Academic literature on the topic 'LIF/STAT3 signalling pathway'
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Journal articles on the topic "LIF/STAT3 signalling pathway"
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Hirai, Hiroyuki, Peter Karian, and Nobuaki Kikyo. "Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor." Biochemical Journal 438, no. 1 (2011): 11–23. http://dx.doi.org/10.1042/bj20102152.
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LIF (leukaemia inhibitory factor) is a key cytokine for maintaining self-renewal and pluripotency of mESCs (mouse embryonic stem cells). Upon binding to the LIF receptor, LIF activates three major intracellular signalling pathways: the JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3), PI3K (phosphoinositide 3-kinase)/AKT and SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase 2]/MAPK (mitogen-activated protein kinase) pathways. These pathways converge to orchestrate the gene expression pattern specific to mESCs. Among the many signalling events downstream of the LIF receptor, activation and DNA binding of the transcription factor STAT3 plays a central role in transducing LIF's functions. The fundamental role of LIF for pluripotency was highlighted further by the discovery that LIF accelerates the conversion of epiblast-derived stem cells into a more fully pluripotent state. In the present review, we provide an overview of the three major LIF signalling pathways, the molecules that interact with STAT3 and the current interpretations of the roles of LIF in pluripotency.
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Sutherland, J. M., R. Keightley, R. L. Robker, D. L. Russell, and E. A. McLaughlin. "126. JAK/STAT SIGNALLING IN FOLLICULOGENESIS." Reproduction, Fertility and Development 22, no. 9 (2010): 44. http://dx.doi.org/10.1071/srb10abs126.
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Primordial follicle activation marks the first stage of pre-pubertal ovarian folliculogenesis, and is therefore fundamental to female fertility. Entry into development is initiated by a group of pleiotropic cytokines and growth factors, originating in and acting upon both the oocyte and granulosa support cells of the ovarian follicle through the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathway. Pivotal to this process is the transcriptional regulation of target genes via STAT complexes and negative regulation by the Suppressors of Cytokine Signalling (SOCS) family of proteins. Preliminary evidence indicates that STAT3 facilitates the activation of primordial follicles, while SOCS4 counterbalances the activity of STAT3, mediating the controlled release of primordial follicles into the growing pool throughout reproductive life. Leukemia Inhibitory Factor (LIF) has been previously demonstrated as a key granulosa cell derived cytokine involved in inducing primordial follicle activation. Through both quantitative gene expression (qPCR) and immunoblotting we have demonstrated that LIF can significantly upregulate STAT3 mRNA production (~2-fold) as well as increase STAT3 protein phosphorylation within neonatal mouse ovarian explants culture. Furthermore, through the generation of a recombinant SOCS4 protein construct, and its use in subsequent protein-protein pull-downs, we were able to multiple targets involved in oocyte maturation, STAT3 interactions, and JAK/STAT signaling. These targets were also found to be significantly upregulated via qPCR analysis in neonatal mouse ovaries treated with LIF. These results support our current model for the involvement of STAT3 and SOCS4 in a basic negative feedback loop within the JAK/STAT signalling pathway that results in the regulation of primordial follicle activation and development.
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Morris, M. B., N. Hamra, A. C. Lonic, and F. Felquer. "182. NOVEL SIGNALLING IN MOUSE EMBRYONIC STEM CELLS GENERATES PRIMITIVE ECTODERM-LIKE CELLS." Reproduction, Fertility and Development 21, no. 9 (2009): 100. http://dx.doi.org/10.1071/srb09abs182.
