• Journal of Microbiology and Biotechnology
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• v.25 no.3
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• pp.418-422
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• 2015

In the course of screening for novel cell cycle inhibitors and apoptotic inducers, CR389, elucidated as 5-(1H-benzoimidazol-2-yl)-1H-pyridin-2-one, was generated as a new hit compound. Flow cytometric analysis and western blots of PA-1 cells treated with $60{\mu}M$ CR389 revealed an appreciable cell cycle arrest at the G2/M phase through direct inhibition of the CDK1 complex. In addition, activation of p53 via phosphorylation at Ser15 and subsequent up-regulation of p21^CIP1 showed that CR389 also induces p53-dependent-p21^CIP1-mediated cell cycle arrest. Furthermore, apoptotic induction in $60{\mu}M$ CR389-treated PA-1 cells is associated with the release of cytochrome c from mitochondria through up-regulation of the proapoptotic Bax protein, which results in the activation of procaspase-9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). Accordingly, CR389 seems to have multiple mechanisms of antiproliferative activity through p53-mediated pathways against human ovarian cancer cells. Therefore, we conclude that CR389 is a candidate therapeutic agent for the treatment of human ovarian cancer via the activation of p53.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.193-201
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• 2018

Connective tissue growth factor (CTGF) is a novel fibrotic mediator, which is considered to mediate fibrosis through extracellular matrix (ECM) synthesis in diabetic cardiovascular complications. Statins have significant immunomodulatory effects and reduce vascular injury. We therefore examined whether fluvastatin has anti-fibrotic effects in vascular smooth muscle cells (VSMCs) and elucidated its putative transduction signals. We show that advanced glycation end products (AGEs) stimulated CTGF mRNA and protein expression in a time-dependent manner. AGE-induced CTGF expression was mediated via ERK1/2, JNK, and Egr-1 pathways, but not p38; consequently, cell proliferation and migration and ECM accumulation were regulated by CTGF signaling pathway. AGE-stimulated VSMC proliferation, migration, and ECM accumulation were blocked by fluvastatin. However, the inhibitory effect of fluvastatin was restored by administration of CTGF recombinant protein. AGE-induced VSMC proliferation was dependent on cell cycle arrest, thereby increasing G1/G0 phase. Fluvastatin repressed cell cycle regulatory genes cyclin D1 and Cdk4 and augmented cyclin-dependent kinase inhibitors p27 and p21 in AGE-induced VSMCs. Taken together, fluvastatin suppressed AGE-induced VSMC proliferation, migration, and ECM accumulation by targeting CTGF signaling mechanism. These findings might be evidence for CTGF as a potential therapeutic target in diabetic vasculature complication.

• BMB Reports
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• v.49 no.7
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• pp.376-381
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• 2016

Several lines of evidence have revealed that phosphorylation of amyloid precursor protein (APP) at Thr668 is involved in the pathogenesis of Alzheimer's disease (AD). Okadaic acid (OA), a protein phosphatase-2A inhibitor, has been used in AD research models to increase tau phosphorylation and induce neuronal death. We previously showed that OA increased levels of APP and induced accumulation of APP in axonal swellings. In this study, we found that in OA-treated neurons, phosphorylation of APP at Thr668 increased and accumulated in axonal swellings by c-jun N-terminal kinase (JNK), and not by Cdk5 or ERK/MAPK. These results suggest that JNK may be one of therapeutic targets for the treatment of AD.

• BMB Reports
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• v.44 no.3
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• pp.147-157
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• 2011

The meiotic process from the primordial stage to zygote in female germ cells is mainly adjusted by post-transcriptional regulation of pre-existing maternal mRNA and post-translational modification of proteins. Several key proteins such as the cell cycle regulator, Cdk1/cyclin B, are post-translationally modified for precise control of meiotic progression. The second messenger (cAMP), kinases (PKA, Akt, MAPK, Aurora A, CaMK II, etc), phosphatases (Cdc25, Cdc14), and other proteins (G-protein coupled receptor, phosphodiesterase) are directly or indirectly involved in this process. Many proteins, such as CPEB, maskin, eIF4E, eIF4G, 4E-BP, and 4E-T, post-transcriptionally regulate mRNA via binding to the cap structure at the 5' end of mRNA or its 3' untranslated region (UTR) to generate a closed-loop structure. The 3' UTR of the transcript is also implicated in post-transcriptional regulation through an association with proteins such as CPEB, CPSF, GLD-2, PARN, and Dazl to modulate poly(A) tail length. RNA interfering is a new regulatory mechanism of the amount of mRNA in the mouse oocyte. This review summarizes information about post-transcriptional and post-translational regulation during mouse oocyte meiotic maturation.

• BMB Reports
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• v.42 no.5
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• pp.245-259
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• 2009

The process by which adult neural stem cells generate new and functionally integrated neurons in the adult mammalian brain has been intensely studied, but much more remains to be discovered. It is known that neural progenitors progress through distinct stages to become mature neurons, and this progression is tightly controlled by cell-cell interactions and signals in the neurogenic niche. However, less is known about the cell-intrinsic signaling required for proper progression through stages of adult neurogenesis. Techniques have recently been developed to manipulate genes specifically in adult neural stem cells and progenitors in vivo, such as the use of inducible transgenic mice and viral-mediated gene transduction. A critical mass of publications utilizing these techniques has been reached, making it timely to review which molecules are now known to play a cell-intrinsic role in regulating adult neurogenesis in vivo. By drawing attention to these isolated molecules (e.g. Notch), we hope to stimulate a broad effort to understand the complex and compelling cascades of intrinsic signaling molecules important to adult neurogenesis. Understanding this process opens the possibility of understanding brain functions subserved by neurogenesis, such as memory, and also of harnessing neural stem cells for repair of the diseased and injured brain.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2217-2221
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• 2016

