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Lachej, Nadežda, Violeta Jonušienė, Augustina Mažeikė, Aušra Sasnauskienė, Daiva Dabkevičienė, Julija Šimienė, Kęstutis Sužiedėlis, and Janina Didžiapetrienė. "Changes in the expression of Notch and Wnt signalling molecules in human endometrial cancer." Acta medica Lituanica 26, no. 3 (January 11, 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, and Matthew John Smalley. "NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity." Cancers 15, no. 17 (August 29, 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, et al. "Regulation of primordial follicle recruitment by cross-talk between the Notch and phosphatase and tensin homologue (PTEN)/AKT pathways." Reproduction, Fertility and Development 28, no. 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, and Maura Wallace. "Non-degradative ubiquitination of the Notch1 receptor by the E3 ligase MDM2 activates the Notch signalling pathway." Biochemical Journal 450, no. 3 (February 28, 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, and Haifeng Zhang. "Effects of serum starvation and vascular endothelial growth factor stimulation on the expression of Notch signalling pathway components." Science Progress 104, no. 3 (July 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, et al. "Conservation of the Notch signalling pathway in mammalian neurogenesis." Development 124, no. 6 (March 15, 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, and Anna Hejmej. "Follicle-stimulating hormone regulates Notch signalling in the seminiferous epithelium of continuously and seasonally breeding rodents." Reproduction, Fertility and Development 34, no. 7 (February 11, 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, et al. "Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis." Annals of the Rheumatic Diseases 75, no. 11 (February 5, 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, and Paolo Madeddu. "Notch signalling in ischaemia-induced angiogenesis." Biochemical Society Transactions 37, no. 6 (November 19, 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, and 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, no. 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.
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Mathieu, Mélissa, Frederic Duval, and Nathalie Labrecque. "Notch signalling shapes the CD8 T cell response following Listeria infection (P1416)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 117.8. http://dx.doi.org/10.4049/jimmunol.190.supp.117.8.
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Abstract Following an infection, naïve CD8 T cells expand and differentiate into effectors able to eliminate the pathogen. At the peak of the response, two populations of effectors are distinguishable: short-lived effector cells (SLECs) meant to die by apoptosis and memory precursor effector cells (MPECs) destined to survive as memory cells that will confer long-term protection. Thus, following activation, the CD8 T cell faces a binary cell fate decision. We postulate that the Notch signalling pathway, known for its role in cellular differentiation and binary cell fate choice, acts as a key player in the MPEC/SLEC choice. To elucidate the role of Notch signalling in CD8 T cell response, we infected mice lacking or not expression of Notch1 and Notch2 in mature CD8 T cells with Listeria monocytogenes expressing OVA. Notch deficiency led to the generation of more OVA-specific effector CD8 T cells but less of these effectors had a SLEC phenotype (CD127loKLRG1hi) at the peak of the response. Surprisingly, Notch did not impair CD8 T cell memory generation following infection. Thus, Notch signalling influences the expansion and the acquisition of a SLEC phenotype following Listeria infection but not the generation of memory cells. Understanding the molecular pathways leading to memory generation is crucial as this knowledge will ultimately contribute to new vaccine development.
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Kangsamaksin, Thaned, Ian W. Tattersall, and Jan Kitajewski. "Notch functions in developmental and tumour angiogenesis by diverse mechanisms1." Biochemical Society Transactions 42, no. 6 (November 17, 2014): 1563–68. http://dx.doi.org/10.1042/bst20140233.
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The Notch signalling pathway is a key regulator of developmental and tumour angiogenesis. Inhibition of Delta-like 4 (Dll4)-mediated Notch signalling results in hyper-sprouting, demonstrating that Notch regulates tip-stalk cell identity in developing tissues and tumours. Paradoxically, Dll4 blockade leads to reduced tumour growth because the newly growing vessels are poorly perfused. To explore the potential for targeting Notch, we developed Notch inhibitors, termed the Notch1 decoys. A Notch1 decoy variant containing all 36 epidermal growth factor (EGF)-like repeats of the extracellular domain of rat Notch1 has been shown to inhibit both Dll and Jagged class Notch ligands. Thus this Notch1 decoy functions differently than Dll4-specific blockade, although it has the potential to inhibit Dll4 activity. Expression of the Notch1 decoy in mice disrupted tumour angiogenesis and inhibited tumour growth. To understand the mechanism by which Notch blockade acts, it is important to note that Notch can function in multiple cell types that make up the vasculature, including endothelial cells and perivascular cells. We investigated Notch function in retinal microglia and determined how myeloid-expressed Notch can influence macrophages and angiogenesis. We found that myeloid-specific loss of Notch1 reduced microglia recruitment and led to improper microglia localization during retinal angiogenesis. Thus either pharmacological inhibition of Notch signalling or genetic deficiencies of Notch function in microglia leads to abnormal angiogenesis.
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Collesi, Chiara, Giulia Felician, Ilaria Secco, Maria Ines Gutierrez, Elisa Martelletti, Hashim Ali, Lorena Zentilin, Michael P. Myers, and Mauro Giacca. "Reversible Notch1 acetylation tunes proliferative signalling in cardiomyocytes." Cardiovascular Research 114, no. 1 (November 24, 2017): 103–22. http://dx.doi.org/10.1093/cvr/cvx228.
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Abstract Aims The Notch signalling pathway regulates the balance between proliferation and differentiation in several tissues, including the heart. Our previous work has demonstrated that the proliferative potential of neonatal cardiomyocytes relies on Notch1 activity. A deep investigation on the biochemical regulation of the Notch signalling in cardiomyocytes is the focus of the current research. Methods and results We show that the Notch1 intracellular domain is acetylated in proliferating neonatal rat cardiomyocytes and that acetylation tightly controls the amplitude and duration of Notch signalling. We found that acetylation extends the half-life of the protein, and enhanced its transcriptional activity, therefore counteracting apoptosis and sustaining cardiomyocyte proliferation. Sirt1 acted as a negative modulator of Notch1 signalling; its overexpression in cardiomyocytes reverted Notch acetylation and dampened its stability. A constitutively acetylated fusion protein between Notch1 and the acetyltransferase domain of p300 promoted cardiomyocyte proliferation, which was remarkably sustained over time. Viral vector-mediated expression of this protein enhanced heart regeneration after apical resection in neonatal mice. Conclusion These results identify the reversible acetylation of Notch1 as a novel mechanism to modulate its signalling in the heart and tune the proliferative potential of cardiomyocytes.
