1
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• pp.35-40
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• 2009

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and related halogenated aromatic hydrocarbons elicit a diverse spectrum of biochemical and toxic responses in laboratory animals and mammalian cells in culture. Toxicity and carcinogenicity of TCDD is well established but the molecular mechanism is still poorly understood. Here, we found the noble responsive genes to TCDD using the differential display analysis. Treatment of HepG2 cells with TCDD showed a significantly different mRNA expression pattern from the untreated cells in differential display analysis. The differentially displayed bands were isolated and used as probes in dot blot and Northern blot analyses. Of thirty-five isolated differentially displayed bands, only two bands were confirmed as positive in dot blot and Northern blot analyses. The nucleotides sequences of these clones were analyzed and the search of Genebank database revealed that one clone is highly homologous with RanBP2 (Ras-related nuclear protein binding protein2; 92%) and the other is an unknown gene. RanBP2 is a nucleoporin with SUMO E3 ligase activity that functions in both nucleocytoplasmic transport and mitosis and its role as a novel tumor suppressor has been recently proposed. Thus, these results may suggest the clue elucidating the toxic mechanism of TCDD through RanBP2.

• Korean Journal of Clinical Laboratory Science
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• v.50 no.4
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• pp.457-461
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• 2018

Corpus luteum (CL) is a transient endocrinal tissue that undergoes repeated formation and regression during the estrous cycle. In this study, we hypothesized that the functional and structural mechanism of angiogenesis is similar between CL and tumor formation. First, we measured mRNA and protein expression of angiogenic receptors (vascular endothelial growth factor receptor-2, VEGFR2; Tie 2) in the early, middle, and late phase CL tissues during the estrous cycle. Ral-interacting protein of 76 kDa (RLIP76) and H-ras mRNA and protein were also expressed in the CL tissues. VEGFR2 and Tie 2 mRNA and protein were expressed in the early and middle phase CLs and decreased in the late phase. H-ras mRNA and protein were expressed in the early and middle phase CLs, but not in the late phase. RLIP76 mRNA was expressed in all phase CLs, and the protein expression was highest in early phase CLs. We suggest that RLIP76 and H-ras, an oncogenic gene, regulate the function of the CL during the estrous cycle, and the proteins will play an important role in the angiogenic mechanism of the CL.

• BMB Reports
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• v.50 no.12
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• pp.599-600
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• 2017

Many studies have focused on the tumor suppressive role of $TGF-{\beta}$ signaling during the early stages of tumorigenesis by activating the target genes involved in cytostasis and apoptosis. We investigated the effects of $TGF-{\beta}$ inhibition on early tumorigenesis in the liver, by employing diverse inhibitory methods. Strikingly, $TGF-{\beta}$ inhibition consistently suppressed hepatic tumorigenesis that was induced either by activated RAS plus p53 downregulation or by the co-activation of RAS and TAZ signaling; this demonstrates the requirements for canonical $TGF-{\beta}$ signaling in tumorigenesis. Moreover, we found that Snail is the target gene of the $TGF-{\beta}$ signaling pathway that promotes hepatic carcinogenesis. The knockdown of Snail suppressed the early tumorigenesis in the liver, as did the $TGF-{\beta}$ inhibition, while the ectopic expression of Snail restored tumorigenesis that was suppressed by the $TGF-{\beta}$ inhibition. Our findings establish the oncogenic $TGF-{\beta}$-Smad-Snail signaling axis during the early tumorigenesis in the liver.

• Molecular & Cellular Toxicology
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• v.2 no.4
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• pp.273-278
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• 2006

95 squamous cell lung carcinoma samples (normal tissue: 40 samples, tumor: 55 samples) were analyzed with 8 K cDNA microarray. 1-way ANOVA test was employed to select differentially expressed genes in tumor with FDR<0.01. Among the selected 1,655 genes, final 212 genes were chosen according to the expression fold change and used for following analysis. The expression of up-regulated 64 genes was verified with Reverse Transcription PCR and 10 genes were identified as candidates for SCC markers. In our opinion, those candidates can be exploited as diagnostic or therapeutic purposes. Gene Ontology (GO) based analysis was performed using those 212 genes, and following categories were revealed as significant biological processes: Immune response (GO: 0006955), antigen processing (GO: 0030333), inflammatory response (GO: 0006954), Cell adhesion (GO: 0007155), and Epidermis differentiation (GO: 0008544). Gene set enrichment analysis (GSEA) also carried out on overall gene expression profile with 522 functional gene sets. Glycolysis, cell cycle, K-ras and amino acid biosynthesis related gene sets were most distinguished. These results are consistent with the known characteristics of SCC and may be interconnected to rapid cell proliferation. However, the unexpected results from ERK activation in squamous cell carcinoma gripped our attention, and further studies are under progress.