• 제목/요약/키워드: Notch pathways

검색결과 26건 처리시간 0.026초

Interacting network of Hippo, Wnt/β-catenin and Notch signaling represses liver tumor formation

  • Kim, Wantae;Khan, Sanjoy Kumar;Yang, Yingzi
    • BMB Reports
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    • 제50권1호
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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.

Epithelial-mesenchymal Transition and Cell Invasion

  • Son, Hwa-Jin;Moon, Aree
    • Toxicological Research
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    • 제26권4호
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    • pp.245-252
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    • 2010
  • Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF)-$\beta$, Wnt, and Notch signaling pathways, have been shown to induce EMT. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Mounting evidence shows that EMT is associated with cell invasion and tumor progression. In this review, we summarize the characteristic features of EMT, pathways leading to EMT, and the role of EMT in cell invasion. Three topics are addressed in this review: (1) Definition of EMT, (2) Signaling pathways leading to EMT, (3) Role of EMT in cell invasion. Understanding the role of EMT in cell invasion will provide valuable information for establishing strategies to develop anti-metastatic therapeutics which modulate malignant cellular processes mediated by EMT.

Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

  • Kobet, Robert A.;Pan, Xiaoping;Zhang, Baohong;Pak, Stephen C.;Asch, Adam S.;Lee, Myon-Hee
    • Biomolecules & Therapeutics
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    • 제22권5호
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    • pp.371-383
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    • 2014
  • The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.

The Role of a Neurovascular Signaling Pathway Involving Hypoxia-Inducible Factor and Notch in the Function of the Central Nervous System

  • Kim, Seunghee;Lee, Minjae;Choi, Yoon Kyung
    • Biomolecules & Therapeutics
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    • 제28권1호
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    • pp.45-57
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    • 2020
  • In the neurovascular unit, the neuronal and vascular systems communicate with each other. O2 and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O2 and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson's disease, and Alzheimer's disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.

Pathway Crosstalk Analysis Based on Protein-protein Network Analysis in Ovarian Cancer

  • Pan, Xiao-Hua
    • Asian Pacific Journal of Cancer Prevention
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    • 제13권8호
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    • pp.3905-3909
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    • 2012
  • Ovarian cancer is the fifth leading cause of cancer death in women aged 35 to 74 years. Although there are several popular hypothesis of ovarian cancer pathogenesis, the genetic mechanisms are far from being clear. Recently, systems biology approaches such as network-based methods have been successfully applied to elucidate the mechanisms of diseases. In this study, we constructed a crosstalk network among ovarian cancer related pathways by integrating protein-protein interactions and KEGG pathway information. Several significant pathways were identified to crosstalk with each other in ovarian cancer, such as the chemokine, Notch, Wnt and NOD-like receptor signaling pathways. Results from these studies will provide the groundwork for a combination therapy approach targeting multiple pathways which will likely be more effective than targeting one pathway alone.

Transcriptional Properties of the BMP, $TGF-\beta$, RTK, Wnt, Hh, Notch, and JAK/STAT Signaling Molecules in Mouse Embryonic Stem Cells

  • Rho Jeung-Yon;Bae Gab-Yong;Chae Jung-Il;Yu Kweon;Koo Deog-Bon;Lee Kyung-Kwang;Han Yong-Mahn
    • Reproductive and Developmental Biology
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    • 제30권2호
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    • pp.143-156
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    • 2006
  • Major characteristics of embryonic stem cells (ESCs) are sustaining of sternness and pluripotency by self-renewal. In this report, transcriptional profiles of the molecules in the developmentally important signaling pathways including Wnt, BMP4, $TGF-\beta$, RTK, Hh, Notch, and JAK/STAT signaling pathways were investigated to understand the self-renewal of mouse ESCs (mESCs), J1 line, and compared with the NIH3T3 cell line and mouse embryonic fibroblast (MEF) cells as controls. In the Wnt signaling pathway, the expression of Wnt3 was seen widely in mESCs, suggesting that the ligand may be an important regulator for self-renewal in mESCs. In the Hh signaling pathway, the expression of Gli and N-myc were observed extensively in mESCs, whereas the expression levels of in a Shh was low, suggesting that intracellular molecules may be essential for the self-renewal of mESCs. IGF-I, IGF-II, IGF-IR and IGF-IIR of RTK signaling showed a lower expression in mESCs, these molecules related to embryo development may be restrained in mESCs. The expression levels of the Delta and HESS in Notch signaling were enriched in mESCs. The expression of the molecules related to BMP and JAK-STAT signaling pathways were similar or at a slightly lower level in mESCs compared to those in MEF and NIH3T3 cells. It is suggested that the observed differences in gene expression profiles among the signaling pathways may contribute to the self-renewal and differentiation of mESCs in a signaling-specific manner.

