• Title, Summary, Keyword: signaling pathway

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The Role of Tripartite Motif Family Proteins in TGF-β Signaling Pathway and Cancer

  • Lee, Ho-Jae
    • Journal of Cancer Prevention
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    • v.23 no.4
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    • pp.162-169
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    • 2018
  • $TGF-{\beta}$ signaling plays a tumor suppressive role in normal and premalignant cells but promotes tumor progression during the late stages of tumor development. The $TGF-{\beta}$ signaling pathway is tightly regulated at various levels, including transcriptional and post-translational mechanisms. Ubiquitination of signaling components, such as receptors and Smad proteins is one of the key regulatory mechanisms of $TGF-{\beta}$ signaling. Tripartite motif (TRIM) family of proteins is a highly conserved group of E3 ubiquitin ligase proteins that have been implicated in a variety of cellular functions, including cell growth, differentiation, immune response, and carcinogenesis. Recent emerging studies have shown that some TRIM family proteins function as important regulators in tumor initiation and progression. This review summarizes current knowledge of TRIM family proteins regulating the $TGF-{\beta}$ signaling pathway with relevance to cancer.

Suppression of the TRIF-dependent Signaling Pathway of Toll-like Receptor by Cadmium in RAW264.7 Macrophages

  • Park, Se-Jeong;Youn, Hyung-Sun
    • Molecular & Cellular Toxicology
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    • v.5 no.3
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    • pp.187-192
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    • 2009
  • Toll-like receptors (TLRs) play an important role in host defense by sensing invading microbial pathogens. The stimulation of TLRs by microbial components triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-$\beta$ (TRIF)-dependent downstream signaling pathways. TLR/MyD88 signaling pathway induces the activation of nuclear factor-kappa B (NF-${\kappa}B$) and the expression of inflammatory cytokine genes, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and IL-$1{\beta}$. On the other hand, TLR/TRIF signaling pathway induces the delayed-activation of NF-${\kappa}B$ and interferon regulatory factor 3 (IRF3), and the expression of type I interferons (IFNs) and IFN-inducible genes. The divalent heavy metal cadmium (Cd) is clearly toxic to most mammalian organ systems, especially the immune system. Yet, the underlying toxic mechanism(s) remain unclear. Cd inhibits the MyD88-dependent pathway by ceasing the activity of inhibitor-${\kappa}B$ kinase. However, it is not known whether Cd inhibits the TRIF-dependent pathway. Presently, Cd inhibited NF-${\kappa}B$ and IRF3 activation induced by lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid. Cd inhibited LPS-induced IRF3 phosphorylation and IFN-inducible genes such as interferon inducible protein-10 and regulated on activation normal T-cell expressed and secreted (RANTES). These results suggest that Cd can modulate TRIF-dependent signaling pathways of TLRs.

Intracellular Signaling Pathway for Host Defense Mechanisms against Piscine Nervous Necrosis Virus (NNV) (어류신경괴사증바이러스(nervous necrosis virus, NNV) 감염에 따른 숙주의 방어기전관련 세포신호전달)

  • Kim, Jong-Oh
    • Journal of Life Science
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    • v.30 no.4
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    • pp.402-409
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    • 2020
  • Nervous necrosis virus (NNV) contains a bi-segmented viral genome, RNA1 (3.4 kb, RdRp), and RNA2 (1.4 kb, capsid protein) in a small particle (25 nm). Despite its extremely compact size, NNV has caused serious damage by infecting approximately 120 fish species worldwide since it was first reported in the late 1980s. In order to minimize the damage caused by NNV infection and develop effective vaccines, it is necessary to understand the intra cellular signaling system according to NNV infection. NNV infection induces cell cycle arrest at the G1 phase via the p53-dependent pathway to use the cellular system for its replication. Otherwise, host cells recognize NNV infection through the RIG-1-like receptor (RLR) signaling pathway to control the virus and infected cells, and then ISGs required for antiviral action are activated via the IFN signaling pathway. Moreover, apoptosis of infected cells is triggered by the unfolded protein response (UPR) through ER stress and mitochondria-mediated cell death. Cell signaling studies on the NNV infection mechanisms are still at an early stage and many pathways have yet to be identified. Understanding the various disease-specific cellular signaling systems associated with NNV infection is essential for rapid and accurate diagnosis and vaccine development.

