• 생명과학회지
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• 제30권9호
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• pp.826-833
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• 2020

Phospholipase C gamma (PLCγ)는 phosphatidylinositol을 가수분해하여 신호전달 과정에 참여하는 PLC의 주요한 isotype으로 γ-specific array의 특징적인 구조를 바탕으로 receptor tyrosine kinases 및 non-receptor tyrosine kinase 신호를 주로 매개한다. PLCγ1과 PLCγ2의 두 isozyme이 존재하며 다양한 세포에서 발현하여 cell proliferation, migration 및 differentiation 등 여러 세포작용을 조절하고 있다. 최근의 연구들에서 PLCγ 돌연변이가 cancer와 immune disease 및 brain disorder 등에 연관된다는 것이 밝혀지고 있으며 genetic model을 통해 PLCγ의 생리적·병리적 기능이 제시되었다. 본 리뷰에서는 최신의 연구 결과들을 바탕으로 PLCγ의 구조와 활성 조절 기전에 대해 기술하고 나아가 여러 질병의 발병과 진행에서 보고된 PLCγ의 돌연변이와 knockout 마우스를 활용한 연구 결과를 바탕으로 생리적·병리적 관점에서 PLCγ의 역할에 대해 고찰하였다.

• Parasites, Hosts and Diseases
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• 제58권3호
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• pp.237-247
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• 2020

Dendritic cell is one of the first innate immune cell to encounter T. gondii after the parasite crosses the host intestinal epithelium. T. gondii requires intact DC as a carrier to infiltrate into host central nervous system (CNS) without being detected or eliminated by host defense system. The mechanism by which T. gondii avoids innate immune defense of host cell, especially in the dendritic cell is unknown. Therefore, we examined the role of host PI3K/AKT signaling pathway activation by T. gondii in dendritic cell. T. gondii infection or T. gondii excretory/secretory antigen (TgESA) treatment to the murine dendritic cell line DC2.4 induced AKT phosphorylation, and treatment of PI3K inhibitors effectively suppressed the T. gondii proliferation but had no effect on infection rate or invasion rate. Furthermore, it is found that T. gondii or TgESA can reduce H₂O₂-induced intracellular reactive oxygen species (ROS) as well as host endogenous ROS via PI3K/AKT pathway activation. While searching for the main source of the ROS, we found that NADPH oxidase 4 (NOX4) expression was controlled by T. gondii infection or TgESA treatment, which is in correlation with previous observation of the ROS reduction by identical treatments. These findings suggest that the manipulation of the host PI3K/AKT signaling pathway and NOX4 expression is an essential mechanism for the down-regulation of ROS, and therefore, for the survival and the proliferation of T. gondii.

• Biomolecules & Therapeutics
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• 제22권2호
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• pp.129-135
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• 2014

Previously, we reported that lysophosphatidylethanolamine (LPE), a lyso-type metabolite of phosphatidylethanolamine, can increase intracellular $Ca^{2+}$ ($[Ca^{2+}]_i$) via type 1 lysophosphatidic acid (LPA) receptor ($LPA_1$) and CD97, an adhesion G-protein-coupled receptor (GPCR), in MDA-MB-231 breast cancer cells. Furthermore, LPE signaling was suggested as like $LPA_1/CD97-G_{i/o}$ proteins-phospholipase $C-IP_3-Ca^{2+}$ increase in these cells. In the present study, we further investigated actions of LPE not only in the $[Ca^{2+}]_i$ increasing effect but also in cell proliferation and migration in MDA-MB-231 breast cancer cells. We utilized chemically different LPEs and a specific inhibitor of $LPA_1$, AM-095 in comparison with responses in SK-OV3 ovarian cancer cells. It was found that LPE-induced $Ca^{2+}$ response in MDA-MB-231 cells was evoked in a different manner to that in SK-OV3 cells in terms of structural requirements. AM-095 inhibited LPE-induced $Ca^{2+}$ response and cell proliferation in MDA-MB-231 cells, but not in SK-OV3 cells, supporting $LPA_1$ involvement only in MDA-MB-231 cells. LPA had significant effects on cell proliferation and migration in MDA-MB-231 cells, whereas LPE had less or no significant effect. However, LPE modulations of MAPKs (ERK1/2, JNK and p38 MAPK) was not different to those by LPA in the cells. These data support the involvement of LPA1 in LPE-induced $Ca^{2+}$ response and cell proliferation in breast MDA-MB-231 cells but unknown GPCRs (not $LPA_1$) in LPE-induced responses in SK-OV3 cells. Furthermore, although LPE and LPA utilized $LPA_1$, LPA utilized more signaling cascades than LPE, resulting in stronger responses by LPA in proliferation and migration than LPE in MDA-MB-231 cells.

