• Proceedings of the PSK Conference
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• 2003.10b
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• pp.168.2-168.2
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• 2003

Akt/Ptotein Kinase B (PKB) is a serine/threonine kinase and activated by PI3K pathway. Akt/PKB regulates a variety of cellular responses including proliferations, differentiations and insulin signaling pathway. Recent evidence also indicates that the abnormal activities or expression of Akt/PKB is closely associated with cancer, diabetes and neuro-degenerative diseases. These findings mean that Akt/PKB is likely to be a new therapeutic target for the treatment of disease. (omitted)

• International Journal of Stem Cells
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• v.17 no.3
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• pp.319-329
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• 2024

Leucine-rich repeat kinase 2 (LRRK2), a large GTP-regulated serine/threonine kinase, is well-known for its mutations causing late-onset Parkinson's disease. However, the role of LRRK2 in glioblastoma (GBM) carcinogenesis has not yet been fully elucidated. Here, we discovered that LRRK2 was overexpressed in 40% of GBM patients, according to tissue microarray analysis, and high LRRK2 expression correlated with poor prognosis in GBM patients. LRRK2 and stemness factors were highly expressed in various patient-derived GBM stem cells, which are responsible for GBM initiation. Canonical serum-induced differentiation decreased the expression of both LRRK2 and stemness factors. Given that LRRK2 is a key regulator of glioma stem cell (GSC) stemness, we developed DNK72, a novel LRRK2 kinase inhibitor that penetrates the blood-brain barrier. DNK72 binds to the phosphorylation sites of active LRRK2 and dramatically reduced cell proliferation and stemness factors expression in in vitro studies. Orthotopic patient-derived xenograft mouse models demonstrated that LRRK2 inhibition with DNK72 effectively reduced tumor growth and increased survival time. We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.

• Journal of Integrative Natural Science
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• v.8 no.1
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• pp.40-47
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• 2015

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a promising target in drug discovery. It is involved in multiple cellular processes and associated with the pathogenesis of several diseases. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of GSK-3 inhibitors to understand the structural basis for inhibitory activity. Comparative molecular field analysis (CoMFA) method was used to derive 3D-QSAR models. A reliable CoMFA model was developed using ligand-based alignment scheme. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$) of 0.594 and a non-cross-validated correlation coefficient ($r^2$) of 0.943. Robustness of the model was checked by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel compounds with enhanced GSK-3 inhibitory activity.

• Journal of the Korean Applied Science and Technology
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• v.25 no.3
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• pp.370-379
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• 2008

Akt, a serine/threonine protein kinase as a viral oncogene, is a critical regulator of PI3K-mediated cell proliferation and survival. On translocation, Akt is phosphorylated and activated, ultimately resulting in stimulation of cell growth and survival. As a part of our program toward the novel Akt1 inhibitors with potent activity over PI3K signaling pathway, we found primary hit compound 2 with an $IC_{50}$ value of $620\mu}M$ from protein kinase focused library. Based on the structural features of 2, new 1,3,4-thiadiazole derivatives were designed by the introduction of aromatic and heteroaromatic moieties onto thiadiazole nucleus. In this work, a series of 1,3,4-thiadiazole derivatives 1a-1 were synthesized and evaluated for Akt1 inhibitory activity.

• Journal of Integrative Natural Science
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• v.7 no.4
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• pp.253-259
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• 2014

Protein kinase C theta (PKC-${\theta}$) is a serine/threonine specific protein kinase. It is largely expressed in the T-cells and CD28 signaling. PKC-${\theta}$ phosphorylates diverse proteins that are involved in the various cellular signaling pathways. Activated PKC-${\theta}$ in turn activates other transcription factors that control the proliferation and differentiation of T- cells. PKC-${\theta}$ is considered to be an interesting therapeutic target due to its crucial role in the proliferation, differentiation and survival of T-cells. In the present study, we have performed ligand-based CoMFA study on a series of pyridylpyrazolopyridine derivatives as PKC-${\theta}$ inhibitors. An acceptable CoMFA model ($q^2$=0.544; ONC=4; $r^2$=0.876) was developed and validated by Bootsrapping and progressive sampling. The CoMFA contour map suggested the regions to increase the activity. Bulky substitutions in R2 position of the piperizine ring could increase the activity. Similarly positive, small substitution in the R1 position of the Pyridine ring could considerably increase the activity. Our work could assist in designing more potent PKC-${\theta}$ inhibitors of pyridylpyrazolopyridine derivatives.

• YAKHAK HOEJI
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• v.56 no.6
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• pp.358-363
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• 2012

Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine protein kinase, plays an important role in wide variety of developmental events. NLK phosphorylates T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional complex and suppresses wnt signaling pathway through inhibition of ${\beta}$-catenin/TCF complex interaction. However, the function of NLK in gastric carcinogenesis has not been investigated. In the present study, we have examined whether the NLK gene is involved in the development and/or progression of gastric cancers. NLK expression was analyzed by immunohistochemical staining in 153 advanced gastric cancer specimens. Immunhistochemical analysis showed increased expression of NLK in 91 (59.5%) out of 153 gastric cancer specimens. Statistically, there was no significant relationship between altered expression of NLK protein and clinicopathological parameters, including tumor differentiation, location, lymph node metastasis. We identified that mRNA and protein expression of NLK was significantly up-regulated in human gastric cancer tissues compare to corresponding normal gastric tissues. In addition, we found that human gastric cancer cell lines exhibited relatively high expression of NLK, as compared with normal gastric cells. The results of this study suggest that aberrant regulation of NLK may contribute to the development or progression of gastric cancers and serve as a potential biomarker for advanced gastric cancer patients.