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The phenotypic status of embryonic stem (ES) cells is controlled in part by signalling pathways which translate inputs mediated by extracellular molecules. An important extracellular protagonist in mouse ES cells is LIF (leukaemia inhibitory factor) which interacts with the gp130–LIFR receptor complex to activate a number of downstream signalling pathways, including the STAT3, MEK/ERK and PI3K/Akt. These pathways, together with others, interact in complex and sometimes competing ways to generate the well-known characteristics of mouse ES cells of self-renewal, high rates of proliferation, and pluripotence. The addition of a second molecule, L-proline, to the extracellular environment alters the pluripotent status of mouse ES cells, converting them to a second pluripotent population equivalent to the primitive ectoderm of the pre-gastrulating embryo. This conversion, from ES cells to primitive ectoderm-like cells, primes the latter for directed differentiation to specific cell types (1). Here we show, using inhibitor studies and kinome array analysis, that this small molecule appears to work by (i) changing the balance in activity of signalling pathways already stimulated by LIF and (ii) activating additional signalling pathways. Specifically, L-proline rapidly further activates the LIF-stimulated MEK/ERK pathway, tipping the balance in favour of primitive-ectoderm formation and away from ES-cell self-renewal sustained by LIF-mediated activation of the STAT3 pathway. In addition, L-proline rapidly stimulates other pathways including p38, mTOR and PI3K/Akt each of which contributes, to a greater or lesser extent, to the conversion to primitive ectoderm-like cells. These results indicate that (i) L-proline acts in novel ways to stimulate embryo-like developmental progression in ES cells and (ii) through the addition of small, nontoxic activators and inhibitors of signalling pathways, the differentiation of pluripotent ES cells might be controlled sufficiently well for the homogeneous production of specific cell types suitable for use in animal models of human disease.
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Haraguchi, S., T. Q. Dang-Nguyen, K. Kikuchi, et al. "157 LEUKEMIA INHIBITORY FACTOR IMPROVES OOCYTE MATURATION AND DEVELOPMENTAL COMPETENCE IN PIGS." Reproduction, Fertility and Development 26, no. 1 (2014): 192. http://dx.doi.org/10.1071/rdv26n1ab157.
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A variety of growth factors and cytokines that are present in follicular fluid provide oocytes with a suitable environment for their maturation. One such cytokine is leukemia inhibitory factor (LIF). Although LIF-supplemented medium enhances embryo development in human, mouse, and bovine, studies investigating the effects of LIF on in vitro maturation (IVM) and subsequent embryo development are inconclusive. Additionally, the underlying mechanisms of LIF in oocyte maturation and embryo development after IVF have not been studied yet. In the present study, we examined the effect of recombinant porcine LIF (pLIF), produced in our laboratory, on porcine oocyte maturation and the mechanism of how LIF involves in oocyte maturation process at molecular level. The biological activity of pLIF was evaluated by sustenance of mouse embryonic stem (ES) cells with an undifferentiating state in ES medium supplemented with pLIF, and the final concentration (1 : 200, equivalent to 1000 U mL–1 of mouse LIF) was determined by serial dilution. Porcine cumulus–oocyte complexes (COC) were cultured in modified NCSU-37 medium supplemented with pLIF during the first 22 h [pLIF (+, –)], the latter 22 h [pLIF (–, +)], or whole 44 h [pLIF (+, +)] of IVM and the proportion of metaphase II (M-II) stage oocytes was observed. Oocyte maturation was enhanced in each group by supplementation with pLIF [pLIF (+, –): 76.1%, n = 138; pLIF (–, +): 82.1%, n = 140; pLIF (+, +): 86.6%, n = 127], when compared with control [pLIF (–, –): 69.6%, n = 112], in which a significant increase of M-II rate (P < 0.05 by ANOVA) and cumulus expansion were observed in the pLIF (+, +) group. The effect of pLIF was only seen for COC but not for denuded oocytes. When oocytes were subjected to IVF (Kikuchi et al. 2002), those matured in pLIF (+, +)-supplemented medium demonstrated higher blastocyst developmental rates (21.1% v. 16.2%; P = 0.07) with increased cell numbers (50.2 cells v. 45.0 cells; P = 0.12) compared with pLIF (–, –) on Day 6 of embryo culture (IVF = 0). Examination of transcripts and proteins of the LIF signalling pathway revealed that mRNA and protein levels of LIF, LIF receptors, and signal transducer and activator of transcription 3 (STAT3) were similar in both pLIF (–, –) and pLIF (+, +) samples. However, notable phosphorylation of STAT3 was observed in the pLIF (+, +) sample. These results suggest that the LIF/STAT3-pathway is functional during oocyte maturation in pigs. Therefore, supplementation of maturation medium with pLIF could improve the developmental competence of oocytes by activation of this pathway. This project was supported by JSPS and HAS under the Japan-Hungary Research Cooperative Program.
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Ilha, Gustavo Freitas, Monique T. Rovani, Bernardo G. Gasperin, et al. "Lack of FSH support enhances LIF–STAT3 signaling in granulosa cells of atretic follicles in cattle." REPRODUCTION 150, no. 4 (2015): 395–403. http://dx.doi.org/10.1530/rep-15-0026.
