• Molecules and Cells
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• 제43권2호
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• pp.188-197
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• 2020

Cells are designed to be sensitive to a myriad of external cues so they can fulfil their individual destiny as part of the greater whole. A number of well-characterised signalling pathways dictate the cell's response to the external environment and incoming messages. In healthy, well-ordered homeostatic systems these signals are tightly controlled and kept in balance. However, given their powerful control over cell fate, these pathways, and the transcriptional machinery they orchestrate, are frequently hijacked during the development of neoplastic disease. A prime example is the Wnt signalling pathway that can be modulated by a variety of ligands and inhibitors, ultimately exerting its effects through the β-catenin transcription factor and its downstream target genes. Here we focus on the interplay between the three-member family of RUNX transcription factors with the Wnt pathway and how together they can influence cell behaviour and contribute to cancer development. In a recurring theme with other signalling systems, the RUNX genes and the Wnt pathway appear to operate within a series of feedback loops. RUNX genes are capable of directly and indirectly regulating different elements of the Wnt pathway to either strengthen or inhibit the signal. Equally, β-catenin and its transcriptional co-factors can control RUNX gene expression and together they can collaborate to regulate a large number of third party co-target genes.

• Genomics & Informatics
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• 제19권1호
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• pp.5.1-5.11
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• 2021

Head and neck squamous cell carcinoma (HNSCC) is the most frequent type of head and neck cancer that usually arises from the mucosal surfaces of several organs including nasal cavity, paranasal sinuses, oral cavity, tongue, pharynx, and larynx. The Wnt signaling pathway is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. The present study aims to assess the gene alterations in the Wnt family of genes so as to derive an association with HNSCC. Computational approaches have been utilized for the identification of gene alterations in the Wnt family of genes. Several databases such as cBioportal, STRING, and UALCAN were used for the purpose. The frequency of alteration was high in case of Wnt family member 11 (5%). Gene amplification, deep deletions, missense and truncating mutations were observed in HNSCC patients. There was a marked difference in the gene expression profile of WNT11 between grades as well as normal samples. The survival probability measured using the Kaplan-Meier curve also presented with a significant difference among male and female subjects experiencing a low/medium level expression. The female patients showed less survival probability when compared to the male subjects. This provides the prognostic significance of the WNT11 gene in HNSCC. Taken together, the present study provides clues on the possible association of WNT11 gene alterations with HNSCC, which has to be further validated using experimental approaches.

• Reproductive and Developmental Biology
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• 제36권1호
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• pp.13-19
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• 2012

In order to provide the basis for developing practical mouse embryonic stem cells (mESCs) culture method, how the endogenous level of self-renewal-stimulating factor genes was altered in the mESCs by different extracellular signaling was investigated in this study. For different extracellular signaling, mESCs were cultured in 2 dimension (D), 3D and integrin-stimulating 3D culture system in the presence or absence of leukemia inhibitory factor (LIF) and transcriptional level of $Lif$, $Bmp4$ and $Wnt3a$ was evaluated in the mESCs cultured in each system. The expression of three genes was significantly increased in 3D system relative to 2D system under LIF-containing condition, while only $Wnt3a$ expression was increased by 3D culture under LIF-free condition. Stimulation of integrin signaling in mESCs within 3D system with exogenous LIF significantly up-regulated transcriptional level of $Bmp4$, but did not induce transcriptional regulation of $Lif$ and $Wnt3a$. In the absence of LIF inside 3D system, the expression of $Lif$ and $Bmp4$ was significantly increased by integrin signaling, while it significantly decreased $Wnt3a$ expression. Finally, the signal from exogenous LIF significantly caused increased expression of $Lif$ in 2D system, decreased expression of $Bmp4$ in both 2D and 3D system, and decreased expression of $Wnt3a$ in integrin-stimulating 3D system. From these results, we identified that endogenous expression level of self-renewal-stimulating factor genes in mESCs could be effectively regulated through artificial and proper manipulation of extracellular signaling. Moreover, synthetic 3D niche stimulating endogenous secretion of self-renewal-stimulating factors will be able to help develop growth factor-free maintenance system of mESCs.

