• BMB Reports
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• 제37권4호
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• pp.402-407
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• 2004

A human gene T-complex protein 10 like (TCP10L) was cloned in our lab. A previous study showed that it expressed specifically in the liver and testis. A transcription experiment revealed that TCP10L was a transcription factor with transcription inhibition activity. In this study, the human MAD4 was identified to interact with TCP10L by a yeast two-hybrid screen. This finding was confirmed by immunoprecipitation and subcellular localization experiments. As MAD4 is a member of the MAD family, which antagonizes the functions of MYC and promotes cell differentiation, the biological function of the interaction between TCP10L and MAD4 may be to maintain the differentiation state in liver cells. Also, we propose that the up-regulation of Myc is caused by the down-regulation of TCP10L in human hepatocarcinomas.

• BMB Reports
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• 제52권3호
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• pp.220-225
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• 2019

We have identified a mechanism to diminish the proliferative capacity of cells during cell expansion using human adipose-derived stromal cells (hAD-SCs) as a model of replicative senescence. hAD-SCs of high-passage numbers exhibited a reduced proliferative capacity with accelerated cellular senescence. Levels of key bioactive sphingolipids were significantly increased in these senescent hAD-SCs. Notably, the transcription of sphingosine kinase 1 (SPHK1) was down-regulated in hAD-SCs at high-passage numbers. SPHK1 knockdown as well as inhibition of its enzymatic activity impeded the proliferation of hAD-SCs, with concomitant induction of cellular senescence and accumulation of sphingolipids, as seen in high-passage cells. SPHK1 knockdown-accelerated cellular senescence was attenuated by co-treatment with sphingosine-1-phosphate and an inhibitor of ceramide synthesis, fumonisin $B_1$, but not by treatment with either one alone. Together, these results suggest that transcriptional down-regulation of SPHK1 is a critical inducer of altered sphingolipid profiles and enhances replicative senescence during multiple rounds of cell division.

• 대한본초학회지
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• 제28권1호
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• pp.33-42
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• 2013

Objective : Morus alba Linne Root Bark (MRAL) is a medicinal herb in Korean Medicine, known for its anti-inflammatory and anti-allergic properties. However, its mechanisms of action and the cellular targets have not yet been found and the study was developed to investigate the allergic suppressive effect of MRAL. The purpose of this study is to investigate the allergic suppressive effects of MRAL on activation of MC/9 mast cells. Methods : Cytotoxic activity of MRAL (50, 100, 200, 400 ${\mu}g/mL$) on MC/9 mast cells measured using EZ-Cytox cell viability assay kit (WST reagent). The levels of interleukin-5 (IL-5), IL-13 and IL-4, IL-5, IL-6, IL-13 mRNA expression were measured by enzyme-linked immunosorbent assay (ELISA) and real-time PCR respectively. The expression of transcription factors such as GATA-1, GATA-2, NFAT, AP-1 and NF-${\kappa}B$ p65 DNA binding activity were measured by western blot and electrophoresis mobility shift assay (EMSA). Results : Our results indicated that MRAL (50 ${\mu}g/mL$, 100 ${\mu}g/mL$) significantly inhibited PMA/Ionomycin-induced production of IL-5 and IL-13 and the expression of IL-4, IL-5, IL-6 and IL-13 mRNA in MC/9 mast cells. Moreover, MRAL (50 ${\mu}g/mL$, 100 ${\mu}g/mL$) inhibited PMA/Ionomycin-induced GATA-1, GATA-2, NFAT-1, NFAT-2, c-Fos protein expression and NF-${\kappa}B$ p65 DNA binding activity in MC/9 mast cells. Conclusions : In conclusion, we suspect the anti-allergenic activities of MRAL, may be related to the regulation of transcription factors GATA-1, GATA-2, NFAT-1, NFAT-2, c-Fos and NF-${\kappa}B$ p65 DNA binding assay causing inhibition of Th2 cytokines IL-5 and IL-13 in mast cells.

