• BMB Reports
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• v.51 no.3
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• pp.157-162
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• 2018

Angiogenesis is a complex, multistep process involving dynamic changes in endothelial cell (EC) shapes and behaviors, especially in specialized cell types such as tip cells (with active filopodial extensions), stalk cells (with less motility) and phalanx cells (with stable junction connections). The Hippo-Yes-associated protein (YAP)/ transcription activator with PDZ binding motif (TAZ) signaling plays a critical role in development, regeneration and organ size by regulating cell-cell contact and actin cytoskeleton dynamics. Recently, with the finding that YAP is expressed in the front edge of the developing retinal vessels, Hippo-YAP/TAZ signaling has emerged as a new pathway for blood vessel development. Intriguingly, the LATS1/2-mediated angiomotin (AMOT) family and YAP/TAZ activities contribute to EC shapes and behaviors by spatiotemporally modulating actin cytoskeleton dynamics and EC junction stability. Herein, we summarize the recent understanding of the role of Hippo-YAP/TAZ signaling in the processes of EC sprouting and junction maturation in angiogenesis.

• BMB Reports
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• v.51 no.5
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• pp.209-210
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• 2018

NAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment. Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis still remain unclear. Here, we found that depletion of both PTEN and SAV1 in liver promotes spontaneous NAFLD and liver cancer through hyperactive AKT via YAP/TAZ-mediated up-regulation of IRS2 transcription. Conversely, NAFLD is rescued by both ablation of YAP/TAZ and activation of the Hippo pathway. Furthermore, human HCC patients with NAFLD showed strong correlation between YAP/TAZ and IRS2 or phospho-AKT expression. Finally, the inhibition of AKT by MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings indicate that Hippo pathway interacts with AKT signaling during the intervention with IRS2 to prevent NAFLD and liver cancer.

• BMB Reports
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• v.50 no.6
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• pp.281-282
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• 2017

Advances in the understanding of the Hippo signaling as a key regulatory pathway of proliferation and apoptosis have provided mechanical insights for controlling organ size and tumorigenicity. Recently, much attention has been directed to the regulation of LATS1/2 (large tumor suppressor) kinases that phosphorylate YAP/TAZ, a transcriptional co-activator in the Hippo pathway, and control the level and nuclear localization of YAP/TAZ. In our recent work, we showed that deubiquitinase YOD1 stabilizes ITCH, and facilitates ITCH-mediated LATS1/2 ubiquitination and degradation, resulting in increased YAP/TAZ level. Furthermore, we found that the YOD1-ITCH-LATS1/2-YAP/TAZ signaling axis is controlled by the differential expression of miR-21 in a cell-density-dependent manner. Using a transgenic mouse model, we showed that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, a strong correlation was observed between YOD1 and YAP expression in liver cancer patients. Overall, our data suggest that YOD1 is a novel regulator of the Hippo pathway, and thereby a potential therapeutic target for liver cancer.

• Proceedings of the KIEE Conference
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• 2004.07c
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• pp.1564-1566
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• 2004

BCP의 이온화에너지 (Ionization Potential; IP)는 5.72ev와 전자친화도 (Electron Affinity; EA)는 2.85ev이며, PEDOT의 IP=5.74ev와 EA=3.3sev이고, TAZ의 IP=6.45ev와 EA=2.77ev, TPD는 IP=5.75ev와 EA=2.S8eV를 나타내었다. 그리고 BCP와 TAZ는 산화전위의 시작점과 증가곡선의 전위 변곡점과의 차이(정공층 갭)와 환원전위의 시작점과 변곡점의 차이(전자층 갭)가 서로 비슷하였으며, PEDOT과 TPD의 경우 정공층의 갭이 전자층의 갭보다 크게 나타났다.

• BMB Reports
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• v.50 no.1
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• pp.1-2
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• 2017

Acquiring a selective growth advantage by breaking the proliferation barrier established by gatekeeper genes is a centrally important event in tumor formation. Removal of the mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper that restrains abnormal growth in hepatocytes. By rigorous genetic approaches, we identified an interacting network of the Hippo, Wnt/${\beta}$-catenin and Notch signaling pathways that control organ size and HCC development. We found that in hepatocytes, the loss of Mst1/2 leads to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz (transcription factors controlled by Mst1/2). This positive feedback loop results in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition in vivo significantly reduced the Yap/Taz activities, hepatocyte proliferation and tumor formation. Furthermore, we uncovered a surprising inhibitory role of Wnt/${\beta}$-catenin signaling to Yap/Taz activities, which are important in tumor initiation. Genetic removal of ${\beta}$-catenin in the liver of the Mst1/2 mutants significantly accelerates tumoriogenesis. Therefore, Wnt/${\beta}$-catenin signaling, known for its oncogenic property, exerts an unexpected function in restricting Yap/Taz and Notch activities in HCC initiation. The molecular interplay between the three signaling pathways identified in our study provides new insights in developing novel therapeutic strategies to treat liver tumors.