• BMB Reports
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• 제49권8호
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• pp.401-402
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• 2016

S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression. S6K1-mediated suppression of Wnt genes facilitates adipogenic differentiation through the expression of adipogenic transcription factors PPARγ and Cebpa. White adipose tissues from S6K1-deficient mice consistently exhibit marked reduction in H2BS36 phosphorylation (H2BS36p) and H3K27 trimethylation (H3K27me3), leading to enhanced expression of Wnt genes. In addition, expression levels of H2BS36p and H3K27me3 are highly elevated in white adipose tissues from mice fed on high-fat diet or from obese humans. These findings describe a novel role of S6K1 as a transcriptional regulator controlling an epigenetic network initiated by phosphorylation of H2B and trimethylation of H3, thus shutting off Wnt gene expression in early adipogenesis.

• 한국발생생물학회지:발생과생식
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• 제11권3호
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• pp.141-153
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• 2007

Wnt 신호 전달 과정은 다세포 생물체의 발생 과정에서 세포의 증식이나 분화를 조절하거나 성인 조직에서 항상성을 유지하는데 결정적인 역할을 한다. 따라서 Wnt 신호 전달의 조절에 이상이 생기면 암을 비롯한 다양한 질병이 유발되어진다. 최근 들어서 Wnt 신호 전달의 이상에 의해 유도될 것이라고 생각되어지는 질병의 수가 많아져서, Wnt 신호 전달의 조절에 관심을 갖는 연구자가 많아지고 있다. 많은 리뷰 논문이 출판되었지만, 대부분의 경우 Wnt 전문가들을 위한 특정 논제를 다루는 경우가 많기 때문에, 처음으로 Wnt 신호 전달을 연구하고자 하는 연구자들이 Wnt 신호 전달의 전체적인 흐름을 파악하는데 어려움을 겪는 예가 있다. 본 총설에서는 Wnt 신호 전달 과정을 전체적으로 설명함으로써 Wnt 신호 전달에서 우리가 알고 있는 사실과 앞으로 연구되어야 할 내용들을 이해하고자 한다.

• Molecules and Cells
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• 제40권1호
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• pp.45-53
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• 2017

Aberrant hypermethylation of Wnt antagonists has been observed in gastric cancer. A number of studies have focused on the hypermethylation of a single Wnt antagonist and its role in regulating the activation of signaling. However, how the Wnt antagonists interacted to regulate the signaling pathway has not been reported. In the present study, we systematically investigated the methylation of some Wnt antagonist genes (SFRP2, SFRP4, SFRP5, DKK1, DKK2, and APC) and their regulatory role in carcinogenesis. We found that aberrant promoter methylation of SFRP2, SFRP4, DKK1, and DKK2 was significantly increased in gastric cancer. Moreover, concurrent hypermethylation of SFRP2 and DKK2 was observed in gastric cancer and this was significantly associated with increased expression of ${\beta}-catenin$, indicating that the joint inactivation of these two genes promoted the activation of the Wnt signaling pathway. Further analysis using a multivariate Cox proportional hazards model showed that DKK2 methylation was an independent prognostic factor for poor overall survival, and the predictive value was markedly enhanced when the combined methylation status of SFRP2 and DKK2 was considered. In addition, the methylation level of SFRP4 and DKK2 was correlated with the patient's age and tumor differentiation, respectively. In conclusion, epigenetic silencing of Wnt antagonists was associated with gastric carcinogenesis, and concurrent hypermethylation of SFRP2 and DKK2 could be a potential marker for a prognosis of poor overall survival.

• Animal Bioscience
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• 제34권6호
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• pp.993-1005
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• 2021

Objective: Zearalenone (ZEA) has estrogen-like effects. Our previous study has shown that ZEA (0.5 to 1.5 mg/kg) could induce abnormal uterine proliferation through transforming growth factor signaling pathway. To further study the other regulatory networks of uterine hypertrophy caused by ZEA, the potential mechanism of ZEA on porcine endometrial epithelial cells (PECs) was explored by the Illumina Hiseq 2000 sequencing system. Methods: The PECs were treated with ZEA at 0 (ZEA0), 5 (ZEA5), 20 (ZEA20), and 80 (ZEA80) µmol/L for 24 h. The collected cells were subjected to cell cycle, RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and western blot analysis. Results: The proportion of cells in the S and G2 phases decreased (p<0.05), but the proportion of cells in the G1 phase increased (p<0.05) in the ZEA80 treatment. Data analysis revealed that the expression of Wnt pathway-related genes, estrogen-related genes, and mitogen-activated protein kinase pathway-related genes increased (p<0.05), but the expression of genetic stability genes decreased (p<0.05) with increasing ZEA concentrations. The relative mRNA and protein expression of WNT1, β-catenin, glycogen synthase kinase 3β (GSK-3β) were increased (p<0.05) with ZEA increasing, while the relative mRNA and protein expression of cyclin D1 (CCND1) was decreased (p<0.05). Moreover, our immunofluorescence results indicate that β-catenin accumulated around the nucleus from the cell membrane and cytoplasm with increasing ZEA concentrations. Conclusion: In summary, ZEA can activate the Wnt/β-catenin signaling pathway by up-regulating WNT1 and β-catenin expression, to promote the proliferation and development of PECs. At the same time, the up-regulation of GSK-3β and down-regulation of CCND1, as well as the mRNA expression of other pathway related genes indicated that other potential effects of ZEA on the uterine development need further study.

