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Artykuły w czasopismach na temat "Notch pathway signalling"
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Lachej, Nadežda, Violeta Jonušienė, Augustina Mažeikė, Aušra Sasnauskienė, Daiva Dabkevičienė, Julija Šimienė, Kęstutis Sužiedėlis i Janina Didžiapetrienė. "Changes in the expression of Notch and Wnt signalling molecules in human endometrial cancer". Acta medica Lituanica 26, nr 3 (11.01.2020): 181–90. http://dx.doi.org/10.6001/actamedica.v26i3.4148.
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Background. Endometrial cancer is the sixth most frequent type of cancer among women worldwide. Type I adenocarcinomas account for 80–85% of endometrial cancer cases and sometimes require more aggressive treatment than the remaining part of this group. Therefore, molecular markers to stratify adenocarcinomas are needed. Materials and methods. In this study, we analysed Notch and Wnt signalling in human endometrial cancer cases to evaluate these pathway elements as potential biomarkers for type I endometrial cancer. Endometrial samples were obtained from 47 women undergoing surgery for stage I–IV endometrial cancer in the National Cancer Institute (Vilnius, Lithuania) in 2015–2016. The expression at the mRNA level of signalling molecules genes (NOTCH1, NOTCH2, NOTCH3, NOTCH4, JAG1, JAG2, DLL1, HES1, AXIN2 and CTNNB1) was analysed by the quantitative real-time polymerase chain reaction. Relative expression of NOTCH1, NOTCH4, HES1 and β-catenin proteins in endometrioid adenocarcinoma was evaluated by the Western blot method. Results. The expression level of Notch receptors, ligands, and the target gene, as well as CTNNB1 and AXIN2, was reduced in stage I endometrioid adenocarcinoma if compared to the adjacent non-tumour tissue. The expression of all receptors, ligands, and target molecules was reduced in adenocarcinomas of later stages. The statistically significant correlations between transcript amounts of Notch receptors and ligands were found. There was a statistically significant difference in the gene expression of Notch signalling pathway components between different tumour differentiation grade samples. A positive correlation between mRNA and protein the expression level of NOTCH1, NOTCH4, HES1 was determined in stage I samples. Conclusions. Analysis of 47 human endometrial cancer samples revealed a reduction in the transcript levels of Notch and Wnt signalling molecule compared to the adjacent non-tumour tissue. These results suggest tumour suppressor function of Notch and Wnt signalling in human endometrial cancer. More detailed research on these signalling pathways should reveal their importance as potential biomarkers.
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Ordonez, Liliana, Giusy Tornillo, Howard Kendrick, Trevor Hay i Matthew John Smalley. "NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity". Cancers 15, nr 17 (29.08.2023): 4324. http://dx.doi.org/10.3390/cancers15174324.
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A better understanding of the mechanisms generating tumour heterogeneity will allow better targeting of current therapies, identify potential resistance mechanisms and highlight new approaches for therapy. We have previously shown that in genetically modified mouse models carrying conditional oncogenic alleles, mammary tumour histotype varies depending on the combination of alleles, the cell type to which they are targeted and, in some cases, reproductive history. This suggests that tumour heterogeneity is not a purely stochastic process; rather, differential activation of signalling pathways leads to reproducible differences in tumour histotype. We propose the NOTCH signalling pathway as one such pathway. Here, we have crossed conditional knockout Notch1 or Notch2 alleles into an established mouse mammary tumour model. Notch1/2 deletion had no effect on tumour-specific survival; however, loss of Notch alleles resulted in a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs). ASQCs and adenomyoepitheliomas (AMEs) also demonstrated a significant increase in AKT signalling independent of Notch status. Therefore, the NOTCH pathway is a suppressor of the ASQC phenotype, while increased PI3K/AKT signalling is associated with ASQC and AME tumours. We propose a model in which PI3K/AKT and NOTCH signalling act interact to determine mouse mammary tumour histotype.