Vascular endothelial growth factor 2 (VEGFR2) was initially identified as a receptor of VEGF on endothelial cells with a role in regulating angiogenesis during organism development and tumorigenesis. Previously, in cancer tissue, VEGFR2 has been reported to be expressed in endothelial cells. In our research, we found that VEGFR2 was expressed not only in endothelial cells but also cancer cells in head and neck squamous cell carcinomas (HNSCCs). Knockdown of VEGFR2 in Hep2 cells could arrest the cell cycle in G0/G1, leading to a decrease in proliferation. We also present evidence that MAPK/ERK signal pathways and expression of CDK1 downstream of VEGFR2 might regulate proliferation and cell cycle arrest. Furthermore, we discovered that down-regulate VEGRF2 in Hep2 cells could significantly affect the invasion ability. Taken together, our data suggest that VEGFR2 might regulate proliferation and invasion in HNSCC cancer cells in vivo.

• Bioinformatics and Biosystems
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• v.2 no.1
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• pp.28-32
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• 2007

The protein phosphorylation is one of the important processes in the cell signaling pathway. A variety of protein kinase families are involved in this process, and each kinase family phosphorylates different kinds of substrate proteins. Many methods to predict the kinase-specific phosphoryrated sites or different types of phosphorylated residues (Serine/Threonine or Tyrosin) have been developed. We employed Supprot Vector Machine (SVM) to attempt the prediction of protein kinase specific phosphorylation sites. 10 different kinds of protein kinase families (PKA, PKC, CK2, CDK, CaM-KII, PKB, MAPK, EGFR) were considered in this study. We defined 9 residues around a phosphorylated residue as a deterministic instance from which protein kinases determine whether they act on. The subsets of PSI-BALST profile was converted to the numerical vectors to represent positive or negative instances. When SVM training, We took advantage of multiple SVMs because of the unbalanced training sets. Representative negative instances were drawn multiple times, and generated new traing sets with the same positive instances in the original traing set. When testing, the final decisions were made by the votes of those multiple SVMs. Generally, RBF kernel was used for the SVMs, and several parameters such as gamma and cost factor were tested. Our approach achieved more than 90% specificity throughout the protein kinase families, while the sensitivities recorded 60% on average.

• Development and Reproduction
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• v.18 no.1
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• pp.65-71
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• 2014

Cell cycle process is regulated by a number of protein kinases and among them, serine/threonine kinases carry phosphate group from ATP to substrates. The most important three kinase families are Cyclin-dependent kinase (Cdk), Polo-like kinase (Plk), and Aurora kinase. Polo-like kinase family consists of 5 members (Plk1-Plk5) and they are involved in multiple functions in eukaryotic cell division. It regulates a variety of aspects such as, centrosome maturation, checkpoint recovery, spindle assembly, cytokinesis, apoptosis and many other features. Recently, it has been reported that Plks are related to tumor development and over-expressed in many kinds of tumor cells. When injected the anti-Plk antibody into human cells, the cells show aneuploidy, and if inhibit Plks, most of the mitotic cell division does not proceed properly. For that reasons, many inhibitors of Plk have been recently emerged as new target for remedy of the cancer therapeutic research. In this paper, we reviewed briefly the characteristics of Plk families and how Plks work in regulating cell cycles and cancer formation, and the possibilities of Plks as target for cancer therapy.

• Journal of Animal Science and Technology
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• v.60 no.6
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• pp.11.1-11.7
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• 2018

After pubertal, cohort of small antral follicles enters to gonadotrophin-sensitive development, called recruited follicles. This study was aimed to identify candidate genes in follicular cyclic recruitment via analysis of protein-protein interaction (PPI) network. Differentially expressed genes (DEGs) in ovine granulosa cells of small antral follicles between follicular and luteal phases were accumulated among gene/protein symbols of the Ensembl annotation. Following directed graphs, PTPN6 and FYN have the highest indegree and outdegree, respectively. Since, these hubs being up-regulated in ovine granulosa cells of small antral follicles during the follicular phase, it represents an accumulation of blood immune cells in follicular phase in comparison with luteal phase. By contrast, the up-regulated hubs in the luteal phase including CDK1, INSRR and TOP2A which stimulated DNA replication and proliferation of granulosa cells, they known as candidate genes of the cyclic recruitment.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.1
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• pp.29-35
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• 2019

Decursin is a major biological active component of Angelica gigas Nakai and is known to induce apoptosis of metastatic prostatic cancer cells. Recently, other reports have been commissioned to examine the anticancer activities of this plant. In this study, we evaluated the inhibitory activity and related mechanism of action of decursin against glioblastoma cell line. Decursin demonstrated cytotoxic effects on U87 and C6 glioma cells in a dose-dependent manner but not in primary glial cells. Additionally, decursin increased apoptotic bodies and phosphorylated JNK and p38 in U87 cells. Decursin also down-regulated Bcl-2 as well as cell cycle dependent proteins, CDK-4 and cyclin D1. Furthermore, decursin-induced apoptosis was dependent on the caspase activation in U87 cells. Taken together, our data provide the evidence that decursin induces apoptosis in glioblastoma cells, making it a potential candidate as a chemotherapeutic drug against brain tumor.