• 생명과학회지
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• 제19권10호
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• pp.1346-1351
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• 2009

Neural crest는 신경계의 발생과정에서 생긴 특정화된 외배엽으로서 말초신경계(peripheral nervous system)의 모든 sensory cells과 peripheral cells, unipolar spinal ganglion cell, cranial sensory ganglia, peripheral nerve의 neurolemmal sheath cells, ganglia의 capsule cells, sympathetic ganglia, chromaffin cells, pigment cell 등의 자율신 경계의 대부분의 세포로 분화 한다. 최근pluripotetic neural crest cells의 운명이 이미 제한되어 있으며, 이러한 fate-restricted crest cells이 neural tube에서 emigration된다고 보고된바 있다. 또한 본 연구자는 Wnt와 Wnt의 antagonist가 neural crest cell의 specification이 일어나는 시기에 발현하여, neural crest cell의 segregation과 differentiation에 직접적으로 관여함을 밝혔다. 이를 보다 명확히 규명하기 위해, 본 연구에서는 neural tube에 Wnt-3a expressing cell의 grafting 혹은 dominant negative GSK construct의 electroporation을 통해 Wnt signaling을 modulation 하여 downstream mediator를 조사하였다. Wnt signaling의 stimulation은 neural crest cell의 melanoblast 로의 commitment를 유도하였으며, 이와 더불어 cadherin 7과 slug의 발현을 조절함을 확인하였다.

• BMB Reports
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• 제55권5호
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• pp.232-237
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• 2022

The Wnt/β-catenin signaling plays crucial roles in early development, tissue homeostasis, stem cells, and cancers. Here, we show that RNF152, an E3 ligase localized to lysosomes, acts as a negative regulator of the Wnt/β-catenin pathway during Xenopus early embryogenesis. Overexpression of wild-type (WT) RNF152 inhibited XWnt8-induced stabilization of β-catenin, ectopic expression of target genes, and activity of a Wnt-responsive promoter. Likewise, an E3 ligase-defective RNF152 had repressive effects on the Wnt-dependent gene responses but not its truncation mutant lacking the transmembrane domain. Conversely, knockdown of RNF152 further enhanced the transcriptional responses induced by XWnt8. RNF152 morphants exhibited defects in craniofacial structures and pigmentation. In line with this, the gain-of-RNF152 function interfered with the expression of neural crest (NC) markers, whereas its depletion up-regulated NC formation in the early embryo. Mechanistically, RNF152 inhibits the polymerization of Dishevelled, which is key to Wnt signaling, in an E3 ligase-independent manner. Together, these results suggest that RNF152 controls negatively Wnt/β-catenin signaling to fine-tune its activity for NC formation in Xenopus embryo.

• Molecules and Cells
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• 제41권2호
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• pp.110-118
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• 2018

The objective of this study was to induce the production of isthmic organizer (IsO)-like cells capable of secreting fibroblast growth factor (FGF) 8 and WNT1 from human embryonic stem cells (ESCs). The precise modulation of canonical Wnt signaling was achieved in the presence of the small molecule CHIR99021 ($0.6{\mu}M$) during the neural induction of human ESCs, resulting in the differentiation of these cells into IsO-like cells having a midbrain-hindbrain border (MHB) fate in a manner that recapitulated their developmental course in vivo. Resultant cells showed upregulated expression levels of FGF8 and WNT1. The addition of exogenous FGF8 further increased WNT1 expression by 2.6 fold. Gene ontology following microarray analysis confirmed that IsO-like cells enriched the expression of MHB-related genes by 40 fold compared to control cells. Lysates and conditioned media of IsO-like cells contained functional FGF8 and WNT1 proteins that could induce MHB-related genes in differentiating ESCs. The method for generating functional IsO-like cells described in this study could be used to study human central nervous system development and congenital malformations of the midbrain and hindbrain.