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Subordinate follicles (SFs) of bovine follicular waves undergo atresia due to declining FSH concentrations; however, the signalling mechanisms have not been fully deciphered. We used an FSH-induced co-dominance model to determine the effect of FSH on signalling pathways in granulosa cells of the second-largest follicles (SF in control cows and co-dominant follicle (co-DF2) in FSH-treated cows). The SF was smaller than DF in control cows while diameters of co-DF1 and co-DF2 in FSH-treated cows were similar. The presence of cleaved CASP3 protein confirmed that granulosa cells of SFs, but not of DFs and co-DFs, were apoptotic. To determine the effect of FSH on molecular characteristics of the second-largest follicles, we generated relative variables for the second largest follicle in each cow. For this, variables of SF or co-DF2 were divided by the variables of the largest follicle DF or co-DF1 in each cow. There was higher transcript abundance of MAPK1/3 and AKT1/2/3 but lower abundance of phosphorylated MAPK3/1 in SF than co-DF2 granulosa cells. Abundance of mRNA and phosphorylated protein of STAT3 was higher in granulosa cells of control SF than FSH-treated co-DF2. SF granulosa cells had higher levels of LIFR and IL6ST transcripts, the two receptors involved in STAT3 activation. Further, lower transcript abundance of interleukin 6 receptor (IL6R), another receptor involved in STAT3 activation, indicated that STAT3 activation in SF granulosa cells could be mainly due to leukemia inhibitory factor (LIF) signalling. These results indicate that atresia due to lack of FSH is associated with activated LIF–STAT3 signalling in SF granulosa cells, as FSH treatment reversed such activation.
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AlMuraikhi, Nihal, Hanouf Alaskar, Sarah Binhamdan, Amal Alotaibi, Moustapha Kassem, and Musaad Alfayez. "JAK2 Inhibition by Fedratinib Reduces Osteoblast Differentiation and Mineralisation of Human Mesenchymal Stem Cells." Molecules 26, no. 3 (2021): 606. http://dx.doi.org/10.3390/molecules26030606.
Full textAbstract:
Several signalling pathways, including the JAK/STAT signalling pathway, have been identified to regulate the differentiation of human bone marrow skeletal (mesenchymal) stem cells (hBMSCs) into bone-forming osteoblasts. Members of the JAK family mediate the intracellular signalling of various of cytokines and growth factors, leading to the regulation of cell proliferation and differentiation into bone-forming osteoblastic cells. Inhibition of JAK2 leads to decoupling of its downstream mediator, STAT3, and the subsequent inhibition of JAK/STAT signalling. However, the crucial role of JAK2 in hBMSCs biology has not been studied in detail. A JAK2 inhibitor, Fedratinib, was identified during a chemical biology screen of a small molecule library for effects on the osteoblastic differentiation of hMSC-TERT cells. Alkaline phosphatase activity and staining assays were conducted as indicators of osteoblastic differentiation, while Alizarin red staining was used as an indicator of in vitro mineralised matrix formation. Changes in gene expression were assessed using quantitative real-time polymerase chain reaction. Fedratinib exerted significant inhibitory effects on the osteoblastic differentiation of hMSC-TERT cells, as demonstrated by reduced ALP activity, in vitro mineralised matrix formation and downregulation of osteoblast-related gene expression, including ALP, ON, OC, RUNX2, OPN, and COL1A1. To identify the underlying molecular mechanisms, we examined the effects of Fedratinib on a molecular signature of several target genes known to affect hMSC-TERT differentiation into osteoblasts. Fedratinib inhibited the expression of LIF, SOCS3, RRAD, NOTCH3, TNF, COMP, THBS2, and IL6, which are associated with various signalling pathways, including TGFβ signalling, insulin signalling, focal adhesion, Notch Signalling, IL-6 signalling, endochondral ossification, TNF-α, and cytokines and inflammatory response. We identified a JAK2 inhibitor (Fedratinib) as a powerful inhibitor of the osteoblastic differentiation of hMSC-TERT cells, which may be useful as a therapeutic option for treating conditions associated with ectopic bone formation or osteosclerotic metastases.