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Hadchouel, Michelle. "Notch signalling pathway and human diseases." Journal of Hepatology 32 (2000): 1–2. http://dx.doi.org/10.1016/s0168-8278(00)80430-4.
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Joutel">, Anne, and Elisabeth Tournier-Lasserve. "Notch signalling pathway and human diseases." Seminars in Cell & Developmental Biology 9, no. 6 (December 1998): 619–25. http://dx.doi.org/10.1006/scdb.1998.0261.
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Brandstadter, Joshua D., and Ivan Maillard. "Notch signalling in T cell homeostasis and differentiation." Open Biology 9, no. 11 (November 2019): 190187. http://dx.doi.org/10.1098/rsob.190187.
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The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in host defence, autoimmunity and alloimmunity. The emerging effects of Notch signalling in T cell responses build upon a more established role for Notch in T cell development. Here, we provide a critical review of this burgeoning literature to make sense of what has been learned so far and highlight the experimental strategies that have been most useful in gleaning physiologically relevant information. We outline the functional consequences of Notch signalling in mature T cells in addition to key specific Notch ligand–receptor interactions and downstream molecular signalling pathways. Our goal is to help clarify future directions for this expanding body of work and the best approaches to answer important open questions.
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Koizumi, K. i., M. Nakajima, S. Yuasa, Y. Saga, T. Sakai, T. Kuriyama, T. Shirasawa, and H. Koseki. "The role of presenilin 1 during somite segmentation." Development 128, no. 8 (April 15, 2001): 1391–402. http://dx.doi.org/10.1242/dev.128.8.1391.
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The Notch signalling pathway plays essential roles during the specification of the rostral and caudal somite halves and subsequent segmentation of the paraxial mesoderm. We have re-investigated the role of presenilin 1 (Ps1; encoded by Psen1) during segmentation using newly generated alleles of the Psen1 mutation. In Psen1-deficient mice, proteolytic activation of Notch1 was significantly affected and the expression of several genes involved in the Notch signalling pathway was altered, including Δ-like3, Hes5, lunatic fringe (Lfng) and Mesp2. Thus, Ps1-dependent activation of the Notch pathway is essential for caudal half somite development. We observed defects in Notch signalling in both the caudal and rostral region of the presomitic mesoderm. In the caudal presomitic mesoderm, Ps1 was involved in maintaining the amplitude of cyclic activation of the Notch pathway, as represented by significant reduction of Lfng expression in Psen1-deficient mice. In the rostral presomitic mesoderm, rapid downregulation of the Mesp2 expression in the presumptive caudal half somite depends on Ps1 and is a prerequisite for caudal somite half specification. Chimaera analysis between Psen1-deficient and wild-type cells revealed that condensation of the wild-type cells in the caudal half somite was concordant with the formation of segment boundaries, while mutant and wild-type cells intermingled in the presomitic mesoderm. This implies that periodic activation of the Notch pathway in the presomitic mesoderm is still latent to segregate the presumptive rostral and caudal somite. A transient episode of Mesp2 expression might be needed for Notch activation by Ps1 to confer rostral or caudal properties. In summary, we propose that Ps1 is involved in the functional manifestation of the segmentation clock in the presomitic mesoderm.
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Chapman, Gavin, Julie L. M. Moreau, Eddie I P, Justin O. Szot, Kavitha R. Iyer, Hongjun Shi, Michelle X. Yam, et al. "Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants." Human Molecular Genetics 29, no. 4 (December 9, 2019): 566–79. http://dx.doi.org/10.1093/hmg/ddz270.
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Abstract Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.
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Ligoxygakis, P., S. Y. Yu, C. Delidakis, and N. E. Baker. "A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex." Development 125, no. 15 (August 1, 1998): 2893–900. http://dx.doi.org/10.1242/dev.125.15.2893.
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The Notch signalling pathway is involved in many processes where cell fate is decided. Previous work showed that Notch is required at successive steps during R8 specification in the Drosophila eye. Initially, Notch enhances atonal expression and promotes atonal function. After atonal autoregulation has been established, Notch signalling represses atonal expression during lateral specification. In this paper we investigate which known components of the Notch pathway are involved in each signalling process. Using clonal analysis we show that a ligand of Notch, Delta, is required along with Notch for both proneural enhancement and lateral specification, while the downstream components Suppressor-of-Hairless and Enhancer-of-Split are involved only in lateral specification. Our data point to a distinct signal transduction pathway during proneural enhancement by Notch. Using misexpression experiments we also show that particular Enhancer-of-split bHLH genes can differ greatly in their contribution to lateral specification.
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Sotillos, S., F. Roch, and S. Campuzano. "The metalloprotease-disintegrin Kuzbanian participates in Notch activation during growth and patterning of Drosophila imaginal discs." Development 124, no. 23 (December 1, 1997): 4769–79. http://dx.doi.org/10.1242/dev.124.23.4769.
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The Notch transmembrane protein is the receptor of an evolutionary conserved pathway that mediates intercellular signalling leading to the specification of different cell types during development. In this pathway, many aspects of the signal transduction mechanism remain poorly understood, especially the role of proteolytic processing of Notch. We present genetic evidence indicating that the metalloprotease-disintegrin kuzbanian (J. Rooke, D. Pan, T. Xu and G. M. Rubin (1996) Science 273, 1227–1231) is a new component of the Notch signalling pathway and is involved in Notch activation. kuzbanian genetic mosaics demonstrate that, during neurogenesis, wing margin formation and vein width specification kuzbanian is autonomously required in the cell where Notch is activated. Genetic interactions between kuzbanian and different genes of the Notch pathway indicate that kuzbanian is required upstream of Suppressor of Hairless. Moreover, the requirement of kuzbanian for signalling by a ligand-dependent Abruptex receptor, but not by a constitutively activated form of Notch, suggests that kuzbanian is involved in the generation of a Notch functional receptor and/or in its activation. However, differences in the phenotypes of loss-of-function Notch and kuzbanian mutations suggest the existence of alternative Kuzbanian-independent mechanisms that generate Notch functional receptors.
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Murta, D., M. Batista, A. Trindade, E. Silva, L. Mateus, A. Duarte, and L. Lopes-da-Costa. "Dynamics of Notch signalling in the mouse oviduct and uterus during the oestrous cycle." Reproduction, Fertility and Development 28, no. 11 (2016): 1663. http://dx.doi.org/10.1071/rd15029.