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Wang, Lin-Qing, Jing-Cai Liu, Chun-Lei Chen, Shun-Feng Cheng, Xiao-Feng Sun, Yong Zhao, Shen Yin i in. "Regulation of primordial follicle recruitment by cross-talk between the Notch and phosphatase and tensin homologue (PTEN)/AKT pathways". Reproduction, Fertility and Development 28, nr 6 (2016): 700. http://dx.doi.org/10.1071/rd14212.
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The growth of oocytes and the development of follicles require certain pathways involved in cell proliferation and survival, such as the phosphatidylinositol 3-kinase (PI3K) pathway and the Notch signalling pathway. The aim of the present study was to investigate the interaction between Notch and the PI3K/AKT signalling pathways and their effects on primordial follicle recruitment. When the Notch pathway was inhibited by L-685,458 or N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT) in vitro, the expression of genes in the pathway and the percentage of oocytes in growing follicles decreased significantly in mouse ovaries. By 2 days postpartum, ovaries exposed to DAPT, short interference (si) RNA against Notch1 or siRNA against Hairy and enhancer of split-1 (Hes1) had significantly decreased expression of HES1, the target protein of the Notch signalling pathway. In contrast, expression of phosphatase and tensin homologue (Pten), a negative regulator of the AKT signalling pathway, was increased significantly. Co immunoprecipitation (Co-IP) revealed an interaction between HES1 and PTEN. In addition, inhibition of the Notch signalling pathway suppressed AKT phosphorylation and the proliferation of granulosa cells. In conclusion, the recruitment of primordial follicles was affected by the proliferation of granulosa cells and regulation of the interaction between the Notch and PI3K/AKT signalling pathways.
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Pettersson, Susanne, Matylda Sczaniecka, Lorna McLaren, Fiona Russell, Karen Gladstone, Ted Hupp i Maura Wallace. "Non-degradative ubiquitination of the Notch1 receptor by the E3 ligase MDM2 activates the Notch signalling pathway". Biochemical Journal 450, nr 3 (28.02.2013): 523–36. http://dx.doi.org/10.1042/bj20121249.
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The Notch receptor is necessary for modulating cell fate decisions throughout development, and aberrant activation of Notch signalling has been associated with many diseases, including tumorigenesis. The E3 ligase MDM2 (murine double minute 2) plays a role in regulating the Notch signalling pathway through its interaction with NUMB. In the present study we report that MDM2 can also exert its oncogenic effects on the Notch signalling pathway by directly interacting with the Notch 1 receptor through dual-site binding. This involves both the N-terminal and acidic domains of MDM2 and the RAM [RBP-Jκ (recombination signal-binding protein 1 for Jκ)-associated molecule] and ANK (ankyrin) domains of Notch 1. Although the interaction between Notch1 and MDM2 results in ubiquitination of Notch1, this does not result in degradation of Notch1, but instead leads to activation of the intracellular domain of Notch1. Furthermore, MDM2 can synergize with Notch1 to inhibit apoptosis and promote proliferation. This highlights yet another target for MDM2-mediated ubiquitination that results in activation of the protein rather than degradation and makes MDM2 an attractive target for drug discovery for both the p53 and Notch signalling pathways.
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Li, Liming, Xiaqing Liu, Mingguang Zhao, Peng Guo i Haifeng Zhang. "Effects of serum starvation and vascular endothelial growth factor stimulation on the expression of Notch signalling pathway components". Science Progress 104, nr 3 (lipiec 2021): 003685042110283. http://dx.doi.org/10.1177/00368504211028387.