• Parasites, Hosts and Diseases
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• 제62권1호
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• pp.30-41
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• 2024

The dense granule protein of Toxoplasma gondii, inhibitor of signal transducer and activator of transcription 1 (IST) is an inhibitor of signal transducer and activator of transcription 1 (STAT1) transcriptional activity that binds to STAT1 and regulates the expression of inflammatory molecules in host cells. A sterile inflammatory liver injury in pathological acute liver failures occurs when excessive innate immune function, such as the massive release of IFN-γ and TNF-α, is activated without infection. In relation to inflammatory liver injury, we hypothesized that Toxoplasma gondii inhibitor of STAT1 transcription (TgIST) can inhibit the inflammatory response induced by activating the STAT1/IRF-1 mechanism in liver inflammation. This study used IFN-γ and TNF-α as inflammatory inducers at the cellular level of murine hepatocytes (Hepa-1c1c7) to determine whether TgIST inhibits the STAT1/IRF-1 axis. In stable cells transfected with TgIST, STAT1 expression decreased with a decrease in interferon regulatory factor (IRF)-1 levels. Furthermore, STAT1 inhibition of TgIST resulted in lower levels of NF-κB and COX2, as well as significantly lower levels of class II transactivator (CIITA), iNOS, and chemokines (CLXCL9/10/11). TgIST also significantly reduced the expression of hepatocyte proapoptotic markers (Caspase3/8/9, P53, and BAX), which are linked to sterile inflammatory liver injury. TgIST also reduced the expression of adhesion (ICAM-1 and VCAM-1) and infiltration markers of programmed death-ligand 1 (PD-L1) induced by hepatocyte and tissue damage. TgIST restored the cell apoptosis induced by IFN-γ/TNF-α stimulation. These results suggest that TgIST can inhibit STAT1-mediated inflammatory and apoptotic responses in hepatocytes stimulated with proinflammatory cytokines.

• 생명과학회지
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• 제26권3호
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• pp.359-363
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• 2016

한약진흥재단(NIKOM)의 640-천연물 라이브러리를 PC12세포에 10 μg/ml/day로 처리하였다. 면역강화에 관여하는 ERAP1 (Endoplasmic Reticulum AminoPeptidase 1)과 수명연장에 관여하는 FOXO1 (FOXO-family transcription factor) 유전자발현을 RT-PCR로 확인하였다. ERAP1 유전자를 1.5-2배까지 상승시킨 것은 22개, 2배 이상 발현시킨 것은 14개였다. FOXO1 유전자를 1.5-2배까지 상승시킨 것은 총 24개, 2배 이상 발현시킨 것은 4개였다. 동시에 ERAP1과 FOXO1 유전자를 2배 이상 상승시키는 것은 족도리풀(Asiasari radix)에서 분리된 (±)-Car-3-ene-2,5-dione, 두꺼비(Bufonis venenum)에서 분리된 Cinobufagin, 대국(Euphorbiae pekinensis)에서 분리된 Corilagin, 현호색(Corydalis tuber)에서 분리된 Corydaline 4종이다. 이들 4종의 천연물은 초파리를 이용한 개체의 수명연장실험에 사용될 것이다.

• 한국식품과학회지
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• 제51권6호
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• pp.558-564
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• 2019

Hypertriglyceridemia is one of the metabolic syndrome that is often observed as a result of lipid abnormalities. It is associated with other lipids, metabolic disorders, cardiovascular disease and liver disease. Korean red ginseng is known to affect obesity, dyslipidemia, liver disease and liver function, but the mechanism of its effect is not clear. This study examined the beneficial effects of hypertriglyceridemia and the mechanism of action of Jinan red ginseng extract (JRG) in hepatoma cells. To measure the levels of triglyceride accumulation, we studied the expression of proteins and mRNAs related to lipidogenesis in hepatoma cells (Huh7 and HepG2). JRG decreases the lipidogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding proteins α (C/EBPα) and C/EBPβ which are major regulators of triglyceride synthesis in hepatoma cells. We also found that JRG reduced sterol regulatory element binding proteins 1c (SREBP-1c), C/EBPα and C/EBPβ by regulating liver X receptor (LXR) and stearoyl CoA desaturase (SCD) expressions. In addition, the first-limited step of synthesis triglyceride (TG), glycerol-3-phosphate (G3P) is decreased by JRG. These results suggest that the anti-hypertriglyceride effect of JRG in hepatoma cells could be accompanied with the inhibition of lipidogenic transcription factors by regulating LXR and SCD expression.