Genomewide Profiling of Rapamycin Sensitivity in Saccharomyces cerevisiae on Synthetic Medium

  • Chang, Yeon-Ji;Shin, Chun-Shik;Han, Dong-Hun;Kim, Ji-Yun;Kim, Kang-In;Kwon, Yong-Min;Huh, Won-Ki
    • Genomics & Informatics
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    • v.8 no.4
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    • pp.177-184
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    • 2010
  • The target of rapamycin (TOR) signaling pathway is a conserved pathway that regulates eukaryotic cell growth in response to environmental cues. Chemical genomic approaches that profile rapamycin sensitivity of yeast deletion strains have given insights into the function of TOR signaling pathway. In the present study, we analyzed the rapamycin sensitivity of yeast deletion library strains on synthetic medium. As a result, we identified 130 strains that are hypersensitive or resistant to rapamycin compared with wild-type cells. Among them, 36 genes are newly identified to be related to rapamycin sensitivity. Moreover, we found 16 strains that show alteration in rapamycin sensitivity between complex and synthetic media. We suggest that these genes may be involved in part of TOR signaling activities that is differentially regulated by media composition.

The Dose Dependent Effects of Ruxolitinib on the Invasion and Tumorigenesis in Gliomas Cells via Inhibition of Interferon Gamma-Depended JAK/STAT Signaling Pathway

  • Delen, Emre;Doganlar, Oguzhan
    • Journal of Korean Neurosurgical Society
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    • v.63 no.4
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    • pp.444-454
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    • 2020
  • Objective : Glioblastoma multiforme (GBM) is the most aggressive for of brain tumor and treatment often fails due to the invasion of tumor cells into neighboring healthy brain tissues. Activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is essential for normal cellular function including angiogenesis, and has been proposed to have a pivotal role in glioma invasion. This study aimed to determine the dose-dependent effects of ruxolitinib, an inhibitor of JAK, on the interferon (IFN)-I/IFN-α/IFN-β receptor/STAT and IFN-γ/IFN-γ receptor/STAT1 axes of the IFN-receptor-dependent JAK/STAT signaling pathway in glioblastoma invasion and tumorigenesis in U87 glioblastoma tumor spheroids. Methods : We administered three different doses of ruxolitinib (50, 100, and 200 nM) to human U87 glioblastoma spheroids and analyzed the gene expression profiles of IFNs receptors from the JAK/STAT pathway. To evaluate activation of this pathway, we quantified the phosphorylation of JAK and STAT proteins using Western blotting. Results : Quantitative real-time polymerase chain reaction analysis demonstrated that ruxolitinib led to upregulated of the IFN-α and IFN-γ while no change on the hypoxia-inducible factor-1α and vascular endothelial growth factor expression levels. Additionally, we showed that ruxolitinib inhibited phosphorylation of JAK/STAT proteins. The inhibition of IFNs dependent JAK/STAT signaling by ruxolitinib leads to decreases of the U87 cells invasiveness and tumorigenesis. We demonstrate that ruxolitinib may inhibit glioma invasion and tumorigenesis through inhibition of the IFN-induced JAK/STAT signaling pathway. Conclusion : Collectively, our results revealed that ruxolitinib may have therapeutic potential in glioblastomas, possibly by JAK/STAT signaling triggered by IFN-α and IFN-γ.

Analysis of MAPK Signaling Pathway Genes in the Intestinal Mucosal Layer of Necrotic Eenteritis-Afflicted Two Inbred Chicken Lines

  • Truong, Anh Duc;Hong, Yeojin;Lee, Janggeun;Lee, Kyungbaek;Lillehoj, Hyun S.;Hong, Yeong Ho
    • Korean Journal of Poultry Science
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    • v.44 no.3
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    • pp.199-209
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    • 2017
  • Mitogen-activated protein kinase (MAPK) signaling pathways play a key role in innate immunity, inflammation, cell proliferation, cell differentiation, and cell death. The main objective of this study was to investigate the expression level of candidate MAPK pathway genes in the intestinal mucosal layer of two genetically disparate chicken lines (Marek's disease-resistant line 6.3 and Marek's disease-susceptible line 7.2) induced with necrotic enteritis (NE). Using high-throughput RNA sequencing, we investigated 178 MAPK signaling pathway related genes that were significantly and differentially expressed between the intestinal mucosal layers of the NE-afflicted and control chickens. In total, 15 MAPK pathway genes were further measured by quantitative real-time PCR(qRT-PCR) and the results were consistent with the RNA-sequencing data. All 178 identified genes were annotated through Gene Ontology and mapped onto the KEGG chicken MAPK signaling pathway. Several key genes of the MAPK pathway, ERK1/2, JNK1-3, p38 MAPK, MAP2K1-4, $NF-{\kappa}B1/2$, c-Fos, AP-1, Jun-D, and Jun, were differentially expressed in the two chicken lines. Therefore, we believe that RNA sequencing and qRT-PCR analysis provide resourceful information for future studies on MAPK signaling of genetically disparate chicken lines in response to pathogens.

E3 ubiquitin ligases and deubiquitinases as modulators of TRAIL-mediated extrinsic apoptotic signaling pathway

  • Woo, Seon Min;Kwon, Taeg Kyu
    • BMB Reports
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    • v.52 no.2
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    • pp.119-126
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    • 2019
  • The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression.