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Brain arteriovenous malformation (BAVM) is an abnormality in the cerebral vascular system. Although the upregulation of the Notch signalling pathway is a deterministic factor in BAVM, the mechanism by which this pathway is upregulated in patients with BAVM is uncertain. The effects of serum starvation and vascular endothelial growth factor (VEGF) stimulation on the Notch signalling pathway in brain microvascular endothelial cells (MECs) and mouse embryonic stem (mES)/embryoid body (EB)-derived endothelial cells were investigated in this study. The duration of serum starvation and VEGF concentration were changed, cell viability was measured, and reasonable time and concentration gradients were selected for subsequent studies. Protein and mRNA expression levels of Notch signalling pathway components in both MECs and mES/EB-derived endothelial cells were detected using western blotting and real-time PCR, respectively. Expression levels of the Notch1, Notch4, Jagged1, delta-like ligand 4 (Dll4) and Hes1 proteins and mRNAs were upregulated by lower VEGF concentrations and shorter-term serum starvation but inhibited by higher VEGF concentrations and longer-term serum starvation. This study revealed effects of changes in the duration of serum starvation and VEGF concentration on the expression of Notch signalling pathway components in both MECs and mES/EB-derived endothelial cells, potentially contributing to BAVM formation.
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Pompa de la, J. L., A. Wakeham, K. M. Correia, E. Samper, S. Brown, R. J. Aguilera, T. Nakano i in. "Conservation of the Notch signalling pathway in mammalian neurogenesis". Development 124, nr 6 (15.03.1997): 1139–48. http://dx.doi.org/10.1242/dev.124.6.1139.
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The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.
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Lustofin, Sylwia, Alicja Kamińska, Małgorzata Brzoskwinia, Laura Pardyak, Piotr Pawlicki, Izabela Szpręgiel, Barbara Bilińska i Anna Hejmej. "Follicle-stimulating hormone regulates Notch signalling in the seminiferous epithelium of continuously and seasonally breeding rodents". Reproduction, Fertility and Development 34, nr 7 (11.02.2022): 560–75. http://dx.doi.org/10.1071/rd21237.
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Context Juxtacrine (contact-dependent) communication between the cells of seminiferous epithelium mediated by Notch signalling is of importance for the proper course of spermatogenesis in mammals. Aims The present study was designed to evaluate the role of follicle-stimulating hormone (FSH) in the regulation of Notch signalling in rodent seminiferous epithelium. Methods We explored the effects (1) of pharmacological inhibition of the hypothalamus–pituitary–gonadal (HPG) axis and FSH replacement in pubertal rats, and (2) of photoinhibition of HPG axis followed by FSH substitution in seasonally breeding rodents, bank voles, on Notch pathway activity. Experiments on isolated rat Sertoli cells exposed to FSH were also performed. Gene and protein expressions of Notch pathway components were analysed using RT-qPCR, western blot and immunohistochemistry/immunofluorescence. Key results Distribution patterns of Notch pathway proteins in bank vole and rat seminiferous epithelium were comparable; however, levels of activated Notch1 and Notch3, hairy/enhancer of split 1 (HES1) and hairy/enhancer of split-related with YRPW motif 1 (HEY1) in bank voles were dependent on the length of the photoperiod. In response to FSH similar changes in these proteins were found in both species, indicating that FSH is a negative regulator of Notch pathway activity in seminiferous epithelium. Conclusions Our results support a common mechanism of FSH action on Notch pathway during onset and recrudescence of spermatogenesis in rodents. Implications Interaction between FSH signalling and Notch pathway in Sertoli cells may be involved in spermatogenic activity changes of the testes occurring during puberty or photoperiod shift in continuously and seasonally breeding rodents, respectively.
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Lin, Neng-Yu, Alfiya Distler, Christian Beyer, Ariella Philipi-Schöbinger, Silvia Breda, Clara Dees, Michael Stock i in. "Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis". Annals of the Rheumatic Diseases 75, nr 11 (5.02.2016): 2037–44. http://dx.doi.org/10.1136/annrheumdis-2015-208420.
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ObjectivesNotch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice.MethodsNotch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments.ResultsNotch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1.ConclusionsInhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.