• BMB Reports
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• 제51권9호
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• pp.425-426
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• 2018

As highly conserved signaling cascades of multicellular organisms, Wnt and Hippo pathways control a wide range of cellular activities, including cell adhesion, fate determination, cell cycle, motility, polarity, and metabolism. Dysregulation of those pathways are implicated in many human diseases, including cancer. Similarly to ${\beta}-catenin$ in the Wnt pathway, the YAP transcription co-activator is a major player in Hippo. Although the intracellular dynamics of YAP are well-known to largely depend on phosphorylation by LATS and AMPK kinases, the molecular effector of YAP cytosolic translocation remains unidentified. Recently, we reported that the Dishevelled (DVL), a key scaffolding protein between canonical and non-canonical Wnt pathway, is responsible for nuclear export of phosphorylated YAP. The DVL is also required for YAP intracellular trafficking induced by E-cadherin, ${\alpha}-catenin$, or metabolic stress. Note that the p53/LATS2 and LKB1/AMPK tumor suppressor axes, commonly inactivated in human cancer, govern the reciprocal inhibition between DVL and YAP. Conversely, loss of the tumor suppressor allows co-activation of YAP and Wnt independent of epithelial polarity or contact inhibition in human cancer. These observations provide novel mechanistic insight into (1) a tight molecular connection merging the Wnt and Hippo pathways, and (2) the importance of tumor suppressor contexts with respect to controlled proliferation and epithelial polarity regulated by cell adhesion.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7439-7444
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• 2013

Aim: ATF3, a member of the ATF/CREB family of transcription factors, has been found to be selectively induced by calcineurin/NFAT inhibition and to enhance keratinocyte tumor formation, although the precise role of ATF3 in human skin cancer and possible mechanisms remain unknown. Methods: In this study, clinical analysis of 30 skin cancer patients and 30 normal donors revealed that ATF3 was accumulated in skin cancer tissues. Functional assays demonstrated that ATF3 significantly promoted skin cancer cell proliferation. Results: Mechanically, ATF3 activated Stat3 phosphorylation in skin cancer cell through regulation of p53 expression. Moreover, the promotion effect of ATF3 on skin cancer cell proliferation was dependent on the p53-Stat3 signaling cascade. Conclusion: Together, the results indicate that ATF3 might promote skin cancer cell proliferation and enhance skin keratinocyte tumor development through inhibiting p53 expression and then activating Stat3 phosphorylation.

• BMB Reports
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• 제46권1호
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• pp.59-64
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• 2013

Signal transducer and activator of transcription 3 (STAT3) and telomerase are considered attractive targets for anticancer therapy. The in vitro anticancer activity of the gold(I) compound auranofin was investigated using MDA-MB 231 human breast cancer cells, in which STAT3 is constitutively active. In cell culture, auranofin inhibited growth in a dose-dependent manner, and N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), markedly blocked the effect of auranofin. Incorporation of 5-bromo-2'-deoxyuridine into DNA and anchorage-independent cell growth on soft agar were decreased by auranofin treatment. STAT3 phosphorylation and telomerase activity were also attenuated in cells exposed to auranofin, but NAC pretreatment restored STAT3 phosphorylation and telomerase activity in these cells. These findings indicate that auranofin exerts in vitro antitumor effects in MDA-MB 231 cells and its activity involves inhibition of STAT3 and telomerase. Thus, auranofin shows potential as a novel anticancer drug that targets STAT3 and telomerase.

• 약학회지
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• 제49권5호
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• pp.428-436
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• 2005

DNA topoisomerase I(TOP1) helps the control of DNA replication, transcription and recombination by assist­ing breaking and rejoining of DNA double strand. Camptothecin (CPT) and its derivative, topotecan, are known to inhibit TOP1 by intercalating into TOP1-DNA complex. Recently various non-CPT intercalators are synthesized for a new class of TOP1 inhibitors. In this study, six compounds isolated from Poria cocos were investigated for their interaction with TOP1­DNA complex using the flexible docking program, FlexiDock. The binding modes were analyzed and compared with the TOP1 inhibition activities. The compounds that showed potent activity were intercalated between the + 1/-1 base pairs of DNA, located near the active site phosphotyrosine723 and formed hydrogen bonds with active site residues. On the other hand, compounds with no activity were not docked at all. The binding modes were well correlated with the inhibition activity, suggesting the possibility that potent inhibitors can be designed from the information presented by the docking study.