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The oviduct and uterus undergo extensive cellular remodelling during the oestrous cycle, requiring finely tuned intercellular communication. Notch is an evolutionarily conserved cell signalling pathway implicated in cell fate decisions in several tissues. In the present study we evaluated the quantitative real-time polymerase chain reaction (real-time qPCR) and expression (immunohistochemistry) patterns of Notch components (Notch1–4, Delta-like 1 (Dll1), Delta-like 4 (Dll4), Jagged1–2) and effector (hairy/enhancer of split (Hes) 1–2, Hes5 and Notch-Regulated Ankyrin Repeat-Containing Protein (Nrarp)) genes in the mouse oviduct and uterus throughout the oestrous cycle. Notch genes are differentially transcribed and expressed in the mouse oviduct and uterus throughout the oestrous cycle. The correlated transcription levels of Notch components and effector genes, and the nuclear detection of Notch effector proteins, indicate that Notch signalling is active. The correlation between transcription levels of Notch genes and progesterone concentrations, and the association between expression of Notch proteins and progesterone receptor (PR) activation, indicate direct progesterone regulation of Notch signalling. The expression patterns of Notch proteins are spatially and temporally specific, resulting in unique expression combinations of Notch receptor, ligand and effector genes in the oviduct luminal epithelium, uterus luminal and glandular epithelia and uterine stroma throughout the oestrous cycle. Together, the results of the present study imply a regulatory role for Notch signalling in oviduct and uterine cellular remodelling occurring throughout the oestrous cycle.
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Wang, Yishu, Enhang Lu, Riqiang Bao, Ping Xu, Fen Feng, Weihui Wen, Qiming Dong, et al. "Notch signalling regulates steroidogenesis in mouse ovarian granulosa cells." Reproduction, Fertility and Development 31, no. 6 (2019): 1091. http://dx.doi.org/10.1071/rd18281.
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The Notch signalling pathway in the mammalian ovary regulates granulosa cell proliferation. However, the effects of Notch signalling on steroidogenesis are unclear. In this study we cultured mouse ovarian granulosa cells from preantral follicles invitro and observed the effect of Notch signalling on steroidogenesis through overexpression, knockdown and inhibition of Notch signalling. Activation of Notch signalling decreased progesterone and oestrogen secretion. In contrast, inhibition of Notch signalling increased the production of progesterone and oestrogen. Expression of the genes for steroidogenic-related enzymes, including 3β-hydroxysteroid dehydrogenase, p450 cholesterol side-chain cleavage enzyme and aromatase, was repressed after stimulation of Notch signalling. The expression of upstream transcription factors, including steroidogenic factor 1 (SF1), Wilms’ tumour 1 (Wt1), GATA-binding protein 4 (Gata4) and Gata6, was also inhibited after stimulation of Notch signalling. Production of interleukin (IL)-6 was positively correlated with Notch signalling and negatively correlated with the expression of these transcription factors and enzymes. In conclusion, Notch signalling regulated progesterone and oestrogen secretion by affecting the expression of upstream transcription factors SF1, Wt1, Gata4 and Gata6, as well as downstream steroidogenic-related enzymes. IL-6, which may be regulated directly by Notch signalling, may contribute to this process. Our findings add to the understanding of the diverse functions of Notch signalling in the mammalian ovary.
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Rauff, Bisma, Arif Malik, Yasir Ali Bhatti, Shafiq Ahmad Chudhary, Ishtiaq Qadri, and Shafquat Rafiq. "Notch signalling pathway in development of cholangiocarcinoma." World Journal of Gastrointestinal Oncology 12, no. 9 (September 15, 2020): 957–74. http://dx.doi.org/10.4251/wjgo.v12.i9.957.
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Bray, Sarah J. "Notch signalling: a simple pathway becomes complex." Nature Reviews Molecular Cell Biology 7, no. 9 (September 2006): 678–89. http://dx.doi.org/10.1038/nrm2009.
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Bellen, Hugo J., Melih Acar, Hamed Jafar Nejad, Anchi Tien, and Akhila Rajan. "Novel players in the Notch signalling pathway." Developmental Biology 306, no. 1 (June 2007): 301. http://dx.doi.org/10.1016/j.ydbio.2007.03.082.
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BARON, M. "An overview of the Notch signalling pathway." Seminars in Cell & Developmental Biology 14, no. 2 (April 2003): 113–19. http://dx.doi.org/10.1016/s1084-9521(02)00179-9.
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Powell, B. C., E. A. Passmore, A. Nesci, and S. M. Dunn. "The Notch signalling pathway in hair growth." Mechanisms of Development 78, no. 1-2 (November 1998): 189–92. http://dx.doi.org/10.1016/s0925-4773(98)00177-4.
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Parks, A. L., K. M. Klueg, J. R. Stout, and M. A. Muskavitch. "Ligand endocytosis drives receptor dissociation and activation in the Notch pathway." Development 127, no. 7 (April 1, 2000): 1373–85. http://dx.doi.org/10.1242/dev.127.7.1373.
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Endocytosis of the ligand delta; is required for activation of the receptor Notch during Drosophila development. The Notch extracellular domain (NotchECD) dissociates from the Notch intracellular domain (NotchICD) and is trans-endocytosed into delta;-expressing cells in wild-type imaginal discs. Reduction of dynamin-mediated endocytosis in developing eye and wing imaginal discs reduces Notch dissociation and Notch signalling. Furthermore, dynamin-mediated delta endocytosis is required for Notch trans-endocytosis in Drosophila cultured cell lines. Endocytosis-defective delta proteins fail to mediate trans-endocytosis of Notch in cultured cells, and exhibit aberrant subcellular trafficking and reduced signalling capacity in Drosophila. We suggest that endocytosis into delta-expressing cells of NotchECD bound to delta plays a critical role during activation of the Notch receptor and is required to achieve processing and dissociation of the Notch protein.
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Capodanno, Y., F. O. Buishand, L. Y. Pang, J. Kirpensteijn, J. A. Mol, and D. J. Argyle. "Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells." Endocrine-Related Cancer 25, no. 2 (February 2018): 131–44. http://dx.doi.org/10.1530/erc-17-0415.
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Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4,SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotypein vivocompared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2andHES1)were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially in cells resistant to 5-FU. Inhibition of the Notch pathway, using a gamma secretase inhibitor (GSI), enhanced the sensitivity of INS CSC-like cells to 5-FU. When used in combination GSI and 5-FU, the clonogenicityin vitroand the tumourigenicityin vivoof INS CSC-like cells were significantly reduced. These findings suggested that the combined strategy of Notch signalling inhibition and 5-FU synergistically attenuated enriched INS CSC populations, providing a rationale for future therapeutic exploitation.
