• Proceedings of the Korean Society of Toxicology Conference
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• 2005.05a
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• pp.165-165
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• 2005

• 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.

• Journal of Acupuncture Research
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• v.18 no.4
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• pp.101-115
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• 2001

Objective : To characterize the antitumorigenic potential of Apamin, one of the major components of bee venom, its effects on cell proliferation and the mitogen-activated protein kinase (MAPK) signal transduction pathway were characterized using the human melanoma cell line SK-MEL-2. Methods & Results : Cell counting analysis for cell death demonstrated that consistent with a previous results, SK-MEL-2 cells treated with $0.5-2.0{\mu}g/ml$ of Apamin showed no recognizable cytotoxic effect whereas detectable induction of cell death was identified at concentrations over $5.0{\mu}g/ml$. [3H]thymidine incorporation assay for cell proliferation demonstrated that DNA replication of SK-MEL-2 cells is inhibited by Apamin in a dose- and time-dependent manner. To explore whether Apamin-induced growth suppression is associated with the MAPK signaling pathway, phosphorylation of Erk, a function mediator of MAPK growth-stimulating signal, was examined Western blot assay using a phospho-specific Erkl/2 antibody. A significant increase of Erkl/2 phosphorylation level was observed in Apamin-treated cells compared with untreated control cells. Qantitative RT-PCR analysis revealed that Apamin inhibit expression of MAPK downstream genes such as c-Jun, c-Fos, and cyclin D1 but not expression of MAPK pathway component genes including Ha-Ras, c-Raf-1, MEK1, and Erk. Conclusion : It is strongly suggested that the antitumorigenic activity of Apamin might result in part from its inhibitory effect on the MAPK signaling pathway in human melanoma cells SK-MEL-2.

• The Journal of Korean Medicine
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• v.21 no.4
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• pp.64-72
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• 2000

Objectives : This study was designed to investigate the neuroprotective effect of Hwansodan(Huanshao-dan) on the apoptosis induced by withdrawal of neurotrophic support. Methods : PCl2 pheochromocytoma cells have been used extensively as a model for studying the cellular and molecular effects of neuronal cells. The viability of cells was measured by MTT assay. We used DNA fragmentation and caspase 3-like protease activation assay. Results : The water extract of Hwansodan(Huanshao-dan) significantly showed protective effects on serum and glucose deprivation-induced apoptotic death. Hwansodan(Huanshao-dan) also prevents DNA fragmentation and caspase 3-like protease activation, representing typical neuronal apoptotic phenomena in PCl2 pheochromocytoma cells and induces tyrosine phosphorylation of proteins around 44 kDa, which was identified as ERK1 with electrophoretic gel mobility shift by Western blot. In addition, MAPK kinase(MEK) inhibitor PD98059 and Ras inactivator, ${\alpha}-hydroxyfarnesylphosphonic$ acid attenuated the neuroprotective effects of Hwansodan(Huanshao-dan) in serum-deprived PCl2 cells. Conclusions : These results indicate that Ras/MEK/ERK signaling pathway plays a key role in neuroprotective effects of Hwansodan(Huanshao-dan) in serum-deprived PCl2 cells. Taken together, we suggest the possibility that Hwansodan(Huanshao-dan) might provide a neurotrophic-like activity in PCl2 cells.

• Korean Journal of Microbiology
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• v.47 no.2
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• pp.110-116
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• 2011

In the previous study with the Saccharomyces cerevisiae S288c strains, no known function of the dual specificity kinase, ScKns1, was reported because its gene deletion did not show any noticeable phenotypic changes. Recent study with fission yeast, however, revealed the involvement of the LAMMER kinase in flocculation, filamentous growth, oxidative stress, and so on. Therefore we made Sckns1-deletion mutants with the ${\Sigma}1278b$-background, with which one can induce filamentous and adhesive growth in contrast to those of the S288c-background. The $Sckns1{\Delta}$ strains of both haploid and diploid showed defect in filamentous growth under conditions for inducing the filamentous growth such as nitrogen starvation and butanol treatment. Both kinds of the deletion mutants also showed decrease in adhesive growth on agar surface. Interestingly enough the defects of the $Sckns1{\Delta}$ strains were suppressed by the over-expression of each gene for the components of the MAPK signaling pathway such as STE11, STE12, and TEC1, respectively, but not by the upstream components, RAS2 and STE20, respectively. Although further investigations are required, these results indicate that the ScKns1 may act in place between the Ste20 and the Ste11 of the S. cerevisiae MAPK cascade.

• Development and Reproduction
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• v.6 no.2
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• pp.77-82
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• 2002

In ascidians, a primitive chordate, maternal cytoplasmic factors and inductive interactions are involved in the specification of cell fates in early embryos. The larval structure of ascidians is relatively simple, and the major mesodermal tissues of the tadpole larva are notochord, muscle, and mesenchyme. Formation of muscle cells is a cell-autonomous process, and localized maternal macho-l mRNA specify muscle fate in the posterior marginal zone of the early embryo. In contrast, inductive influence from endoderm precursors plays important roles in the specification of notochord and mesenchyme fates. FGF-Ras-MAPK signaling is involved In the induction of both tissues. The difference in responsiveness of the posterior mesenchyme and anterior notochord precursors to FGF signaling is caused by the presence or absence of intrinsic factors that inherited from the posterior-vegetal egg cytoplasm, respectively. In these inductions, directed signal polarizes the induced cells and promotes asymmetric cell divisions to produce two daughter cells with distinct fates.