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Roberts, Andrew W., Lisa Mielke, Sam Wormald, et al. "Suppressor of Cytokine Signaling-3 (SOCS3) Selectively Modulates Progenitor Cell Proliferation and Differentiation Induced by G-CSF and IL-6, and the Synergy between SCF and IL-6." Blood 108, no. 11 (2006): 631. http://dx.doi.org/10.1182/blood.v108.11.631.631.
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Abstract Studies using primary cells from mice with germline or tissue-specific deletion of SOCS3 indicate that SOCS3 is a negative regulator of IL-6, LIF, Leptin and G-CSF-induced cellular responses. Mice with selective deletion of SOCS3 gene in blood and endothelial cells develop a fatal inflammatory disease characterized by tissue infiltration with neutrophils and macrophages, and display hyper-responsiveness to G-CSF in vitro and in vivo (Immunity2004; 20:153–65). Previous structure-function studies in cell lines have suggested that SOCS3 negatively regulates cytokine signalling by targeting the activated receptor for ubiquination and proteasomal degradation. An alternative model proposes that SOCS3 selectively inactivates phosphorylated STAT3, or targets phosphorylated STAT3 for ubiquination and proteasomal degradation. To test in primary cells which model best fits physiology, we investigated signal transduction and cellular responses of SOCS3-deficient and wild-type lin- kit+ progenitor cells after stimulation with G-CSF, IL-6 and other haemopoietic cytokines. Activation of the STAT3, STAT5 and MAP kinase pathways was monitored by immunoblotting with phospho-specific antibodies, and quantified by flow cytometry after stimulating cells for between 5 min and 4 hours. Proliferation and differentiation were quantified in liquid and agar cultures stimulated with SCF, IL-3, GM-CSF, G-CSF, IL-6 and IL-11 alone, or in combination with SCF for 4 or 7 days. No differences in signalling, proliferation or differentiation between SOCS3-deficient and wild-type cells were observed after stimulation with SCF, IL-3, GM-CSF or combinations of these. However, marked differences were observed for G-CSF and IL-6, with increased cellular output and a skewing of differentiation away from purely neutrophil to a mixed neutrophil and macrophage output. Both cytokines induced prolonged phosphorylation of STAT3 in the absence of SOCS3 (consistent with previous observations in macrophages and neutrophils), but no perturbations in MAP Kinase activation. STAT5 phosphorylation was not detectable after stimulation with G-CSF or IL-6 in either genotype, but was robust and equal between genotypes after stimulation with IL-3. Stimulation with either G-CSF or IL-6 for 4 hours resulted in consistent differences between genotypes in transcriptional profiles, and increased transcription of CEBPβ was identified as a candidate regulator of the observed altered differentiation. Most intriguingly, in the absence of SOCS3, progenitor cells failed to show any synergy (or even additive effect) in proliferation when cultured in SCF plus IL-6, and the skewing of differentiation towards macrophages was magnified. As for individual cytokines, no differences in signalling pathway activation other than STAT3 were observed when progenitors were incubated with combinations of SCF and IL-6 or G-CSF. We conclude that SOCS3 primarily regulates STAT3 activation downstream of receptor activation by G-CSF or IL-6, rather than inhibiting all signal transduction from the activated receptors. These observations argue that further structure-function studies are required to define the relative importance of ubiquination and kinase inhibition as physiological mechanisms for SOCS3’s suppressor activities. They also provide new insight to the molecular regulation of synergy between SCF and IL-6.
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Robb, L., S. Rakar, and W. Alexander. "015.Disrupted decidualisation in SOCS3 gene mutant mice." Reproduction, Fertility and Development 16, no. 9 (2004): 15. http://dx.doi.org/10.1071/srb04abs015.
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Cytokines comprise a large family of secreted glycoproteins that regulate many fundamental biological processes. Cytokine signals are relayed to target cells via binding to cell surface receptors. The receptors signal via members of the Janus kinases (JAKs) and signal transduction and activators of transcription family (STATs). The SOCS proteins negatively regulate cytokine signalling by inhibiting components of the JAK/STAT pathway. Genetically modified mice in which individual SOCS genes are ablated have revealed key biological roles for these proteins. SOCS3 null mice die at mid gestation due to placental insufficiency. By embryonic Day (E) 9.5 there is a marked decrease in the spongiotrophoblast layer and an increase in trophoblast giant cells in SOCS3 null placentae. With increasing gestational age, there is progressive disorganisation of the SOCS3 null placental labyrinth. Takahashi et al. (1) used tetraploid aggregation to demonstrate that the placental defect was attributable to intrinsic defects in the SOCS3-deficient trophoblast cells or yolk sac endoderm. Based on evidence from in vitro assays, SOCS3 has a role in downstream negative regulation of signalling via a large number of cytokines. To identify the cytokine responsible for the placental phenotype, we crossed SOCS3 null embryos with mice lacking leukaemia inhibitory factor (LIF). This rescued the placental phenotype of the SOCS3 null mice, thereby demonstrating that alterations in LIF signalling are responsible for profound abnormalities of the murine placenta. (1) Takahashi et al. (2003) EMBO J. 22, 372–384.