• Molecules and Cells
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• v.44 no.7
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• pp.458-467
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• 2021

GPR43 (also known as FFAR2 or FFA2) is a G-protein-coupled receptor primarily expressed in immune cells, enteroendocrine cells and adipocytes that recognizes short-chain fatty acids, such as acetate, propionate, and butyrate, likely to be implicated in innate immunity and host energy homeostasis. Activated GPR43 suppresses the cAMP level and induces Ca²⁺ flux via coupling to Gα_i and Gα_q families, respectively. Additionally, GPR43 is reported to facilitate phosphorylation of ERK through G-protein-dependent pathways and interacts with β-arrestin 2 to inhibit NF-κB signaling. However, other G-protein-dependent and independent signaling pathways involving GPR43 remain to be established. Here, we have demonstrated that GPR43 augments Rho GTPase signaling. Acetate and a synthetic agonist effectively activated RhoA and stabilized YAP/TAZ transcriptional coactivators through interactions of GPR43 with Gα_q/11 and Gα_12/13. Acetate-induced nuclear accumulation of YAP was blocked by a GPR43-specific inverse agonist. The target genes induced by YAP/TAZ were further regulated by GPR43. Moreover, in THP-1-derived M1-like macrophage cells, the Rho-YAP/TAZ pathway was activated by acetate and a synthetic agonist. Our collective findings suggest that GPR43 acts as a mediator of the Rho-YAP/TAZ pathway.

• Proceedings of the Materials Research Society of Korea Conference
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• 2008.05a
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• pp.37.1-37.1
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• 2008

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4549-4553
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• 2014

Background: Infection is a serious cause of mortality in febrile neutropenia of pediatric cancer patients. Recently, monotherapy has replaced the combination therapy in empirical treatment of febrile neutropenia. Since there has been no reported trial comparing the efficacy of meropenem and piperacillin-tazobactam (PIP/TAZ) monotherapies, the present retrospective study was conducted to compare safety and efficacy in febrile neutropenic children with cancer. Materials and Methods: Charts of febrile, neutropenic children hospitalized at our center between March 2008 and April 2011 for hemato-oncological malignancies were reviewed. Patients received PIP/TAZ 360 mg/kg/day or meropenem 60 mg/kg/day intravenously in three divided doses. Duration of fever and neutropenia, absolute neutrophil count, modification, and success rate were compared between the two groups. Resolution of fever without antibiotic change was defined as success and resolution of fever with antibiotic change or death of a patient was defined as failure. Modification was defined as changing the empirical antimicrobial agent during a febrile episode. Results: Two hundred eighty four febrile neutropenic episodes were documented in 136 patients with a median age of 5 years. In 198 episodes meropenem and in 86 episodes PIP/TAZ were used. Duration of fever and neutropenia, neutrophil count, sex, and primary disease were not different between two groups. Success rates and modification rate between two groups showed no significant differences (p>0.05). Overall success rate in the meropenem and PIP/TAZ groups were 92.4% and 91.9% respectively. No serious adverse effects occurred in either of the groups. Conclusions: Meropenem and PIP/TAZ monotherapy are equally safe and effective in the initial treatment of febrile neutropenia in children with cancer.

• Molecules and Cells
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• v.43 no.5
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• pp.491-499
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• 2020

Hippo signaling acts as a tumor suppressor pathway by inhibiting the proliferation of adult stem cells and progenitor cells in various organs. Liver-specific deletion of Hippo pathway components in mice induces liver cancer development through activation of the transcriptional coactivators, YAP and TAZ, which exhibit nuclear enrichment and are activated in numerous types of cancer. The upstream-most regulators of Warts, the Drosophila ortholog of mammalian LATS1/2, are Kibra, Expanded, and Merlin. However, the roles of the corresponding mammalian orthologs, WWC1, FRMD6 and NF2, in the regulation of LATS1/2 activity and liver tumorigenesis in vivo are not fully understood. Here, we show that deletion of both Wwc1 and Nf2 in the liver accelerates intrahepatic cholangiocarcinoma (iCCA) development through activation of YAP/TAZ. Additionally, biliary epithelial cell-specific deletion of both Lats1 and Lats2 using a Sox9-Cre^ERT2 system resulted in iCCA development through hyperactivation of YAP/TAZ. These findings suggest that WWC1 and NF2 cooperate to promote suppression of cholangiocarcinoma development by inhibiting the oncogenic activity of YAP/TAZ via LATS1/2.

• Transactions on Electrical and Electronic Materials
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• v.12 no.2
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• pp.84-87
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• 2011

We fabricated phosphorescent organic light-emitting devices with a 1,1-bis[(di-4-tolylamino)phenyl]cyclohexane (TAPC) host layer. Two kinds of devices, one of ITO/TAPC/TAPC:FIrpic/TAZ/LiF/Al (device A) and one of ITO/TAPC:FIrpic/TAPC/TAZ/LiF/Al (device B), were prepared to investigate electrical and optical properties. Iridium(III) bis[(4,6-difluorophenyl)-pyridinato-N,$C^{2'}$]picolinate (FIrpic) and 3-(4-biphenylyl)-4-phenyl-5-(4-tert-butylphenyl)-1,2,4-triazole (TAZ) were used as a blue phosphorescent guest material and an electron transport layer, respectively. The TAPC layer in device B strongly contributes to whitish emission, higher driving voltage, and lower current efficiency characteristics compared with device A. The mechanisms of these electrical and optical characteristics of the devices were investigated.