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Zen, Ayman Al Haj, i Paolo Madeddu. "Notch signalling in ischaemia-induced angiogenesis". Biochemical Society Transactions 37, nr 6 (19.11.2009): 1221–27. http://dx.doi.org/10.1042/bst0371221.
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Notch signalling represents a key pathway essential for normal vascular development. Recently, great attention has been focused on the implication of Notch pathway components in postnatal angiogenesis and regenerative medicine. This paper critically reviews the most recent findings supporting the role of Notch in ischaemia-induced neovascularization. Notch signalling reportedly regulates several steps of the reparative process occurring in ischaemic tissues, including sprouting angiogenesis, vessel maturation, interaction of vascular cells with recruited leucocytes and skeletal myocyte regeneration. Further characterization of Notch interaction with other signalling pathways might help identify novel targets for therapeutic angiogenesis.
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Sun, Xiao-Feng, Xing-Hong Sun, Shun-Feng Cheng, Jun-Jie Wang, Yan-Ni Feng, Yong Zhao, Shen Yin, Zhu-Mei Hou, Wei Shen i Xi-Feng Zhang. "Interaction of the transforming growth factor-β and Notch signaling pathways in the regulation of granulosa cell proliferation". Reproduction, Fertility and Development 28, nr 12 (2016): 1873. http://dx.doi.org/10.1071/rd14398.
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The Notch and transforming growth factor (TGF)-β signalling pathways play an important role in granulosa cell proliferation. However, the mechanisms underlying the cross-talk between these two signalling pathways are unknown. Herein we demonstrated a functional synergism between Notch and TGF-β signalling in the regulation of preantral granulosa cell (PAGC) proliferation. Activation of TGF-β signalling increased hairy/enhancer-of-split related with YRPW motif 2 gene (Hey2) expression (one of the target genes of the Notch pathway) in PAGCs, and suppression of TGF-β signalling by Smad3 knockdown reduced Hey2 expression. Inhibition of the proliferation of PAGCs by N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT), an inhibitor of Notch signalling, was rescued by both the addition of ActA and overexpression of Smad3, indicating an interaction between the TGF-β and Notch signalling pathways. Co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assays were performed to identify the point of interaction between the two signalling pathways. CoIP showed direct protein–protein interaction between Smad3 and Notch2 intracellular domain (NICD2), whereas ChIP showed that Smad3 could be recruited to the promoter regions of Notch target genes as a transcription factor. Therefore, the findings of the present study support the idea that nuclear Smad3 protein can integrate with NICD2 to form a complex that acts as a transcription factor to bind specific DNA motifs in Notch target genes, such as Hey1 and Hey2, and thus participates in the transcriptional regulation of Notch target genes, as well as regulation of the proliferation of PAGCs.
Rozprawy doktorskie na temat "Notch pathway signalling"
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Collu, Giovanna Maria. "Crosstalk between dishevelled and the notch signalling pathway". Thesis, University of Manchester, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492040.
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De, Celis Ibeas Jesus Maria. "Identification of new targets of the notch signalling pathway". Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621218.
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Mansour, M. R. "Role of the Notch signalling pathway in acute leukaemia". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1420122/.