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Duque, M., E. S. Zanneti, J. H. Galiguis, C. E. Pope, and M. C. Gomez. "228 Wnt SIGNALLING PATHWAY ACTIVATION IN CAT EMBRYONIC STEM LIKE-CELLS AND ITS ROLE IN MAINTAINING PLURIPOTENCY." Reproduction, Fertility and Development 28, no. 2 (2016): 245. http://dx.doi.org/10.1071/rdv28n2ab228.
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Stem cells from domestic animals are important for deriving therapeutic applications, generating models for human diseases, and developing alternative methods for conservation and preservation of endangered species. Cat embryonic stem like-cells (cESC) have been derived from in vivo and in vitro-produced blastocysts (Gómez et al. 2010 Theriogenology 74, 498). Although cESC colonies can be cultured in an undifferentiated state for several passages, they gradually lose their capacity to maintain pluripotency. Therefore, to maintain pluripotency of cat ESC during in vitro culture, it is necessary to develop a better understanding of the mechanisms involved in self-renewal and differentiation, as well as to enhance in vitro culture conditions. In mouse ESC, the Wnt/β-catenin signalling pathway has been identified as an essential pathway for maintenance of pluripotency and avoidance of differentiation (Kirby et al. 2012). Nonetheless, activation of the Wnt signalling and its role in human ESC remains controversial. Wnt activation is mediated by the cytoplasmic protein – Disheveled – that inactivates a multi-protein complex, including glycogen synthase kinase 3 (GSK3β) and inhibits β-catenin degradation. In the present study, we evaluated the role of Wnt/β-catenin signalling in self-renewal and maintenance of an undifferentiated state of cat ESC. Cat ESC were cultured on mitotically inactivated cat embryonic fibroblasts (CEF) in modified-ESC medium (DMEM-F12, 200 mM l-glutamine + 0.14% β-mercaptoethanol, 1.25% nonessential amino acids, 15% knockout replacement serum, 5% fetal bovine serum, 1000 U mL–1 leukemia inhibitory factor (LIF), and 10 ng mL–1 basic fibroblast growth factor, bFGF) and supplemented with GSK3β inhibitor -SB216763 (10 μM v. 20 μM v. 0 μM). The concentrations of β-catenin and GSK3β in cat ESC colonies were measured by ELISA, and the effect of GSK3β on cat ESC was measured by their cell size, morphology, expression of pluripotent markers at the mRNA and protein level (POU5F1, NANOG, SOX-2), and their ability to differentiate into ectoderm cell lineage. Our results indicated that GSK3β inhibitor inactivates GSK3β, leading to an increase in total β-catenin in cat ESC. Moreover, colonies cultured in the presence of GSK3β inhibitor showed flattened shape and irregular borders (compared with the dome shape and marked borders in nontreated colonies), and both the concentration and the passage significantly reduced the colony cell size, the expression of POU5F1 and SOX-2 at the mRNA and protein level, and lowered their ability to differentiate into neurogenic-like cells compared with that of colonies cultured without the GSK3β inhibitor. Even though we demonstrated that the Wnt/β-catenin signalling pathway influenced the expression of POU5F1 and SOX-2 of cat ESC, it is not clear why the accumulation of β-catenin did not enhance self-renewal. Further studies are required to evaluate the influence of GSK3β inhibitor and other small molecules on self-renewal of cat ESC cultured without the presence of a feeder cell layer.
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Hamdi, M., R. Mazzarella, K. Cañon-Beltrán, et al. "36 Analysis of miRNA content of oviduct and uterine extracellular vesicles across the bovine estrous cycle." Reproduction, Fertility and Development 33, no. 2 (2021): 125. http://dx.doi.org/10.1071/rdv33n2ab36.