Roles of Signaling Pathways in the Epithelial-Mesenchymal Transition in Cancer

  • Liu, Xia;Yun, Fen;Shi, Lin;Li, Zhe-Hai;Luo, Nian-Rong;Jia, Yong-Feng
    • Asian Pacific Journal of Cancer Prevention
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    • 제16권15호
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    • pp.6201-6206
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    • 2015
  • The epithelial-mesenchymal transition (EMT) is a cellular process though which an epithelial phenotype can be converted into a phenotype of mesenchymal cells. Under physiological conditions EMT is important for embryogenesis, organ development, wound repair and tissue remodeling. However, EMT may also be activated under pathologic conditions, especially in carcinogenesis and metastatic progression. Major signaling pathways involved in EMT include transforming growth factor ${\beta}(TGF-{\beta})$, Wnt, Notch, Hedgehog and other signaling pathways. These pathways are related to several transcription factors, including Twist, Smads and zinc finger proteins snail and slug. These interact with each other to provide crosstalk between the relevant signaling pathways. This review lays emphasis on studying the relationship between EMT and signaling pathways in carcinogenesis and metastatic progression.

Cancer Stem Cells and Response to Therapy

  • Tabarestani, Sanaz;Ghafouri-Fard, Soudeh
    • Asian Pacific Journal of Cancer Prevention
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    • 제13권12호
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    • pp.5947-5954
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    • 2012
  • The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal, either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be due to their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.

제브라피쉬를 이용한 새로운 유전자의 발굴 및 기능분석 (Zebrafish as a Tool for Function Genomics)

  • 김현택;김철희
    • 한국발생생물학회지:발생과생식
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    • 제7권2호
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    • pp.69-80
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    • 2003
  • 대량의 발생 유전학적 연구가 가능한 척추동물로서 최근 제브라피쉬가 새로운 동물모델로 급부상하고 있다 다양한 형태의 돌연변이들로부터 새로운 유전자들이 발굴되어지고 있으며, 인간 유전체의 기능 분석 수단으로 활용되어지고 있다. 신경계의 형성과 분화에 이상이 있는 hendless와 mind bomb이라는 두 가지 돌연변이주에서 positional cloning에 의한 원인 유전자의 발굴과 기능 분석의 예로써 현재 제브라피쉬의 연구 현황을 살펴보고자 한다. headless의 원인 유전자로 Tcf-3가 밝혀졌으며, 초기 발생단계에서 Wnt 신호전달이 두뇌의 형태형성과 영역 결정에서 핵심적 역할을 하고 있다는 사실이 밝혀졌다. mind bomb에서의 비정상적인 신경세포의 운명 결정은 lateral inhibition과 Notch 신호전달의 결함에 의한 것이고, 그 원인 유전자는 Notch ligand인 Delta에 결합하는 새로운 ubiquitin E3 ligase로 밝혀졌다. 이러한 돌연변이를 통한 연구는 현재 인간 질환모델의 개발이라는 방향으로 확대되고 있다.

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Indole-3-Carbinol Promotes Goblet-Cell Differentiation Regulating Wnt and Notch Signaling Pathways AhR-Dependently

  • Park, Joo-Hung;Lee, Jeong-Min;Lee, Eun-Jin;Hwang, Won-Bhin;Kim, Da-Jeong
    • Molecules and Cells
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    • 제41권4호
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    • pp.290-300
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    • 2018
  • Using an in vitro model of intestinal organoids derived from intestinal crypts, we examined effects of indole-3-carbinol (I3C), a phytochemical that has anticancer and aryl hydrocarbon receptor (AhR)-activating abilities and thus is sold as a dietary supplement, on the development of intestinal organoids and investigated the underlying mechanisms. I3C inhibited the in vitro development of mouse intestinal organoids. Addition of ${\alpha}$-naphthoflavone, an AhR antagonist or AhR siRNA transfection, suppressed I3C function, suggesting that I3C-mediated interference with organoid development is AhR-dependent. I3C increased the expression of Muc2 and lysozyme, lineage-specific genes for goblet cells and Paneth cells, respectively, but inhibits the expression of IAP, a marker gene for enterocytes. In the intestines of mice treated with I3C, the number of goblet cells was reduced, but the number of Paneth cells and the depth and length of crypts and villi were not changed. I3C increased the level of active nonphosphorylated ${\beta}$-catenin, but suppressed the Notch signal. As a result, expression of Hes1, a Notch target gene and a transcriptional repressor that plays a key role in enterocyte differentiation, was reduced, whereas expression of Math1, involved in the differentiation of secretory lineages, was increased. These results provide direct evidence for the role of AhR in the regulation of the development of intestinal stem cells and indicate that such regulation is likely mediated by regulation of Wnt and Notch signals.