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Tharehalli, Umesh, Michael Svinarenko, Johann Kraus, Silke Kühlwein, Robin Szekely, Ute Kiesle, Annika Scheffold, et al. "YAP Activation Drives Liver Regeneration after Cholestatic Damage Induced by Rbpj Deletion." International Journal of Molecular Sciences 19, no. 12 (November 29, 2018): 3801. http://dx.doi.org/10.3390/ijms19123801.
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Liver cholestasis is a chronic liver disease and a major health problem worldwide. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of bile duct structures. Here we investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of recombination signal binding protein for immunoglobulin kappa j region (Rbpj), which represents a key regulator of Notch signalling, induces severe cholestasis through impaired intra-hepatic bile duct (IHBD) maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with the change of several signalling pathways including a Kyoto Encyclopedia of Genes and Genomes (KEGG) gene set representing the Hippo pathway, further yes-associated protein (YAP) activation and upregulation of SRY (sex determining region Y)-box 9 (SOX9), which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that in vivo Rbpj depletion is followed by YAP activation, which influences the transdifferentiation of hepatocytes and thereby contributing to liver regeneration.
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Duval, Frédéric Antoine, Mélissa Mathieu, Jean-François Daudelin, and Nathalie Labrecque. "The Notch signaling pathway: a new mastor regulator of effector CD8 T cell differentiation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 129.12. http://dx.doi.org/10.4049/jimmunol.196.supp.129.12.
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Abstract Following an infection, naïve CD8 T cells expand and differentiate into effectors able to eliminate the pathogen. At the peak of the response, two major populations of effectors are distinguishable: short-lived effector cells (SLECs) meant to die by apoptosis and memory precursor effector cells (MPECs) destined to survive as memory cells that confer long-term protection. We postulated that the Notch signaling pathway, known for its role in cellular differentiation and binary cell fate choice, acts as a key player in the MPEC/SLEC differentiation choice. To elucidate the role of Notch signalling, we have analyzed CD8 T cell response in mice lacking or not the expression of Notch1 and Notch2 in mature CD8 T cells. Following infection with Listeria or vaccination with antigen-pulsed dendritic cells, Notch deficiency drastically diminished SLEC generation and affect cytokines production without impairing CD8 memory T cell generation. Interestingly, altered SLEC differentiation occurs despite normal expression of the transcription factors, T-bet and Blimp-1, known to be necessary for SLEC differentiation. Moreover, the reduced generation of SLECs in absence of Notch signaling correlated with defective expression of CD25 by effectors. However, restoration of CD25 expression along with daily IL-2 complementation in Notch1/2-deficient T cells did not correct SLEC differentiation. These results suggest either that Notch regulates the expression of new players involved in SLEC differentiation or Notch signaling collaborates with already known actors of SLEC differentiation such as T-bet or Blimp-1. The identification of the genes regulated by Notch should help to reveal its role in CD8 T cell response.
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Brennan, Keith, and Robert B. Clarke. "Combining Notch inhibition with current therapies for breast cancer treatment." Therapeutic Advances in Medical Oncology 5, no. 1 (August 15, 2012): 17–24. http://dx.doi.org/10.1177/1758834012457437.
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Over recent years, there has been an increasing interest in targeting Notch signalling for the treatment of breast cancer. This has stemmed from the realization that many Notch pathway components display altered expression in breast cancer, and that Notch signalling impacts on many of the cellular properties associated with tumour initiation and progression. Consequently, Notch pathway inhibitors are now entering the initial stages of clinical trials. However, there is a definite need to consider how best to use these inhibitors and therefore which treatment strategies are likely to yield the most promising results. In particular, recent studies suggest that the greatest success will come from combining Notch pathway inhibitors with current breast cancer therapies.
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Acar, Ahmet, Bruno M. Simões, Robert B. Clarke, and Keith Brennan. "A Role for Notch Signalling in Breast Cancer and Endocrine Resistance." Stem Cells International 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/2498764.
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Over the past decade, there has been growing interest in the Notch signalling pathway within the breast cancer field. This interest stemmed initially from the observation that Notch signalling is aberrantly activated in breast cancer and its effects on various cellular processes including proliferation, apoptosis, and cancer stem cell activity. However more recently, elevated Notch signalling has been correlated with therapy resistance in oestrogen receptor-positive breast cancer. As a result, inhibiting Notch signalling with therapeutic agents is being explored as a promising treatment option for breast cancer patients.
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Rossi, Davide, Alessio Bruscaggin, Sara Monti, Stefania Cresta, Rosella Famà, Luca Arcaini, Silvia Franceschetti, et al. "Molecular Lesions Of Signalling Pathway Genes In Indolent B-Cell Lymphoproliferations Mimicking Splenic Marginal Zone Lymphoma." Blood 122, no. 21 (November 15, 2013): 4250. http://dx.doi.org/10.1182/blood.v122.21.4250.4250.