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The Notch signalling pathway is important in development and differentiation of a diverse range of both embryonic and adult tissues. There is now strong evidence implicating aberrant Notch signalling in the pathogenesis of T-cell acute lymphoblastic leukaemia (T-ALL), with over 50% of paediatric patients having activating mutations in NOTCH-1. This thesis aims to explore several aspects of the Notch pathway in both T-ALL and acute myeloid leukaemia (AML). Chapter one summarises the published data on the Notch signalling pathway itself, addressing the basic understanding of Notch activation through cell-to-cell interaction, as well as the mechanisms through which it is regulated. The role that Notch signaling plays in normal haematopoiesis is also discussed. Chapter three addresses the incidence and characteristics of NOTCH-1 mutations in a cohort of adult patients with T-ALL in comparison to the published study of paediatric T-ALL, as well as in a cohort of patients with infantile leukaemia and AML. Secondly, the prognostic significance of NOTCH-1 and FBXW7 mutation status of adult T-ALL patients treated on the UKALLXII was investigated. Thirdly, a novel mutation affecting the LNR domain of NOTCH-1 is reported. Chapter four includes data quantifying NOTCH-1 mutation level in T-ALL patients, as well as the stability of NOTCH-1 mutations at presentation and relapse. These data indicate NOTCH-1 mutations commonly occur as secondary events in leukaemia pathogenesis, and suggest widespread clonal heterogeneity in T-ALL. Chapter five explores the functional and prognostic consequences of a novel alternatively spliced isoform of the CSL transcription factor in AML, which was termed CSL-TREX (for TRuncates Exon X). The functional consequences of expressing CSL-TREX in CD34+ cells, in luciferase reporter assays and co-immunoprecipitation experiments with NOTCH-1 is reported. Chapter six summarises the overall implications of these findings to T-ALL and AML, and the future directions of research in this area.
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Shao, Jin. "Notch signalling pathway regulates the terminal differentiation of osteoblasts". Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/119172/2/Jin_Shao_Thesis.pdf.
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This project contributes to our understanding of bone cell biology and sheds light on the potential therapeutic application of Notch signalling pathway on bone-related diseases. The thesis was a step forward in answering how bone cells communicate with each other and determinate their own fates. It provides the first evidence demonstrating Notch signalling is critical in bone cell functions.
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Huang, Caoxin. "Notch signalling pathway in murine embryonic stem cell derived haematopoiesis". Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8071.
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Haematopoiesis is the process to produce haematopoietic stem cells (HSCs), haematopoietic progenitors (HPCs) and terminally differentiated cell types. In the adult, HSCs resided in bone marrow while in the embryo, haematopoiesis occurred sequentially in several niches including yolk sac, aorta-gonad-mesonephros (AGM) region, placenta and fetal liver. The AGM region is the first place where HSCs arise in vivo and therefore should provide important factors to induce haematopoiesis. The mouse embryonic stem cells (mESC) system is a powerful platform to mimic the development process in vitro and is widely utilized to study the underlying mechanisms because they are pluripotent and can be genetically manipulated. A novel co-culture system has been established by culturing differentiating mESCs with primary E10.5 AGM explants and a panel of clonal stromal cell lines derived from dorsal aorta and surrounding mesenchyme (AM) in AGM region. Results of these co-culture studies suggested that the AM-derived stromal cell lines could be a potent resource of signals to enhance haematopoiesis. Molecular mechanism involved in haematopoiesis is a key research direction for understanding the regulation network of haematopoiesis and for further clinical research. A series of studies have demonstrated involvement of the Notch signalling pathway in haematopoiesis during development but with controversial conclusions because of the difference of models concerning various time windows and manipulating populations. This project aimed to investigate the role of Notch signalling pathway during haematopoiesis in the AGM environment. We analyzed the expression of Notch ligands in AGM-derived stromal cells with or without haematopoietic enhancing ability. No correlation was observed between ligand expression and haematopoietic enhancing ability in stromal cell lines or between Notch activity in EBs and haematopoietic enhancing ability. We demonstrated that inhibition of the Notch signalling pathway using the γ-secretase inhibitor could abrogate Notch activity in both mES-derived cells and the haematopoietic enhancing AM stromal cell line. To better understand the involvement of the Notch signalling pathway in a more specific spatial-temporal environment, we established a co-culture system of haemangioblast like cells (Flk1+) with one of AM region derived stromal cell lines with haematopoietic enhancing ability . We found that the AM stromal cell line could enhance Flk1+ derived haematopoiesis as assessed by haematopoietic colony formation activity and production of CD41+cKit+ progenitor cells. Based on the issue that the inhibitor could potentially affect both the ES cells and stromal cells, we carried out genetic approaches to overexpress or knock down Notch signalling pathway in this Flk1+/AM co-culture system. Interestingly, it was found that when Notch activity was enhanced in Flk1+ cells, the production of haematopoietic progenitors was inhibited and the number of cells expressing the pan-haematopoietic marker CD45 was reduced. By using the inducible dominant negative MAML1 system to knock down Notch activity, it was found that the haematopoiesis in the Flk1+/AM co-culture system was not affected, which could be accounted for the low Notch activity in this system. These results supported the hypothesis that the Notch signalling pathway plays a role in modulating Flk1+ derived haematopoietic differentiation within the AGM microenvironment.