• BMB Reports
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• 제44권1호
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• pp.58-63
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• 2011

Zinc finger (ZNF) proteins play a critical role in cell growth, proliferation, apoptosis, and intracellular signal transduction. In this paper, we cloned and characterized a novel human KRAB-related zinc finger gene, ZNF425, which encodes a protein of 752 amino acids. ZNF425 is strongly expressed in the three month old human embryos and then is almost undetectable in six month old embryos and in adult tissues. An EGFP-ZNF425 fusion protein can be found in both the nucleus and the cytoplasm. ZNF425 appears to act as a transcription repressor. Over-expression of ZNF425 inhibits the transcriptional activities of SRE, AP-1, and SRF. Deletion analysis indicates that the C2H2 domain is the main region responsible for the repression. Our results suggest that the ZNF425 gene is a new transcriptional inhibitor that functions in the MAPK signaling pathway.

• Molecules and Cells
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• 제38권11호
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• pp.982-990
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• 2015

Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-${\beta}$-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti-inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF-${\kappa}B$) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-${\kappa}B$ signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage.

• 생명과학회지
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• 제33권11호
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• pp.859-867
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• 2023

루페올은 5환성 트리테르펜의 일종으로 많은 질병에 치료 효과가 있는 것으로 보고되었으나, 인슐린 저항성에 미치는 영향은 명확하지 않다. 본 연구에서는 3T3-L1 지방세포에서 루페올의 IRS-1 인산화 억제능을 통해 인슐린 저항성 개선효과를 조사하였다. 3T3-L1 세포를 배양하고 TNF-α를 24시간 동안 처리하여 인슐린 저항성을 유도하였다. 서로 다른 농도의 루페올(15, 30 μM) 또는 100 nM의 rosiglitazone을 처리한 세포를 배양한 후, 용해된 세포를 이용하여 western blotting을 시행하였다. 실험결과 루페올은 지방세포에서 TNF-α에 의해 유발되는 인슐린 신호전달의 음성 조절자와 염증 활성화 단백질 kinase에 대한 개선 효과를 나타냈다. 인슐린 신호전달의 음성 조절자인 PTP-1B와 JNK의 활성 및 IKK와 염증활성화 단백질키나아제의 활성을 억제하였다. 또한, 루페올은 IRS-1의 serine 인산화는 하향 조절하고 tyrosine 인산화는 상향 조절하였다. 그 후, 하향 조절된 PI3K/AKT 경로가 활성화되고, GLUT 4의 세포막 전위가 자극되어, 결과적으로 인슐린 저항성이 유도된 3T3-L1 지방세포에서에서 세포내 포도당 흡수가 증가하였다. 본 연구결과, 루페올은 3T3-L1 지방세포에서 인슐린 신호전달 및 염증 활성화 단백질 kinsase들의 음성 조절인자를 억제하여, IRS-1의 serine 인산화를 하향 조절함으로써 TNF-α 유발 인슐린 저항성을 개선할 수 있을 것으로 사료된다.

• 생명과학회지
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• 제28권2호
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• pp.265-273
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• 2018

에스트로겐(E2)은 유방암의 발달과 진행에 관여하며, 에스트로겐 수용체(ER)에 의해 매개된다. ER은 유방암세포에서 epidermal growth factor receptor와 insulin-like growth factor-1 receptor의 신호전달경로들 사이에서 다양한 cross-talk을 통하여 세포의 증식, 이주, 침습 및 약물에 대한 저항성을 일으키는데 중요한 역할을 수행한다. 유방암은 내분비신호전달의 항상성 붕괴에 의해 주로 발생되며, 특히 E2/IGF-1/EGF와 ER/G-protein estrogen receptor (GPER)/IGF-1R/EGFR, 그리고 이들의 세포내 신호전달 매개인자들의 통제되지 않는 발현과 활성증가에 의해 유발된다. 이러한 변화는 E2와 성장인자 신호전달 사이의 복잡한 cross-talk에 영향을 주어 결국 암의 진행과 내분비조절인자들에 대한 저항성을 갖게 된다. 따라서, E2와 성장인자들 사이의 cross-talk에 관한 분자적 기전을 단계별로 규명하는 것은 유방암의 다양한 유형에 따른 맞춤형 치료에 기여할 것으로 사료된다. 특히, 다양한 유전형 및 표현형을 가진 유방암의 치료를 위한 전략으로서, ER+ 호르몬의존성 유방암세포에 대한 aromatase 억제제 및 E2작용 차단제의 사용과 E2와 성장인자들 사이의 cross-talk에 의한 암세포의 증식억제를 위한 IGF-1R/EGFR 활성차단제의 사용 등을 들 수 있다. 뿐만 아니라, ER과 EGFR/IGF-1R 사이의 cross-talk에 의해 조절되는 ECM 분자들의 발현변화는 유방암세포의 전이에 대한 표적치료제를 위해 활용될 수 있다. 따라서, 암의 진행과 관련된 ER, GPER, IGF-1R 및 EGFR 매개에 의한 신호전달경로들 사이의 cross-talk에 관한 보다 더 자세한 분자적 수준의 규명이 필요할 것으로 사료된다.