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Abstract Background Almost 60% cases of splenic marginal zone lymphoma (SMZL) cases harbor molecular lesions affecting signalling pathways involved in normal marginal zone (MZ) differentiation, including the NOTCH pathway, the NF-kB pathway, the toll-like receptor (TLR) pathway and the B-cell receptor (BCR) pathway. However, little is known with regard to these lesions in other indolent B-cell lymphoproliferative disorders mimicking SMZL. Methods Candidate gene mutations (NOTCH2, NOTCH1, BIRC3, TNFAIP3, TRAF3, IKBKB, MYD88, CD79A, CD79B, CARD11) were investigated in 60 indolent B-cell lymphoproliferative disorders, including nodal marginal zone lymphoma (NMZL=33), monoclonal B-cell lymphocytosis showing a MZL-like phenotype (MZL-like MBL=16), and variant hairy cell leukemia (vHCL=11). In all cases, tumor representation was >50% in order to allow the detection of clonal lesions. All cases lacked the BRAF V600E mutation as assessed by AS-PCR. Results Overall, the genetics of NMZL and MZL-like MBL was consistent with that of SMZL, suggesting the involvement of a common oncogenic pathway in these disorders. Among NMZL, 51% (17/33) of cases were characterized by mutually exclusive genetic lesions affecting MZ differentiation genes, including NOTCH2 stabilizing mutations in 24% (8/33) of cases, TNFAIP3 disrupting mutations in 12% (4/33), MYD88 activating mutations in 12% (4/33), and NOTCH1, TRAF3 and BIRC3 mutations in 3% (1/33) of cases each. Among MZL-like MBL, 37% (6/16) of cases harbored mutually exclusive lesions of MZ genes, including MYD88 mutations in 25% (4/16) of cases, NOTCH2 mutations in 12% (2/16), and TNFAIP3 and CD79B mutations in 6% (1/16) of cases each. On the contrary, all cases (n=11) of vHCL lacked mutations of NOTCH, NF-kB, TLR or BCR genes, suggesting that none of these signaling pathways plays a relevant role in this disease. Among NMZL, MYD88 mutations were enriched among cases harboring an IgM type monoclonal component (3/4, 75% vs 1/18, 5%, p=.010) and showing cytological clues of plasma cell differentiation of lymph node tumor cells (3/6, 50% vs 0/9; p=.040). NOTCH2 mutations did not correlate with any pathologic feature (i.e. lymph node pattern of infiltration, presence of monocytoid B cells, immunoglobulin gene usage or mutation status). Among MZL-like MBL, neither MYD88 mutations nor NOTCH2 mutations correlated with specific clinico-pathologic features (i.e. presence of an IgM type monoclonal component, intrasinusoidal bone marrow infiltration, plasma cell differentiation). Conclusions These data suggest that: i) SMZL, NMZL and MZL-like MBL share a similar genotype and are all promoted by the same molecular deregulation of MZ differentiation genes; and ii) vHCL stands as a genetically different entity among indolent B-cell lymphoproliferations. These data might help to refine the differential diagnosis of indolent B-cell lymphoproliferations mimicking SMZL. Disclosures: No relevant conflicts of interest to declare.
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Marti-Chafer, S., E. Jimenez-Mallen, T. Mendoza, D. C. Macias-Ceja, C. Bauset, M. Seco-Cervera, S. Calatayud, J. Cosin-Roger, M. D. Barrachina, and D. Ortiz-Masiá. "P038 Notch pathway in fibrosis: a new anti-fibrotic therapy in Crohn's disease?" Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i205. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0168.
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Abstract Background Fibrosis represent the main complications related to Crohn's disease (CD). Notch signalling mediate fibrogenic process, including epithelial-mesenchymal transition (EMT) and fibroblast senescence but its role in CD fibrosis is currently unknown. Previous studies have shown a high expression of NOTCH4, NOTCH3, DLL3 and DLL4 in CD fibrotic tissue. DLL4 mainly activates transcription factors involved in EMT, and macrophages could act as a possible source of DLL4 (Edo, et al., 2022. JCC (i200)).The general aim of the present study is to determine the possible potential of Notch pathway as a therapeutic target in intestinal fibrosis associated with CD. Specifically, we pretend: to analyze the localization of NOTCH3/4 receptors in the intestinal tissue of patients with CD complicated; to study the relevance of NOTCH3/4 receptors in the EMT; to study the relevance of Notch pathway in the senescence of intestinal fibroblast. Methods We have analyzed in intestinal samples from CD patients with complicated lesions: the localization of NOTCH3/4 receptors by IH and the protein expression of senescence markers (BCL2 and P53) by WB. We carry out in vitro studies and analyze: the protein expression of HES1 (effector Notch pathway) and EMT markers in DLL4-HT29 treated cells transfected with miNOTCH3 or miNOTCH4; and the protein expression of senescence proteins in HSIF fibroblasts treated with DLL4 or DLL3. Results NOTCH3 was located preferentially in muscular areas -muscularis mucosa, endothelium and muscularis externa- with a striking staining of infiltrated cells in the mucosa of the unaffected area. NOTCH4 is found more specifically in the crypts of the mucosa, as well as in cells of the lamina propria of the unaffected mucosa. The expression of senescence proteins in the tissue showed elevated levels of BCL2 and P53, compared to the unaffected tissue of the same patient. DLL4 increased the protein expression of EMT markers in HT29 cells, and NOTCH4 silencing significantly reverted the expression of these EMT markers. NOTCH3 silencing produced no significant changes after DLL4-HT29 treatment. DLL3, and not DLL4, produced in intestinal fibroblasts a significant increase in the protein expression levels of BCL2, and P53, compared to the vehicle (Figure). Conclusion NOTCH pathway is involved in the regulation of key cellular functions and processes essential for the pathogenesis of intestinal fibrosis in CD patients. DLL4-NOTCH4 interaction triggers transcription factors involved in mesenchymal epithelial transition in colonic epithelial cells, while DLL3 seems to have a more relevant role in activation of senescence in fibroblasts.
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Gazave, Eve, Quentin I. B. Lemaître, and Guillaume Balavoine. "The Notch pathway in the annelid Platynereis : insights into chaetogenesis and neurogenesis processes." Open Biology 7, no. 2 (February 2017): 160242. http://dx.doi.org/10.1098/rsob.160242.
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Notch is a key signalling pathway playing multiple and varied functions during development. Notch regulates the selection of cells with a neurogenic fate and maintains a pool of yet uncommitted precursors through lateral inhibition, both in insects and in vertebrates. Here, we explore the functions of Notch in the annelid Platynereis dumerilii (Lophotrochozoa). Conserved components of the pathway are identified and a scenario for their evolution in metazoans is proposed. Unexpectedly, neither Notch nor its ligands are expressed in the neurogenic epithelia of the larva at the time when massive neurogenesis begins. Using chemical inhibitors and neural markers, we demonstrate that Notch plays no major role in the general neurogenesis of larvae. Instead, we find Notch components expressed in nascent chaetal sacs, the organs that produce the annelid bristles. Impairing Notch signalling induces defects in chaetal sac formation, abnormalities in chaetae producing cells and a change of identity of chaeta growth accessory cells. This is the first bilaterian species in which the early neurogenesis processes appear to occur without a major involvement of the Notch pathway. Instead, Notch is co-opted to pattern annelid-specific organs, likely through a lateral inhibition process. These features reinforce the view that Notch signalling has been recruited multiple times in evolution due to its remarkable ‘toolkit’ nature.
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Murta, D., M. Batista, E. Silva, A. Trindade, L. Mateus, A. Duarte, and L. Lopes-da-Costa. "Differential expression of Notch component and effector genes during ovarian follicle and corpus luteum development during the oestrous cycle." Reproduction, Fertility and Development 27, no. 7 (2015): 1038. http://dx.doi.org/10.1071/rd13399.