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With the aim of investigating the possible hormonal regulatory effect of the oestrous cycle on miRNA content in the extracellular vesicles (EVs) of bovine oviducal and uterine fluids (OF, UF), we performed a bioinformatic analysis of these miRNAs, their target genes, and their biological pathways. Reproductive tracts were collected from slaughtered heifers and selected according to their corpus luteum morphology, corresponding to the 4 stages of the oestrous cycle (n=5 per stage; S1: days 1 to 4, S2: days 5–10, S3: days 11–17, S4: days 18–20) and transported to the laboratory on ice. EVs were obtained by size exclusion chromatography (PURE-EVs-Hansa Biomed) from the flushing of 1.2mL and 2.5mL of OF and UF, respectively. To concentrate the EVs, they were ultracentrifuged and suspended in 100µL of PBS. Total RNA extraction was obtained from 70µL of the previous pellet, using miRNeasy Mini Kit (Qiagen). Then, 100 to 200ng of the obtained RNA was reverse transcribed using miScript II RT Kit (Qiagen). MicroRNA (miRNA) expression profiling was done by primer-based real-time quantitative PCR of 383 mature miRNA sequences. Possible miRNA target genes and their biological pathways were predicted using the miRWalk database. Among EV miRNAs in OF, bta-miR-130a, bta-miR-382, and bta-miR-1291 were the most abundant at all stages of the oestrous cycle, displaying a significantly progressive increase from stages 1 to 4 (P&lt;0.05). In UF, bta-miR-17-5p, bta-miR-206, bta-miR-22-5p, bta-miR-502a, and bta-miR-503-3p were the most abundant at all stages of the cycle, showing greater differences between S1 and S3 (P&lt;0.05). Other miRNAs were exclusively present in a specific stage of the oestrous cycle in OF: bta-miR-21-5p (S1), bta-miR-146a (S2), bta-miR-128 (S3), and bta-miR-147 (S4). In UF, bta-miR-218 (S1), bta-miR-208b (S2), bta-miR-340 (S3), and bta-miR-335 (S4) were found. Table 1 presents some of these miRNAs, their predicted target genes, and functional pathways. In conclusion, this study highlights the effect of the oestrous cycle on miRNAs contained in the EVs of OF and UF. These miRNAs are related to relevant biological pathways implicated in oviduct and uterus modulation across the cycle, but they may also prepare those organs for embryo/conceptus presence and development. Table 1. Micro (mi)RNAs of oviductal (OF) and uterine fluid (UF) extracellular vesicles (EVs), their target genes, and biological pathways Reproductive fluid miRNAs Target genes Target pathways OF bta-miR-130a BMPR2, SMAD5, SMAD4 BMP signalling bta-miR-1291 SLC2A1 Glucagon signalling bta-miR-21–5p LIF Pluripotency stem cells regulation UF bta-miR-17-5p STAT3 Prolactin signalling bta-miR-206 ESR1 Oestrogen signalling bta-miR-340 HRAS Ras/MAPK/ERK signalling (embryo implantation) This research was funded by MINECO-Spain AGL2015-70140-R, PID2019-111641RB-I00, RTI2018-093548-B-I00; SENESCYT-Ecuador (YNC); FAPESP-Brazil 2017/20339-3 (CLVL), 2014/22887-0 (JCS), 2019/04981-2 (RM); CNPq-Brazil 304276/2018-9, 420152/2018-0 (CLVL).
Dissertations / Theses on the topic "LIF/STAT3 signalling pathway"
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Hall, John Simon. "Identification and investigation of the transcriptional targets of Oct4 and the LIF/Stat3-signalling pathway, within the context of the mouse embryonic stem cell genome." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/14968.
