Journal articles: 'Leukaemia Inhibitory Factor Receptor'

1

CICHY, Joanna, Stefan ROSE-JOHN, and James TRAVIS. "Oncostatin M, leukaemia-inhibitory factor and interleukin 6 trigger different effects on α1-proteinase inhibitor synthesis in human lung-derived epithelial cells." Biochemical Journal 329, no. 2 (January 15, 1998): 335–39. http://dx.doi.org/10.1042/bj3290335.

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Interleukin 6 (IL-6), oncostatin M (OSM) and leukaemia-inhibitory factor (LIF) share a common signal-transducing subunit in each of their receptors and thus mediate an overlapping spectrum of biological activities. Although all of these cytokines stimulate the production of α1-proteinase inhibitor (α1-PI) in hepatocyte-derived cells, only OSM is able to up-regulate levels of this inhibitor in epithelial cells originating from the lung. In this study we characterized human lung-derived epithelial-like HTB58 cells for their ability to synthesize α1-PI after treatment with IL-6, OSM and LIF. The results demonstrate that the resistance of HTB58 cells to the effects of IL-6 and LIF was not because of a lack of their individual functional receptors and suggest that OSM utilizes two different receptors, gp130/LIF receptor and gp130/OSM receptor, in lung-derived epithelial cells.

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Schäfer-Somi, S., D. Klein, HB Beceriklisoy, S. Sabitzer, SS Ay, AR Agaoglu, I. Kücükaslan, D. Kaya, OA Aksoy, and S. Aslan. "Uterine Progesterone Receptor and Leukaemia Inhibitory Factor mRNA Expression in Canine Pregnancy." Reproduction in Domestic Animals 44 (July 2009): 109–14. http://dx.doi.org/10.1111/j.1439-0531.2009.01390.x.

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Fry, RC. "The effect of leukaemia inhibitory factor (LIF) on embryogenesis." Reproduction, Fertility and Development 4, no. 4 (1992): 449. http://dx.doi.org/10.1071/rd9920449.

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Leukaemia inhibitory factor (LIF) was originally identified as a haemopoetic factor that induced the differentiation of certain myeloid leukaemia cell lines. In contrast to this action, LIF was subsequently shown to inhibit the spontaneous differentiation of murine embryonic stem cells in culture, thus maintaining their pluripotency and ability to contribute to the germline of chimaeric mice. In the mouse, mRNA for LIF is expressed by the endometrial glands of the uterus coincident with the time of blastocyst implantation and receptors have been found on the preimplantation blastocyst. The signal for LIF expression appears to be of maternal origin, perhaps regulated by oestradiol. Recombinant LIF improves the development of murine and ovine blastocysts in culture although there is some species specificity with respect to the type of LIF that is bioactive. It is proposed here that LIF acts on the trophectoderm of the rapidly expanding blastocyst and improves the implantation rate of otherwise compromised embryos. Further studies in livestock should elicit therapeutic uses for LIF in embryo culture, embryo transfer and embryo survival in vivo.

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THIEL, Stefan, Iris BEHRMANN, Andreas TIMMERMANN, Heike DAHMEN, Gerhard MÜLLER-NEWEN, Fred SCHAPER, Jan TAVERNIER, Vincent PITARD, Peter C. HEINRICH, and Lutz GRAEVE. "Identification of a Leu-Ile internalization motif within the cytoplasmic domain of the leukaemia inhibitory factor receptor." Biochemical Journal 339, no. 1 (March 25, 1999): 15–19. http://dx.doi.org/10.1042/bj3390015.

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Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor LIF is internalized. In this study, we show that the LIFR is endocytosed independently of gp130. By using a heterochimaeric receptor system we identified a dileucine-based internalization motif within the cytoplasmic domain of the LIFR. Our findings suggest that a heterodimeric LIFR/gp130 complex and homodimeric gp130/gp130 complex are endocytosed via distinct internalization signals.

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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 (July 27, 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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KASZA, Aneta, Krzysztof ROGOWSKI, Witold KILARSKI, Radoslaw SOBOTA, Tytus BERNAS, Jurek DOBRUCKI, James TRAVIS, Aleksander KOJ, Marcin BUGNO, and Tomasz KORDULA. "Differential effects of oncostatin M and leukaemia inhibitory factor expression in astrocytoma cells." Biochemical Journal 355, no. 2 (April 6, 2001): 307–14. http://dx.doi.org/10.1042/bj3550307.