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Ovarian dynamics throughout the female oestrous cycle (EC) are characterised by cyclical follicle and corpus luteum (CL) development. These events are tightly regulated, involving extensive cell-to-cell communication. Notch is an evolutionarily well conserved cell-signalling pathway implicated in cell-fate decisions in several tissues. Here, we evaluated the extra-vascular expression patterns of Notch component and effector genes during follicle and CL development throughout the EC. Five mature CD1 female mice were killed at each EC stage. Blood samples were collected for progesterone measurement, ovaries were processed for immunohistochemistry and expression patterns of Notch components (Notch1, 2 and 3, Jagged1 and Delta-like1 and 4) and effectors (Hes1, Hes2 and Hes5) were characterised. Nuclear detection of Notch effectors indicates that Notch signalling is active in the ovary. Notch components and effectors are differentially expressed during follicle and CL development throughout the EC. The spatial and temporal specific expression patterns are associated with follicle growth, selection and ovulation or atresia and CL development and regression.
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Hirsinger, E., P. Malapert, J. Dubrulle, M. C. Delfini, D. Duprez, D. Henrique, D. Ish-Horowicz, and O. Pourquie. "Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation." Development 128, no. 1 (January 1, 2001): 107–16. http://dx.doi.org/10.1242/dev.128.1.107.
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During Drosophila myogenesis, Notch signalling acts at multiple steps of the muscle differentiation process. In vertebrates, Notch activation has been shown to block MyoD activation and muscle differentiation in vitro, suggesting that this pathway may act to maintain the cells in an undifferentiated proliferative state. In this paper, we address the role of Notch signalling in vivo during chick myogenesis. We first demonstrate that the Notch1 receptor is expressed in postmitotic cells of the myotome and that the Notch ligands Delta1 and Serrate2 are detected in subsets of differentiating myogenic cells and are thus in position to signal to Notch1 during myogenic differentiation. We also reinvestigate the expression of MyoD and Myf5 during avian myogenesis, and observe that Myf5 is expressed earlier than MyoD, consistent with previous results in the mouse. We then show that forced expression of the Notch ligand, Delta1, during early myogenesis, using a retroviral system, has no effect on the expression of the early myogenic markers Pax3 and Myf5, but causes strong down-regulation of MyoD in infected somites. Although Delta1 overexpression results in the complete lack of differentiated muscles, detailed examination of the infected embryos shows that initial formation of a myotome is not prevented, indicating that exit from the cell cycle has not been blocked. These results suggest that Notch signalling acts in postmitotic myogenic cells to control a critical step of muscle differentiation.
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Verma, Navin Kumar, Mobashar Hussain Urf Turabe Fazil, Ong Seow Theng, Madhavi Latha S. Chalasani, P. Praseetha, Sunil Kumar, Aditya K. Panda, et al. "The LFA-1 signal for cell migration influences Notch and TGF-β pathways with functional consequences for T-cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 58.4. http://dx.doi.org/10.4049/jimmunol.196.supp.58.4.
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Abstract The integrin LFA-1 plays a key role in T-cell motility, which is critical for host defense and is also main driver of autoimmune diseases. However, whether and how LFA-1 signalling can modulate T-cell effector functions remain to be understood. We performed gene expression analysis of LFA-1-stimulated human T-cells and identified genomic signatures associated with Notch and TGF-β pathways, both involved in T-cell differentiation. The activation of Notch pathway in motile T-cells was confirmed by the nuclear translocation of cleaved Notch intracellular domain and up-regulation of target genes Hey1 and Hes1. LFA-1 stimulation of naïve peripheral blood mononuclear cells was found to promote T-cell Th1 polarization through a GSK3β signalling-dependent Notch pathway. We further detected that LFA-1 signalling up-regulated Stat3 and/or JNK activation-dependent expression of Smad7, Smurf2 and Ski causing T-cell TGF-β unresponsiveness. LFA-1-stimulated naïve T-cells were refractory to TGF-β-mediated induction of Foxp3+ iTreg or RORγt+ Th17 differentiation. Of note, peripheral or splenic T-cells isolated from patients with rheumatoid arthritis, type1 diabetes or thyroiditis showed constitutively high expression of Tbet. Pretreatment of cells with blocking anti-LFA-1 antibody, specific inhibitors or siRNA against identified molecules restored LFA-1-mediated modulation of T-cell functional phenotypes. Thus, LFA-1-mediated signalling is crucial for T-cell immunoregulation concurrent with T-cell motility, involving both Notch and TGF-β pathways. These findings have implications for normal immunologic functions and also have therapeutic relevance for inflammatory diseases.
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Fiúza, Ulla-Maj, and Alfonso Martinez Arias. "Cell and molecular biology of Notch." Journal of Endocrinology 194, no. 3 (September 2007): 459–74. http://dx.doi.org/10.1677/joe-07-0242.
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Notch signalling is a cell–cell communication process, which allows the establishment of patterns of gene expression and differentiation, regulates binary cell fate choice and the maintenance of stem cell populations. So far, the data published has elucidated the main players in the Notch signalling pathway. However, its regulatory mechanisms are exhibiting an increasing complexity which could account for the multitude of roles it has during development and in adult organisms. In this review, we will describe the multiple roles of Notch and how various factors can regulate Notch signalling.
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Le Corre, Laure, Salix Boulet, Dave Maurice De Sousa, and Nathalie Labrecque. "Role of the Notch-TRIB2 axis in CD8+ T cell differentiation." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 98.48. http://dx.doi.org/10.4049/jimmunol.206.supp.98.48.
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Abstract Following activation, naïve CD8+ T cells expand and differentiate into two effector subpopulations: short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). After the effector response has taken place, SLECs undergo apoptosis, while MPECs mature into memory T cells that protect against reinfection. Notch, a highly conserved pathway, was shown to control SLEC differentiation. Our transcriptomic analysis has revealed that Notch signalling controls the transcription of a large number of genes in activated CD8+ T cells. Among them is Trib2, coding for the pseudokinase Tribbles homolog 2. TRIB2 was reported to activate AKT in some tumour cell lines while Notch-deficient CD8+ T cells show decreased AKT activation, suggesting that Notch transcriptional induction of Trib2 might be important to properly activate AKT and promote SLEC differentiation. Therefore, we hypothesize that induction of TRIB2 expression by Notch signalling promotes SLEC differentiation through AKT activation. To test this, we overexpressed TRIB2 in Notch1–2 deficient CD8+ T cells using retroviral transduction and followed their differentiation after their adoptive transfer into Listeria infected mice. Our results show that overexpression of TRIB2 partially restores SLEC generation in absence of Notch. In conclusion, we uncovered that TRIB2 promotes SLEC differentiation through the Notch pathway. These findings provide a better understanding of the molecular events controlling the differentiation of SLECs, a cell type essential for the elimination of infected cells and cancer.