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López-Schier, Hernán Marcelo. "The role of the notch signalling pathway in Drosophila axis formation". Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620532.
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Stephenson, Natalie. "Mechanotransduction of the Notch signalling pathway via the negative regulatory region". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/mechanotransduction-of-the-notch-signalling-pathway-via-the-negative-regulatory-region(c13c0f01-3095-4895-a536-1dfc324d9899).html.
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The Notch receptor is part of a highly conserved omnipresent developmental pathway that has crucial roles in developing and self-renewing tissues. During activation of the signalling pathway Notch binds to its ligand, presented on a neighbouring cell. It is thought that this results in a conformational change within the Negative Regulatory Region (NRR) unmasking a key proteolytic site (S2) and allows for metalloprotease cleavage. This facilitates further cleavage by gamma-secretase, initiating downstream events. Thus far, the molecular mechanism by which the S2 site is revealed has not been defined, though indirect evidence favours a model whereby transendocytosis of the Notch extracellular domain into the ligand bearing cell results in mechanical unfolding of the NRR. Research presented here suggests the NRR of human Notch2 (hN2) unfolds within a mechanosensing force range. Furthermore, through the application of a force (200 pN) the hN2-NRR was shown to unfold sufficiently to expose the S2 site allowing cleavage by metalloproteases. Molecular dynamics (MD) simulations offer insight into the unfolding process of the hN2-NRR, revealing near-sequential unfolding of its constituent LNR and HD domains. Removing the linker region between LNR’s A and B appears to be the first force ‘barrier’ in the unfolding pathway, producing the largest increase in solvent accessibility at the S2 cleavage site. Through docking simulations, this unfolding event was shown to expose the S2 cleavage site sufficiently to allow access to the metalloprotease TACE. Removing coordinated metal ions from the hN2-NRR structure resulted in a dramatic decrease in the forces required for unfolding during AFM experiments, highlighting their role in increasing the resistance of the hN2-NRR to forced unfolding. Removal of disulphide bonds within the structure resulted in a loss of detectable LNR unfolding, highlighting their role in LNR stabilisation.Six HD destabilising mutants, characterised through their role in the hN1 disease, T-cell Acute Lymphoblastic Leukemia, showed three key changes to the unfolding pathway of the hN2-NRR. Firstly, mutants A1647P, L1573P and V1623D showed a dramatic decrease in force required for unfolding in AFM experiments. MD simulations highlighted a lack of force required for the unfolding the LNRA:B linker previously characterised as the key event in removing NRR autoinhibition. Secondly, all the mutants studied here showed changes to the stability of the alpha3-helix (within the HD domain) resulting in transient shifts or bending during unfolding of the LNRA:B linker and the LNRB. Finally, changes were observed within the LNRC of A1647P and L1566P. Within these mutants the LNRC was observed to be unfolding, an event not present during wild-type unfolding. Within mutant L1566P this is thought to be due to the disruption of the conserved salt-bridge occurring between Arg1567 (HD domain) and Asp1506 (LNRC). Within mutant A1647P this is likely due to widespread domain destabilisation. Overall, research presented here has provided the first direct evidence that the NRR is mechanosensing and that mechanical force can allow for cleavage at the S2 site. Further characterisation has been performed to analyse the unfolding pathway through ion chelation, disulphide oxidation and mutagenesis studies.