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The effects of the production of two closely related cytokines, oncostatin M (OSM) and leukaemia inhibitory factor (LIF), by astrocytoma cells were investigated using the stable cell line human U373-MG, which expressed and secreted both biologically active polypeptides. The expression of LIF by these cells caused resistance to this cytokine due to loss of the LIF receptor (LIFR), from the cell surface, suggesting its retention. In contrast, cells expressing OSM were stimulated by this cytokine, utilizing an autocrine mechanism, and possessed receptors for OSM, but not LIF, on the cell surface. In these cells the continuous up-regulation of OSM-induced gene expression was found even though the Janus kinase-signal transducer and activator of transcription (‘JAK/STAT’) pathway was almost exhausted due to long-term autocrine stimulation of the cells by OSM. The amount of LIFR was down-regulated in both LIF- and OSM-producing cells and this effect was not found in wild-type U373-MG cells treated with externally added cytokines. To investigate the mechanism of autocrine stimulation by OSM we constructed a stable cell line expressing a form of OSM that is retained in the endoplasmic reticulum (ER). This biologically active cytokine was not secreted, but was localized in the ER. In addition, it did not stimulate the astrocytoma cells in an autocrine manner. We conclude that expression of LIF causes resistance of astrocytoma cells to this cytokine, whereas expression of OSM leads to autocrine stimulation.

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Owczarek, C. M., M. J. Layton, D. Metcalf, P. Lock, T. A. Willson, N. M. Gough, and N. A. Nicola. "Inter-species chimeras of leukaemia inhibitory factor define a major human receptor-binding determinant." EMBO Journal 12, no. 9 (September 1993): 3487–95. http://dx.doi.org/10.1002/j.1460-2075.1993.tb06023.x.

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ZHANG, Jian-Guo, Catherine M. OWCZAREK, Larry D. WARD, Geoffrey J. HOWLETT, Louis J. FABRI, Bronwyn A. ROBERTS, and Nicos A. NICOLA. "Evidence for the formation of a heterotrimeric complex of leukaemia inhibitory factor with its receptor subunits in solution." Biochemical Journal 325, no. 3 (August 1, 1997): 693–700. http://dx.doi.org/10.1042/bj3250693.

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Leukaemia inhibitory factor (LIF) is a polyfunctional cytokine that is known to require at least two distinct receptor components (LIF receptor α-chain and gp130) in order to form a high-affinity, functional, receptor complex. Human LIF binds with unusually high affinity to a naturally occurring mouse soluble LIF receptor α-chain, and this property was used to purify a stable complex of human LIF and mouse LIF receptor α-chain from pregnant-mouse serum. Recombinant soluble human gp130 was expressed, with a FLAG® epitope (DYKDDDDK) at the N-terminus, in the methylotropic yeast Pichia pastoris and purified using affinity chromatography. The formation of a trimeric complex in solution was established by native gel electrophoresis, gel-filtration chromatography, sedimentation equilibrium analysis, surface plasmon resonance spectroscopy and chemical cross-linking. The stoichiometry of this solution complex was 1:1:1, in contrast with that of the complex of interleukin-6, the interleukin-6-specific low-affinity receptor subunit and gp130, which is 2:2:2.

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9

Harvey, M. B., K. J. Leco, M. Y. Arcellana-Panlilio, X. Zhang, D. R. Edwards, and G. A. Schultz. "Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor." Development 121, no. 4 (April 1, 1995): 1005–14. http://dx.doi.org/10.1242/dev.121.4.1005.

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Several proteinases from different multigene families have been implicated in the uterine invasion required for establishment of pregnancy in some mammals. In this study, the expression of matrix metalloproteinase gelatinase B (MMP-9), urokinase-type plasminogen activator (uPA) and their inhibitors was investigated during early mouse embryo development. Transcripts for tissue inhibitors of metalloproteinases (TIMP-1,-2,-3) and uPA receptor were detected throughout pre- and peri-implantation development whilst MMP-9 and uPA mRNAs were first detected in peri-implantation blastocysts associated with the invasive phase of implantation. Through use of in situ hybridization, it was shown that MMP-9 transcripts were strongly expressed in the network of trophoblast giant cells at the periphery of implanting 7.5 day embryos and TIMP-3 transcripts were strongly expressed in the decidua immediately adjacent to the implanting embryo. uPA transcripts were preferentially expressed in the ectoplacental cone and its derivatives. Because these proteinases are regulated by growth factors and cytokines in other tissues, the effect of leukaemia inhibitory factor (LIF) and epidermal growth factor (EGF) on their activity was investigated. Both LIF and EGF, like the proteinases, have been implicated in peri-implantation development. Blastocysts collected on day 4 of pregnancy were cultured 2 days in TCM 199 + 10% fetal bovine serum to allow outgrowth followed by 24 hour culture in defined media containing either LIF or EGF. Conditioned media were assayed for uPA activity by a chromogenic assay and MMP activity by gelatin zymography. Both LIF and EGF stimulated uPA and MMP-9 activity in blastocyst outgrowths after 3 days of culture (day 7). Proteinase activity was assayed again at the 5th to 6th day of culture (day 9 to 10). EGF was found to have no effect whereas LIF decreased production of both proteinases. These results demonstrate that proteinase activity in early embryos can be regulated by growth factors and cytokines during the implantation process and, in particular, they demonstrate the possible involvement of LIF in establishment of the correct temporal programme of proteinase expression.