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Sun, X., and S. Artavanis-Tsakonas. "The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands." Development 122, no. 8 (August 1, 1996): 2465–74. http://dx.doi.org/10.1242/dev.122.8.2465.
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We examined the function of the intracellular domains of the two known Drosophila Notch ligands, Delta and Serrate, by expressing wild-type and mutant forms in the developing Drosophila eye under the sevenless promoter. The expression of intracellularly truncated forms of either Delta (sev-DlTM) or Serrate (sev-SerTM) leads to extra photoreceptor phenotypes, similar to the eye phenotypes associated with loss-of-function mutations of either Notch or Delta. Consistent with the notion that the truncated ligands reduce. Notch signalling activity, the eye phenotypes of sev-DlTM and sev-SerTM are enhanced by loss-of-function mutations in the Notch pathway elements, Notch, Delta, mastermind, deltex and groucho, but are suppressed by a duplication of Delta or mutations in Hairless, a negative regulator of the pathway. These observations were extended to the molecular level by demonstrating that the expression of Enhancer of split m delta, a target of Notch signalling, is down-regulated by the truncated ligands highly expressed in neighbouring cells. We conclude that the truncated ligands act as antagonists of Notch signalling.
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Horvath, Matej, Zorana Mihajlovic, Vera Slaninova, Raquel Perez-Gomez, Yuri Moshkin, and Alena Krejci. "The silent information regulator 1 (Sirt1) is a positive regulator of the Notch pathway in Drosophila." Biochemical Journal 473, no. 22 (November 10, 2016): 4129–43. http://dx.doi.org/10.1042/bcj20160563.
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The silent information regulator 1 (Sirt1) has been shown to have negative effects on the Notch pathway in several contexts. We bring evidence that Sirt1 has a positive effect on Notch activation in Drosophila, in the context of sensory organ precursor specification and during wing development. The phenotype of Sirt1 mutant resembles weak Notch loss-of-function phenotypes, and genetic interactions of Sirt1 with the components of the Notch pathway also suggest a positive role for Sirt1 in Notch signalling. Sirt1 is necessary for the efficient activation of enhancer of split [E(spl)] genes by Notch in S2N cells. Additionally, the Notch-dependent response of several E(spl) genes is sensitive to metabolic stress caused by 2-deoxy-d-glucose treatment, in a Sirt1-dependent manner. We found Sirt1 associated with several proteins involved in Notch repression as well as activation, including the cofactor exchange factor Ebi (TBL1), the RLAF/LAF histone chaperone complex and the Tip60 acetylation complex. Moreover, Sirt1 participates in the deacetylation of the CSL transcription factor Suppressor of Hairless. The role of Sirt1 in Notch signalling is, therefore, more complex than previously recognized, and its diverse effects may be explained by a plethora of Sirt1 substrates involved in the regulation of Notch signalling.
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Venkatesh, Vandana, Raghu Nataraj, Gopenath S. Thangaraj, Murugesan Karthikeyan, Ashok Gnanasekaran, Shanmukhappa B. Kaginelli, Gobianand Kuppanna, Chandrashekrappa Gowdru Kallappa, and Kanthesh M. Basalingappa. "Targeting Notch signalling pathway of cancer stem cells." Stem Cell Investigation 5 (March 2018): 5. http://dx.doi.org/10.21037/sci.2018.02.02.
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Baonza, Antonio, and Matthew Freeman. "Notch signalling and the initiation of neural development in the Drosophila eye." Development 128, no. 20 (October 15, 2001): 3889–98. http://dx.doi.org/10.1242/dev.128.20.3889.
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Neural determination in the Drosophila eye occurs progressively. A diffusible signal, Dpp, causes undetermined cells first to adopt a ‘pre-proneural’ state in which they are primed to start differentiating. A second signal is required to trigger the activation of the transcription factor Atonal, which causes the cells to initiate overt photoreceptor neurone differentiation. Both Dpp and the second signal are dependent on Hedgehog (Hh) signalling. Previous work has shown that the Notch signalling pathway also has a proneural role in the eye (as well as a later, opposite function when it restricts the number of cells becoming photoreceptors – a process of lateral inhibition). It is not clear how the early proneural role of Notch integrates with the other signalling pathways involved. We provide evidence that Notch activation by its ligand Delta is the second Hh-dependent signal required for neural determination. Notch activity normally only triggers Atonal expression in cells that have adopted the pre-proneural state induced by Dpp. We also report that Notch drives the transition from pre-proneural to proneural by downregulating two repressors of Atonal: Hairy and Extramacrochaetae.
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Guo, Jin-Jin, Ying-Jie Li, and Lu-Lu Xin. "Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways." Bangladesh Journal of Pharmacology 10, no. 4 (November 8, 2015): 937. http://dx.doi.org/10.3329/bjp.v10i4.23699.
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<p class="Abstract">Despite advances in conventional therapies, treatment of prostate cancer is still a challenge. The study aims to assess the possible anti-cancer effects of tangeretin, a dietary flavonoid on human prostate cancer cells (DU145, PC3, LNCaP). Tangeretin (25, 50 and 100 µM) significantly inhibited cancer cell viability and induced DNA fragmentation and apoptosis by increasing caspase-3 and pro-apoptotic proteins (Bad and Bax) with reduced anti-apoptotic proteins (Bcl-2 and Bcl-xL) expressions. Significant inhibition of androgen receptor (AR) and prostate specific antigen (PSA) were seen. Dose-dependent inhibition in Notch signal was observed in expression of Notch 1 and Jagged 1 along with PI3/Akt/mTOR signalling pathway. The results suggest that tangeretin inhibited prostate cancer cell proliferation and induced apoptosis via inhibiting critical pathways in cancer development - AR signalling and PI3/Akt/mTOR - Notch signalling pathways.</p><p> </p>
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Putowski, Maciej, and Krzysztof Giannopoulos. "Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations—NOTCH1, SF3B1, MYD88, BIRC3." Journal of Clinical Medicine 10, no. 16 (August 22, 2021): 3735. http://dx.doi.org/10.3390/jcm10163735.