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Liu, Dong. "Towards understanding the signalling requirements of thymic epithelial progenitor cells". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31405.
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Thymic epithelial cells (TECs) are indispensable for the development of T cells in the thymus. Two subtypes of TECs exist in the thymus, medullary mTECs and cortical cTECs. Both mTECs and cTECs originate from endodermal thymic epithelial progenitor cells (TEPCs) in the embryo, but how the differentiation of TEPCs is regulated is not well understood. The aims of this thesis were to establish the role of Notch signalling in TEPC differentiation, and how it interacts with known regulators such as FOXN1 and the NFκB pathway. Gene expression data showed that Notch is active in TEPCs and exhibits a correlation with the mTEC lineage. Loss of Notch function led to a significant reduction in the number of mTECs in the thymus, and this can be attributed to aberrant mTEC specification. Furthermore, the duration of Notch activity in determining mTEC number appears limited to the early phase of organogenesis, and precedes RANK/NFκB mediated mTEC proliferation. Gain of Notch function resulted in a considerable shift to a primitive, TEPC-like phenotype, and subsequently a latent increase in mTEC frequency. Finally, transcriptomic and functional analyses pointed to a cross-repressive mechanism between Notch and FOXN1 in TEPCs. Taken together, these results identified Notch as a novel regulator of mTEC specification, likely through maintaining the potency of fetal TEPCs, a prerequisite for mTEC lineage commitment.
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Gupta, D. "Structural and functional study on Notch signalling pathway and its regulatory proteins". Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599795.
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The cell surface Notch receptor and its ligand, presented on adjacent cells, bind through their extracellular regions and lead to the release of Notch intracellular domain (NICD). NICD then translocates to the nucleus to form the Notch transcription activating complex. ANK domain of NICD plays an essential part in the formation of this complex and the role of ANK domain was analysed both structurally and functionally using site directed mutagenesis. A single residue E2072 on the sixth ANK repeat was found crucial to maintain the stability of the Notch transcription activating complex. It can therefore be considered as a putative “hot-spot” for the purpose of drug discovery. Recently the interaction of Neutralized (an E3 ubiquitin ligase) with Tom (a Bearded protein) was identified. This study was undertaken to understand and structurally characterise the Tom-Neuralized interaction. Expression constructs were designed using the information from sequence analysis of Tom and Neuralized proteins and expressed using bacterial expression system. The NHR1 domain, expressed as an N-terminal His-tag protein, was used to determine the crystal structure of NHR1 domain. The structure was found to be structurally related to SPRY proteins consisting of jelly roll topology. Potential binding sites were predicted that localised on a cluster referred as ‘hydrophobic patch’ in this study. The expression of Tom remained insoluble under most experimental conditions and therefore a 12 amino acid peptide was synthesized. Biophysical analysis showed the binding affinity between NHR1 and Tom was weak but still could form the complex. Comparison of NHR and SPRY domain proteins suggested that the binding interface of the two could be common indicating that the interaction of Delta could require the same binding interface of NHR1 domain as Tom. Lastly, interaction of NHR1 with PI4P was analysed and verified using interfacial studies, which showed that NHR1 protein localised below the lipidic layer.
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Lendínez, Javier González. "Unravelling a new role of Notch signalling pathway in HSC development using a Hes1-EGFP mouse model". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25897.