Down-regulation of EZH2 by RNA Interference Inhibits Proliferation and Invasion of ACHN Cells via the Wnt/β-catenin Pathway

  • Yuan, Jun-Bin;Yang, Luo-Yan;Tang, Zheng-Yan;Zu, Xiong-Bing;Qi, Lin
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.12
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    • pp.6197-6201
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    • 2012
  • Although enhancer of zeste homolog 2 (EZH2) has been reported as an independent prognostic factor in renal cell carcinoma (RCC), little is known about the exact mechanism of EZH2 in promoting the genesis of RCC. However, several studies have shown that dysregulation of the Wnt/${\beta}$-catenin signaling pathway plays a crucial role. Therefore, we determined whether EZH2 could affect ACHN human RCC cell proliferation and invasion via the Wnt/${\beta}$-catenin pathway. In the present study, we investigated the effects of short interfering RNA (siRNA)-mediated EZH2 gene silencing on Wnt/${\beta}$-catenin signaling in ACHN cells. EZH2-siRNA markedly inhibited the proliferation and invasion capabilities of ACHN, while also reducing the expression of EZH2, Wnt3a and ${\beta}$-catenin. In contrast, cellular expression of GSK-$3{\beta}$ (glycogen synthase kinase-$3{\beta}$), an inhibitor of the Wnt/${\beta}$-catenin pathway, was conspicuously higher after transfection of EZH2 siRNA. These preliminary findings suggest EZH2 may promote proliferation and invasion of ACHN cells via action on the Wnt/${\beta}$-catenin signaling pathway.

Association of Insulin-related Genes Expression with Carcass Weight in Loin Muscle of Korean Cattle (Hanwoo) (한우 등심조직 내 인슐린 조절 유전자의 발현이 도체중에 미치는 영향에 관한 연구)

  • Lim, Dajeong;Cho, Yong-Min;Chai, Han-Ha;Lee, Seung-Hwan;Choi, Bong-Hwan;Kim, Nam-Kuk
    • Journal of Life Science
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    • v.25 no.1
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    • pp.8-15
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    • 2015
  • The peroxisome proliferator-activated receptor (PPAR) signaling pathway is well known as a candidate pathway related to meat quality in mammals. In particular, there are many studies on the relationship between the PPAR signaling pathway and intramuscular fat. However, recent studies have demonstrated that genes in the PPAR signaling pathway are associated with carcass weight in cattle. Among 48 genes in the PPAR signaling pathway, 16 genes are related to the insulin that regulates the adipocyte glucose metabolism and thus affects body weight. Therefore, we conducted an investigation to try to identify candidate genes associated with the carcass weight and relationships between the expressions of these 16 genes in the loin muscle of Hanwoo (Korean cattle). From regression analysis, the three genes (ACSL6, FADS2, and ILK) showed significant effects with regard to carcass weight (p<0.05). Finally, we analyzed the common regulators of the significant genes from pathway analysis. The significant genes are regulated by insulin as well as D-glucose. These findings show that the differentially expressed genes are possible candidate genes associated with carcass weight in the longissimus muscle of Korean cattle.

Neurotoxin-Induced Pathway Perturbation in Human Neuroblastoma SH-EP Cells

  • Do, Jin Hwan
    • Molecules and Cells
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    • v.37 no.9
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    • pp.672-684
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    • 2014
  • The exact causes of cell death in Parkinson's disease (PD) remain unknown despite extensive studies on PD.The identification of signaling and metabolic pathways involved in PD might provide insight into the molecular mechanisms underlying PD. The neurotoxin 1-methyl-4-phenylpyridinium ($MPP^+$) induces cellular changes characteristic of PD, and $MPP^+$-based models have been extensively used for PD studies. In this study, pathways that were significantly perturbed in $MPP^+$-treated human neuroblastoma SH-EP cells were identified from genome-wide gene expression data for five time points (1.5, 3, 9, 12, and 24 h) after treatment. The mitogen-activated protein kinase (MAPK) signaling pathway and endoplasmic reticulum (ER) protein processing pathway showed significant perturbation at all time points. Perturbation of each of these pathways resulted in the common outcome of upregulation of DNA-damage-inducible transcript 3 (DDIT3). Genes involved in ER protein processing pathway included ubiquitin ligase complex genes and ER-associated degradation (ERAD)-related genes. Additionally, overexpression of DDIT3 might induce oxidative stress via glutathione depletion as a result of overexpression of CHAC1. This study suggests that upregulation of DDIT3 caused by perturbation of the MAPK signaling pathway and ER protein processing pathway might play a key role in $MPP^+$-induced neuronal cell death. Moreover, the toxicity signal of $MPP^+$ resulting from mitochondrial dysfunction through inhibition of complex I of the electron transport chain might feed back to the mitochondria via ER stress. This positive feedback could contribute to amplification of the death signal induced by $MPP^+$.