• 생명과학회지
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• 제25권8호
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• pp.947-952
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• 2015

Par-4는 종양 억제 유전자로 암세포 선택적으로 세포사멸을 증진하는 기능을 가진다. Par-4 유전자는 nuclear localization sequences (NLS), leucine zipper (LZ), nuclear export sequence (NES), selective for apoptosis in cancer cells (SAC)의 네 가지 도메인을 가지고 있다. 이 중에서도 SAC 도메인이 Par-4에 의한 세포사멸에 중요한 역할을 하며, 이러한 Par-4의 활성화는 세포 내 경로와 세포 외 경로로 나누어진다. 세포질 내의 Par-4는 핵 내로 이동하여 NF-κB 매개의 세포 성장 경로를 억제하고 세포 밖으로 분비된 Par-4는 세포 표면에 존재하는 수용체인 GRP78과 결합하여 세포 사멸을 유도한다. 따라서 Par-4의 발현을 증가시키는 물질에 의한 세포 사멸뿐만 아니라 암세포에서 발현이 낮은 Par-4의 과발현을 통하여 세포사멸 민감화가 증진된다. 따라서 Par-4는 암 치료의 강력한 표적으로의 가능성을 가지고 있다.

• 대한화장품학회:학술대회논문집
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• 대한화장품학회 2003년도 IFSCC Conference Proceeding Book I
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• pp.13-34
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• 2003

Fructose-1, 6-diphosphate (FOP), a glycolytic metabolite is reported to ameliorate inflammation and inhibit the nitric oxide production in murine macrophages stimulated with endotoxin. It is also reported that FOP has cytoprotective effects against hypoxia or ischemia/reperfusion injury in brain and heart. In this study, we examined whether FDP has protective effects on UV-induced oxidative damage in skin cell culture system and human skin in vivo. FDP had a protective role in UVB-induced LDH release and ROS accumulation in HaCaT although it did not show direct radical scavenging effect in the experiment using 1, 1-diphenyl-2-picrylhydrazyl (DPPH). FDP also preserved cellular GSH content after UV irradiation in HaCaT and normal human fibroblast culture system. Cellular oxidative stress induces multiple downstream signaling pathways that regulate expression of multiple gene including MMP-1 and collagen, we examined the effects of FDP on UV-induced alteration of these protein expression in fibroblast culture and human skin in vivo. The increased MMP-1 expression in fibroblast and human skin by UV irradiation was significantly decreased by FDP. FDP also prevented the UV-induced decrease of collagen expression in fibroblast and human skin. Moreover, the decreasing the intracellular levels of reducing equivalents in human fibroblast by glutathione (GSH) depletion lowered the UVA dose threshold for reduction of procollagen expression, indicating that the differences of glutathione contents define the susceptibility of fibroblasts towards UV-induced reduction of procollagen expression. FDP also preserved cellular GSH content after UV irradiation, indicating that FDP has protective effects on UV-induced reduction of procollagen expression, which are possibly through maintaining intracellular reducing equivalent. Based on these premises, we examined the effect of daily use of a moisturizer containing FDP on facial wrinkle in comparison with vehicle moisturizer lacking FDP. In the clinical study, FDP significantly decreased facial wrinkle compared with vehicle alone after 6 months of use. Our results suggest that FDP has anti-aging effects in skin by increasing cellular antioxidant system and preventing oxidative signal and inflammatory reaction. Therefore FDP may be useful anti-aging agent for cosmetic purpose.

• Biomolecules & Therapeutics
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• 제24권5호
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• pp.543-551
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• 2016

This study was designed to evaluate the pharmacological effects of Vaccinium bracteatum Thunb. methanol extract (VBME) on microglial activation and to identify the underlying mechanisms of action of these effects. The anti-inflammatory properties of VBME were studied using lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We measured the production of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase (COX)-2, prostaglandin $E_2$ ($PGE_2$), tumor necrosis factor-alpha (TNF-${\alpha}$), interleukin-1 beta (IL-$1{\beta}$), and interleukin-6 (IL-6) as inflammatory parameters. We also examined the effect of VBME on intracellular reactive oxygen species (ROS) production and the activity of nuclear factor-kappa B p65 (NF-${\kappa}B$ p65). VBME significantly inhibited LPS-induced production of NO and $PGE_2$ and LPS-mediated upregulation of iNOS and COX-2 expression in a dose-dependent manner; importantly, VBME was not cytotoxic. VBME also significantly reduced the generation of the pro-inflammatory cytokines TNF-${\alpha}$, IL-$1{\beta}$, and IL-6. In addition, VBME significantly dampened intracellular ROS production and suppressed NF-${\kappa}B$ p65 translocation by blocking $I{\kappa}B-{\alpha}$ phosphorylation and degradation in LPS-stimulated BV2 cells. Our findings indicate that VBME inhibits the production of inflammatory mediators in BV-2 microglial cells by suppressing NF-${\kappa}B$ signaling. Thus, VBME may be useful in the treatment of neurodegenerative diseases due to its ability to inhibit inflammatory mediator production in activated BV-2 microglial cells.