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Using microarray technology it has been possible to identify genes both induced by LIF and differentially expressed upon Oct4 knockout in the ZHBTc4.1 cell system. Analysis of the biological function of two genes from the LIF pathway (<i>Egr1 and Gbx2</i>) revealed altered morphology, transcriptome and putative ability to self-renew upon over-expression. The analysis of genes enriched in ES cells compared with trophoblast and neural stem cells, which are subsequently down-regulated upon Oct4 deletion revealed 42 genes including; <i>Nr0b1 </i>and <i>8430410A17Rik. </i>Enrichment analysis combined with examination of the convergence between the LIF/Stat3 and Oct4 pathways revealed <i>Klf2, Klf4 </i>and <i>Klf5 </i>as genes which are tightly associated with pluripotency. <i>Klf2 </i>has the ability to engage long term LIF-independent self-renewal in <i>Lifr<sup>-/-</sup> </i>ES cells. Long term culture of mES cells is associated with karyotypic changes which seemingly enhance self-renewal at the expense of pluripotent contribution. Understanding selection may identify genes and loci with novel functions in self-renewal. Using array based comparative genome hybridisation (aCGH) it was possible to identify a recurrently aberrant region on chromosome 14, which contains <i>Rb1, Spry2 </i>and <i>Klf5. </i>Trisomy chr. 11, amplification of a 37Mb region containing the <i>Nanog </i>locus on chromosome 6 and an 11Mb deletion on chromosome 17 were also discerned. The regions on chromosomes 6 and 11 are syntenic with recurrently aberrant regions in human ES cells, implying conservation of either the mechanism of aberration, or a selective pressure that is retained across different species of ES cell. Utilisation of array-based technologies has facilitated the identification of number genes which are enriched in mES cells and are rapidly down-regulated upon Oct4 deletion, some of which are also implicated in the LIF/Stat3 pathway. One gene in particular; <i>Klf2 </i>a member of the Krüppel-like family is capable of maintaining cytokine independent self-renewal upon over-expression. <i>Klf4 </i>and <i>Klf5 </i>also seem to be entwined with Oct4 and LIF/Stat3 function. Karyotypic aberrations in mES cells were also identified, which represent putative selective loci which may shift the balance between self-renewal and survival over differentiation and death.
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Giudice, Vincent. "Étude structurale et fonctionnelle d'un nouvel ARN non codant, Asgard, contrôlant l'autorenouvellement des cellules souches embryonnaires." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10271/document.
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Chez la souris, le Leukemia Inhibitory Factor (LIF) joue un rôle clé dans le maintien des cellules souches embryonnaires (ES) à l’état pluripotent. Le LIF agit en activant le facteur de transcription STAT3 via les kinases Jak. Cette activation est nécessaire et suffisante au maintien des cellules ES en autorenouvellement en présence de sérum. Une étude du transcriptome de STAT3 réalisée au laboratoire a permis d’identifier plusieurs gènes cibles de ce facteur, parmi lesquels plusieurs gènes inconnus. L’un d’eux, le gène 1456160_at, est fortement exprimé dans les cellules ES de souris et son expression diminue après induction de la différenciation. Ce gène a été appelé Asgard pour Another Self-renewal GuARDian. La caractérisation et le séquençage de ce gène ont permis de mettre en évidence qu'Asgard code pour un microARN. De nombreux microARNs jouent un rôle clé dans le maintien de l'autorenouvellement des cellules ES et dans le contrôle de la différenciation. Des expériences d’inhibition et de surexpression ont permis de montrer que Asgard est impliqué dans la régulation de la différenciation endoderme versus mésoderme. Des analyses préliminaires ont permis d’identifier Pbx3, FoxA2 et Sox17 comme cibles potentielles. Bien que les mécanismes d’action du microARN Asgard restent à confirmer, ce travail a permis d’identifier un nouveau gène clé de l'autorenouvellement des cellules ES de souris<br>The Leukemia Inhibitory Factor (LIF) activates the transcription factor STAT3, which results in the maintenance of mouse embryonic stem cells in the undifferentiated state by inhibiting mesodermal and endodermal differentiation. We identified several target genes of STAT3 by transcriptomic analysis. Among them, we focused on an unknown gene referred as 1456160_at on Affymetrix array. This gene is highly expressed in embryonic stem cells and its expression level decreases during differentiation. We named this gene Asgard for Another Self-renewal GuARDian. Its characterization and sequencing revealed that Asgard encodes for a microRNA sequence. Several microRNAs have been shown to play key role in the maintenance of self-renewal of mouse ES cells and in the control of differentiation. Inhibition and overexpression assays showed that Asgard inhibits endodermal differentiation in order to maintain self-renewal. Through preliminary analysis, we identified Pbx3, FoxA2 and Sox17 as potential targets of the microRNA Asgard. Our work enables us to identify a new key gene of self-renewal of mouse ES cells
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Kroon, Paula. "Importance of the IL-6/STAT3 signalling pathway in prostate cancer stem cells." Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/3714/.