• BMB Reports
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• v.43 no.7
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• pp.485-490
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• 2010

Neurotrophins regulate many aspects of neuronal function through activation of the high affinity Trk receptors. Shc family proteins are implicated in the coupling of RTK to the Ras/mitogen-activated protein kinase signaling cascade. Here we report that the fourth Shc family member, ShcD, associates with TrkB receptor and regulates BDNF-induced MAPK activation. Yeast two-hybrid assay and Co-IP experiments demonstrate ShcD interacts with TrkB in a kinase-activity-dependent manner. Confocal analysis shows ShcD cololizes well with TrkB in transfected 293T cells. Subsequent mapping experiments and mutational analysis indicate that both PTB and SH2 domains are capable of binding to TrkB and PTB domain binds to TrkB NPQY motif. Furthermore, ShcD is involved in BDNF-induced MAPK activation. In summary, we demonstrate that ShcD is a substrate of TrkB and mediates TrkB downstream signaling pathway.

• Mycobiology
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• v.37 no.3
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• pp.161-170
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• 2009

Cryptococcus neoformans is a basidiomycete human fungal pathogen that causes meningoencephalitis in both immunocompromised and immunocompetent individuals. The ability to sense and respond to diverse extracellular signals is essential for the pathogen to infect and cause disease in the host. Four major stress-activated signaling (SAS) pathways have been characterized in C. neoformans, including the HOG (high osmolarity glycerol response), PKC/Mpk1 MAPK (mitogen-activated protein kinase), calcium-dependent calcineurin, and RAS signaling pathways. The HOG pathway in C. neoformans not only controls responses to diverse environmental stresses, including osmotic shock, UV irradiation, oxidative stress, heavy metal stress, antifungal drugs, toxic metabolites, and high temperature, but also regulates ergosterol biosynthesis. The PKC(protein kinase C)/Mpk1 pathway in C. neoformans is involved in a variety of stress responses, including osmotic, oxidative, and nitrosative stresses and breaches of cell wall integrity. The $Ca^{2+}$/calmodulin- and Ras-signaling pathways also play critical roles in adaptation to certain environmental stresses, such as high temperature and sexual differentiation. Perturbation of the SAS pathways not only impairs the ability of C. neoformans to resist a variety of environmental stresses during host infection, but also affects production of virulence factors, such as capsule and melanin. A drug(s) capable of targeting signaling components of the SAS pathway will be effective for treatment of cryptococcosis.

• Molecules and Cells
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• v.43 no.2
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• pp.153-159
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• 2020

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. NF1 patients are predisposed to formation of several type solid tumors as well as to juvenile myelomonocytic leukemia. Loss of NF1 results in dysregulation of MAPK, PI3K and other signaling cascades, to promote cell proliferation and to inhibit cell apoptosis. The RUNX1 gene is associated with stem cell function in many tissues, and plays a key role in the fate of stem cells. Aberrant RUNX1 expression leads to context-dependent tumor development, in which RUNX1 may serve as a tumor suppressor or an oncogene in specific tissue contexts. The co-occurrence of mutation of NF1 and RUNX1 is detected rarely in several cancers and signaling downstream of RAS-MAPK can alter RUNX1 function. Whether aberrant RUNX1 expression contributes to NF1-related tumorigenesis is not fully understood. This review focuses on the role of RUNX1 in NF1-related tumors and blood disorders, and in sporadic cancers.

• Molecular & Cellular Toxicology
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• v.4 no.2
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• pp.113-123
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• 2008

Microglia, which is the primary immune effector cells in the central nervous system, constitutes the first line of defense against infection and injury in the brain. The goal of this study was to determine the protective (anti-inflammation) mechanisms of forsythia suspense (FS) on LPS-induced activation of BV-2 microglial cells. The effects of FS on gene expression profiles in activated BV-2 microglial cells were evaluated using microarray analysis. BV-2 microglial cells were cultured in a 100mm dish $(1{\times}10^7/dish)$ for 24hr and then pretreated with $1{\mu}g/mL$ FS or left untreated for 30 min. Next, $1{\mu}g/mL$ LPS was added to the samples and the cells were reincubated at $37^{\circ}C$ for 30 min, 1hr, and 3hr. The gene expression profiles of the BV-2 microglial cells varied depending on the FS. The oligonucleotide microarray analysis revealed that MAPK pathway-related genes such as Mitogen activated protein kinase 1 (Mapk1), RAS protein activator like 2 (Rasal2), and G-protein coupled receptor 12 (Gpr12) and nitric oxide biosynthesis-related genes such as nitric oxide synthase 1 (neuronal) adaptor protein (Nos1ap), and dimethylarginine dimethylaminohydrolase 1 (Ddah1) were down regulated in FS-treated BV-2 microglial cells. FS can affect the MAPK pathway and nitric oxide biosynthesis in BV-2 microglial cells.