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In the mid-gestation embryo, the first definitive transplantable hematopoietic stem cells (dHSCs) emerge by embryonic day E10.5-E11 in the aorta-gonadomesonephros (AGM) region, as a result of a step-wise maturation of precursors called pre-HSCs. The analysis of several Notch mutants suggests that Notch signalling is essential for the execution of the definitive hematopoietic programme in the AGM. Mouse embryos deficient for Notch1, RBP-Jk or Jagged1 cannot efficiently generate intra-embryonic hematopoeitic progenitors. It has also been reported that knockdown of Notch target genes (Hes1, Hes5) results in hematopoietic impairment. However a clear picture of the role of Notch pathway in HSC development is still missing. In this work we characterised precise stages and cell types during HSC development in which Notch signalling is involved. First we used a Hes1-dEGFP reporter mouse line that allowed us to monitor Notch pathway activity in a narrow window of time. The results suggest that the level of Notch activity fluctuates in HSC lineage in the AGM region and is down-regulated in dHSCs in the foetal liver (where dHSCs migrate after generation in the AGM region). By using transplantation assay, we further showed that fluctuations of Notch activity are essential for HSC development, and that this pattern in the HSC lineage might work as a switch between maturation and proliferation of PreHSC1, PreHSC2 and dHSC, in which temporary decrease might be required to mature from one type to another, both in vitro and in vivo. These findings might need to be taken into consideration for in vitro generation of haematopoietic stem cells, where a fine tuning of Notch signalling activity could greatly improve their emergence.
Książki na temat "Notch pathway signalling"
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D’Amato, Gaetano, Guillermo Luxán i José Luis de la Pompa. Defining cardiac domains from the inside: NOTCH in endocardial–myocardial interactions. Redaktorzy José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso i Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0011.
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In this chapter we illustrate the signalling interactions of the endocardium with the other cardiac tissues to coordinate cardiac development. First, we describe the developmental origins of the endocardium. Then we focus on the Notch pathway because of its unique signalling activity in the endocardium, and briefly describe the elements of this signalling mechanism and the key cardiogenic processes that require endocardial Notch signalling: patterning of the early embryonic endocardium into prospective territories for valves and ventricular chambers, early valve formation, ventricular trabeculation, and compaction. Finally, we discuss how Notch dysfunction in the endocardium results in cardiac structural malformations that can lead to congenital heart disease.
Części książek na temat "Notch pathway signalling"
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Robert, Jacques. "Notch Pathway". W Textbook of Cell Signalling in Cancer, 101–7. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-14340-8_8.
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Alsiary, Rawiah A., Talat Abdullah Albukhari i Waheed A. Filimban. "Transcription Factors in Cancer". W Molecular Targets and Cancer Therapeutics (Part 1), 273–319. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815080384123010010.
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Different types of signalling pathways have been approved to be involved in cancer imitation and progression. These signalling pathways include the JAK-STAT signalling, NF-κB signalling, Wnt, Notch and Hedgehog. STAT (Signal Transducer and Activator of Transcription) transports signals between proteins from the cell membrane into the nucleus to contribute to cancer progression. NF-κB signalling is essential for the survival of the B cell tumor types. The Wnt, Notch, and Hedgehog signalling pathways play a significant role in carcinogenesis by upregulating the genes associated with these pathways. Hence, pharmacological inhibitors of WNT, NOTCH, and HH pathways are required in clinical studies. Such inhibitors have features that make them important during the clinical trial since they offer great potential as novel therapeutics for cancer. They also have an antitumor response which should be taken into consideration. The three signalling pathways are also known to shape cell fate determination and differentiation. In case of depletion of a single molecular component within the three pathways, embryonic lethality will form.
Streszczenia konferencji na temat "Notch pathway signalling"
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Giuranno, L., C. Wansleeben, L. Barbeau i M. Vooijs. "PO-107 Notch signalling pathway is required for proliferation, repair and differentiation of primary human lung stem cells upon irradiation". W Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.632.
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Novikova, M., N. Khromova, V. Rybko, V. Dugina, B. Kopnin i P. Kopnin. "PO-081 Notch signalling pathway plays a crucial role in maintaining the cancer stem cell population in lung and colorectal cancer". W Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.124.
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Brilliant, A., Y. Brilliant i S. Sazonov. "PO-270 Signalling pathways WNT, hedgehog and NOTCH in breast cancer with presence and absence of cancer stem cells". W Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.301.
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