• Microbiology and Biotechnology Letters
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• v.30 no.3
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• pp.235-240
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• 2002

Streptomycetes is a group of Gram-positive soil bacteria that growas a branching vegetative mycelium leading to the formation of spores, and display a physiological differenti-ation related to the synthesis of many secondary metabolites including antibiotics. Their complex life cycle and multicellular differentiation require various levels of regulation and types of signal transduction systems including eukaryotic-type serine/threonine protein kinases and prokaryotic-type histidine/aspartic acid protein kinases. Akt kinase that was found in cells is a sorine/threonine kinase controlling signal pathway for multi-tude of important cellular events. The activation or inactivation of Akt kinase in the cell is one of the critical regulatory points to deliver cell proliferation, differentiation, survival or apoptosis signal. To find the regula-tory protein homologous to Akt in Streptomyces, the fluorescien-labeled synthetic peptide (FITC-TRRSR-TESIT) was designed from the consensus sequence of target proteins for Akt kinase. From the difference of the mobility between the nonphosphorylated and phosphorylated synthetic peptides on Agarose gel electro-phoresis, the Akt-phosphorylating activity was monitored. The cell-free extract prepared from Streptomyces griseus IFO 13350 and the Akt homologous protein was purified by ammonium sulfate fractionation and many steps of column chromatographies such as, DEAE-Sepharose, Mono Q, Resource Phenyl-Soporose and Gel permeation column chromatographies. As a result, the protein phosphorylating the fluorescien-labeled Akt substrate was identified and it's molecular weight was estimated as 39 kDa on SDS-PAGE.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.32 no.2
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• pp.112-117
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• 2010

Aurora kinases represent a novel family of serine/threonine kinases crucial for cell cycle control. Aurora-2 kinase is mainly involved in centrosome function, mitotic entry, and spindle assembly. Aurora-2 kinase overexpression causes centrosome amplification and the formation of multipolar mitotic spindles, which leads to tumor aneuploidy and so it has been found to play an important role in tumorigenicity in many cancers such as colorectal cancer, breast cancer and cervical cancer. Hence, the goal of this study is to identify the correlation of clinicopathlogical factors and overexpression of Aurora-2 kinase in oral squamous cell carcinoma. We studied the immunohistochemical staining of Aurora-2 kinase in 20 specimens of 20 patients with oral squamous cell carcinoma and the relationships between Aurora-2 kinase over expression and each of the clinico-pathological parameters were analyzed by Pearson correlation analysis. Statistical significance was set at P < 0.05. The results were as follows. 1. In the immunohistochemical study of poorly differentiated and invasive oral squamous cell carcinoma, the high level staining of Aurora-2 kinase was observed. 2. The correlation between immunohistochemical Aurora-2 kinase expression and histopathological differentiation of specimens was significant. These findings suggest that overexpression of Aurora-2 kinase may play a important role in carcinogenesis of oral squamous cell carcinoma.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.42 no.1
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• pp.95-101
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• 2016

In the present study, we extracted the hydrosol from flower of Chrysanthemum boreale Makino (CBMF hydrosol) by steam distillation and tested the effect of the CBMF hydrosol on skin regeneration using normal human keratinocytes (HaCaTs). CBMF hydrosol induced proliferation as well as migration in HaCaTs in a dose-dependent manner. Treatment with $1{\mu}g/mL$ CBMF hydrosol increased proliferation to $143.71{\pm}3.37%$ and migration to $139.98{\pm}5.72%$ compared with a control group. CBMF hydrosol also significantly enhanced the phosphorylations of extracellular signal-regulated kinase (Erk) 1/2 and serine/threonine-specific protein kinase (Akt) in HaCaTs. Moreover, CBMF hydrosol dose-dependently induced sprout outgrowth in HaCaTs. These results demonstrate that CBMF hydrosol has skin regeneration and wound healing activity in HaCaTs. Therefore, CBMF hydrosol could be used as a potential cosmetic material.

• Journal of Life Science
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• v.26 no.7
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• pp.868-874
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• 2016

Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 are members of the serine or threonine protein kinase superfamily that phosphorylates the hydroxyl group of serine or threonine through the highly conserved kinase region. The RIPK family plays a crucial role not only in inflammation and innate immunity, but also in mediating programmed cell death, such as apoptosis and necroptosis. The interaction between RIPK1 and other TNFR1-related proteins has been shown to assemble a signaling complex I that controls activation of the pro-survival transcription factor NF-κB upon binding of cytokines to TNF receptor 1 (TNFR1). Moreover, RIPK1 and RIPK3 interact through their RIP homotypic interaction motifs (RHIMs) to mediate programmed necrosis, which has long been considered an accidental and uncontrolled cell death form with morphological characteristics differing from those of apoptosis. Highly conserved sequences of RHIM in RIPK1 and RIPK3 were shown to regulate their binary interaction, leading to assembly of a cytosolic amyloid complex termed the “necrosome”. The necrosome also contains mixed lineage kinase domain-like protein (MLKL), which has been found recently to be a substrate of RIPK3 to mediate downstream signaling. This review provides an overview of the functional and physiological characteristics of RIPKs and MLKL in TNF signaling.