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Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the high genetic and epigenetic heterogeneity in CLL. The novel mutations could be pharmacologically targeted for individualized approach in some of the CLL patients. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signalling targeting mechanisms in CLL include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. In vitro studies characterizing the effect of the splicing inhibitors resulted in increased apoptosis of CLL cells regardless of splicing factor 3B subunit 1 (SF3B1) status. Several therapeutic strategies have been also proposed to directly or indirectly inhibit the toll-like receptor/myeloid differentiation primary response gene 88 (TLR/MyD88) pathway. Another potential approach is targeting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inhibition of this prosurvival pathway. Newly discovered mutations and their signalling pathways play key roles in the course of the disease. This opens new opportunities in the management and treatment of CLL.
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Horvat, Luka, Mariastefania Antica, and Maja Matulić. "The Effect of Casein Kinase 2 Inhibition on three Leukemic Cell Lines." Current Drug Therapy 15, no. 3 (October 14, 2020): 209–15. http://dx.doi.org/10.2174/1574885514666190724111509.
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Background:: Casein Kinase 2 (CK2) is a Ser/Thr protein kinase that coregulates a great number of signalling pathways in the cell. It is involved in cell cycle regulation and cell proliferation, apoptosis, DNA damage response and gene transcription. Its substrates are numerous kinases and transcription factors. It was found to be upregulated in different tumours, and certain types of leukaemia are very sensitive to its inhibition. Objective:: We analysed the effects of casein kinase 2 inhibition on three leukaemia cell lines of B and T cell origin: Jurkat, a T cell line, CLL, a chronic B lymphocytic leukaemia cell line and 697, a pre-B acute lymphocytic leukaemia cell line. Besides cell proliferation and cytotoxicity analysis, the aim was to investigate the influence of CK2 inhibition on elements of the Notch signalling pathway. Notch signalling has an important role in blood cell differentiation, and CK2 regulates Ikaros, a tumour suppressor interfering with Notch signalling Methods:: and T leukaemia cells were treated with different concentrations of the CK2 inhibitor, CX-4945, for 6 days, and cell viability and proliferation were determined by Trypan Blue Exclusion Method. Analysis of gene expression was performed by RT-qPCR. Results:: All three cell lines were sensitive to CK2 inhibition and among them, 697 cells had two times lower IC50. In Jurkat and CLL cells changes in c-Myc and Notch pathway gene expression were found. Conclusion:: As CK2 is involved in numerous signalling circuits, we concluded that each cell type could have a cell-specific response in gene expression.
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Xu, Song, Jinsong Hu, Dehui Xu, Isabelle Vande Broek, Xavier Leleu, Ben Van Camp, Karin Vanderkerken, and Ivan Van Riet. "Impaired Osteogenic Differentiation of Mesenchymal Stem Cells Derived From Multiple Myeloma Patients Is Associated with a Failure In the Deactivation of the NOTCH Pathway." Blood 116, no. 21 (November 19, 2010): 1894. http://dx.doi.org/10.1182/blood.v116.21.1894.1894.
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Abstract Abstract 1894 Mesenchymal stem cells (MSCs) give rise to bone marrow (BM) stromal cells and play an essential role in the formation and function of the MM microenvironment. Some recent studies revealed that MSCs from myeloma patients (MM-hMSCs) show an enhanced spontaneous and myeloma cell-induced production of cytokines and a distinctive gene expression profile, when compared to MSCs from normal donors (ND-hMSCs). However, regarding the osteogenic differentiation ability of MM-hMSCs conflicting observations were reported. In this study, we observed that MM-hMSCs, especially for those from MM patients with bone lesions, exhibited in the presence of osteogenic differentiation (OD) medium, significantly decreased alkaline phosphatase (ALP) activity, reduced expression of specific osteogenic markers (OPN, BMP2, OTX and BSP) and impaired matrix mineralization, compared to ND-hMSCs. However, MGUS-hMSCs, did not show a significantly impaired osteogenesis ability. Primary CFU-ALP assay from BM samples of diseased mice in the 5T33MM model also confirmed that the osteogenic differentiation ability of MSCs was impaired. Previous reports indicated that MM cells can suppress MSCs osteogenesis by HGF and DKK1 as observed in vitro (Giuliani et al, Cancer Res. 2007; Standal et al, Blood. 2007). Since MM-hMSCs have been cultured in vitro for several weeks and without any stimulation of MM cells, we believe that the impaired osteogenic differentiation of MM-hMSCs was due to an intrinsic abnormality. Several reports suggested that NOTCH signalling can maintain bone marrow mesenchymal progenitors in a more undifferentiated state by suppressing osteoblast differentiation (Hilton et al, Nat Med. 2008; Zanotti et al, Endocrinology. 2008). Therefore, we postulate that impaired osteogenic ability of MM-hMSCs might be (at least partly) related to abnormal NOTCH activity during osteogenesis. We found by quantitative real time PCR that NOTCH1, NOTCH2, Dll-1, Jagged-1, and NOTCH pathway downstream genes hes1, hey1, hey2, heyL were considerably decreased in ND-hMSCs after shifting them from normal culture medium to OD medium, indicating that NOTCH signalling was gradually suppressed during MSC osteogenesis. However, it was observed that the expression of NOTCH1, Jagged-1, Hes1 and Hes5 in MM-hMSCs did not decrease to the level of ND-hMSC with statistical difference. This implicates that the NOTCH signaling pathway remains in MM-hMSCs over-activated even in the presence of osteogenesis inducing signals. When the NOTCH signalling inhibitor DAPT was added to MM-hMSCs in OD medium, we found that hes1 expression was suppressed while, RUNX2 expression, a key transcription factor for osteoblastogenesis, as well as ALP activity, osteogenic genes expression and mineralization deposition were all increased. In conclusion our data indicate that MM-hMSCs exhibit in vitro lower osteogenic differentiation ability compared to ND-hMSCs, and that this impairement is associated with an inappropriate NOTCH pathway deactivation during the osteogenesis process. Targeting hMSCs in vivo by NOTCH inhibitors might have therapeutical potential to control bone disease in MM patients. Disclosures: No relevant conflicts of interest to declare.
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Gui, Xianyong, Ziran Meng, Yarrow J. McConnell, Shuhong Liu, Vincent G. Falck, Lloyd A. Mack, and Walley J. Temple. "Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours." Journal of Clinical Pathology 70, no. 1 (July 1, 2016): 40–50. http://dx.doi.org/10.1136/jclinpath-2016-203645.
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BackgroundTumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells).MethodsThe expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray.ResultsCCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation.ConclusionsWnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.