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Prostate cancer is the most diagnosed cancer in men in the Western world. Currently, most treatments are directed towards an androgen receptor-expressing cell, which encompasses the majority of prostate tumours. Unfortunately, the tumour recurs in the majority of patients. This recurrence is thought to arise due to the presence of a rare population of prostate cancer stem cells. These cells are also hypothesized to be responsible for tumour initiation, maintenance, recurrence and metastasis. It is therefore important to develop novel therapies to target these tumour-initiating cells. Interleukin-6 (IL-6) is a pro-inflammatory cytokine, which is involved in the regulation of a multitude of cellular functions, including proliferation, apoptosis, and differentiation. IL-6 and the associated JAK-STAT signalling pathway have been implicated in the development and progression of a variety of tumours, including prostate cancer. In this study we have demonstrated that these stem-like cells, selected from primary prostate cancer cultures have elevated IL-6 levels and express the IL-6 receptor, suggesting that these cells are constitutively active. Targeting IL-6, and downstream activation of STAT3, resulted in a significant decrease in colony forming ability of these stem-like cells. Moreover, treatment with a small molecule inhibitor of STAT3 resulted in a modest inhibition of tumour growth, with a significant increase in the proportion of CD24+ luminal cells. Whilst the impact on established tumours was modest, LLL12 abolished tumour initiation, suggesting that activation of STAT3, through IL-6, is important for the maintenance of the undifferentiated stem-like cells within prostate tumours. Targeting the JAK-STAT signalling pathway in this cell population might result in a more durable response to current standard of care therapies.
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Hrabánková, Klára. "Využití polymerních proléčiv s cucurbitacinem D pro léčbu experimentálních nádorů." Master's thesis, 2021. http://www.nusl.cz/ntk/nusl-446100.
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Chemotherapy is still the most widely used anti-cancer treatment. The majority of chemotherapeutics inhibit proliferating cells generally, not selectively cancer cells. The side effects associated with chemotherapy can be partly limited by conjugating a cytotoxic drug with a polymer nanocarrier. Such binding facilitates solubility in aqueous solutions, reduces systemic toxicity; and passively targets the drug directly into the tumour through the enhanced permeability and retention (EPR) effect. This thesis focuses on testing polymer conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) carrying cucurbitacin D (CuD), a naturally occurring compound with potential anti-cancer activity. The mechanism of action is not elucidated yet, but several studies have depicted the inhibitory effect on signal transducer and activator of transcription 3 (STAT3) transcription factor. A STAT3 signalling pathway is overexpressed in several cancer cell lines and is also involved in the differentiation of myeloid- derived suppressor cells (MDSCs). We examined the therapeutic effect of the HPMA copolymers based on CuD in combined therapy with other polymer chemotherapeutics. CuD conjugates have shown in vitro cytotoxic effect on several model cancer cell lines. The combination with conjugates carrying doxorubicin...
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Menon, Priyanka Rajeev. "The importance of homotypic interactions of unphosphorylated STAT proteins in cytokine-induced signal transduction." Doctoral thesis, 2021. http://hdl.handle.net/21.11130/00-1735-0000-0005-15A2-C.
Full textBook chapters on the topic "LIF/STAT3 signalling pathway"
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Koide, Hiroshi, and Takashi Yokot. "The LIF/STAT3 Pathway in ES Cell Self-renewal." In Embryonic Stem Cells: The Hormonal Regulation of Pluripotency and Embryogenesis. InTech, 2011. http://dx.doi.org/10.5772/14496.
Full textConference papers on the topic "LIF/STAT3 signalling pathway"
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Simone Clement, Michelle, Boe Sandahl Sorensen, Sinead Cuffe, Stephen Finn, and Kathy Gately. "Targeting STAT3 pathway signalling in EGFR TKI resistant NSCLC." In ERS International Congress 2020 abstracts. European Respiratory Society, 2020. http://dx.doi.org/10.1183/13993003.congress-2020.330.
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Chou, JC, PS Wang, SW Wang, and H. Lin. "PO-183 Prolactin activation of JAK2/STAT3 signalling pathway through GHR in NSCLC." In 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-eacr25.704.
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Huang., Wen-Chien. "Abstract 769: Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/â-catenin /STAT3 axis signalling pathway in human non-small cell lung carcinomas." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-769.
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