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CHAMBERS, Ian, Alison COZENS, Joanne BROADBENT, Morag ROBERTSON, Muriel LEE, Meng LI, and Austin SMITH. "Structure of the mouse leukaemia inhibitory factor receptor gene: regulated expression of mRNA encoding a soluble receptor isoform from an alternative 5′ untranslated region." Biochemical Journal 328, no. 3 (December 15, 1997): 879–88. http://dx.doi.org/10.1042/bj3280879.

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The low-affinity leukaemia inhibitory factor receptor (LIF-R) is a component of cell-surface receptor complexes for the multifunctional cytokines leukaemia inhibitory factor, ciliary neurotrophic factor, oncostatin M and cardiotrophin-1. Both soluble and transmembrane forms of the protein have been described and several LIF-R mRNAs have been reported previously. In order to determine the coding potential of LIF-R mRNAs we have isolated and characterized the mouse LIF-R gene. mRNA encoding soluble LIF-R (sLIF-R) is formed by inclusion of an exon in which polyadenylation signals are provided by a B2 repeat. This exon is located centrally within the LIF-R gene but is excluded from the transmembrane LIF-R mRNA by alternative splicing. The transmembrane receptor is encoded by 19 exons distributed over 38 kb. Two distinct 5ʹ non-coding exons have been identified, indicating the existence of alternative promoters. One of these is G/C rich and possesses a consensus initiator sequence as well as potential Sp1 binding sites. Expression of exon 1 from this promoter occurs in a wide variety of tissues, whereas expression of the alternative 5ʹ untranslated region (exon 1a) is normally restricted to liver, the principal source of sLIF-R. During pregnancy expression of exon 1a becomes detectable also in the uterus. Expression of exon 1a increases dramatically during gestation and is accompanied by a similar quantitative rise in expression of sLIF-R mRNA. These findings establish that expression of LIF-R is under complex transcriptional control and indicate that regulated expression of the soluble cytokine receptor isoform may be due principally to an increase in the activity of a dedicated promoter.

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11

Sato, Yoko, Kaoru Yoshida, Shiari Nozawa, Miki Yoshiike, Michiko Arai, Takeshige Otoi, and Teruaki Iwamoto. "Establishment of adult mouse Sertoli cell lines by using the starvation method." REPRODUCTION 145, no. 5 (May 2013): 505–16. http://dx.doi.org/10.1530/rep-12-0086.

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Sertoli cells were isolated from the testes of 6-week-old mice and stable Sertoli cell lines with higher proliferation rates were subcloned after starvation of primary cultured cells. After two rounds of this subcloning, 33 subcloned lines were selected on the basis of their proliferation rates. In addition, these subclones were screened according to their phagocytic activity and the characteristics of mature Sertoli cells, such as the expression of androgen receptors (ARs) and progesterone receptors, by using western blotting and immunocytochemical analysis, in addition to their morphology and proliferation rates. After the third round of subcloning, 12 subclones were selected for the final selection using RT-PCR for identification of genes specifically expressed by various testicular cells. Three clones were selected that expressed Sertoli-cell-specific genes, i.e. stem cell factor, clusterin, AR, α-inhibin, transferrin, Wilms' tumour-1, Müllerian inhibitory substance, sex-determining region Y-box 9, FSH receptor (Fshr) and occludin; however, these clones did not express globulin transcription factor 1, steroidogenic factor or androgen-binding protein. These clones also expressed growth and differentiation factors that act on germ cells, such as leukaemia inhibitory factor, transforming growth factor β1 and basic fibroblast growth factor 2, but did not express c-kit (specific for germ cells), LH receptor and 3β-hydroxyl-dehydrogenase (specific for Leydig cells). Immunocytochemical data confirmed the expression of clusterin in these clones. Furthermore, the Bromodeoxyuridine incorporation assay confirmed the proliferation activity of these clones throughFshrafter treatment with FSH. These clones are considered to be valuable tools for the study of Sertoli cell-specific gene expression and function.

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12

Yang, Z.-M., S.-P. Le, D.-B. Chen, K. Yasukawa, and M. J. K. Harper. "Expression patterns of leukaemia inhibitory factor receptor (LIFR) and the gp130 receptor component in rabbit uterus during early pregnancy." Reproduction 103, no. 2 (March 1, 1995): 249–55. http://dx.doi.org/10.1530/jrf.0.1030249.

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13

Hilton, D. J., N. A. Nicola, and D. Metcalf. "Analysis of the distribution and characteristics of receptors for leukaemia inhibitory factor." Cell Differentiation and Development 27 (August 1989): 10–11. http://dx.doi.org/10.1016/0922-3371(89)90070-1.

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14

De Breuck, S., L. Baeyens, and L. Bouwens. "Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas." Diabetologia 49, no. 1 (December 21, 2005): 108–16. http://dx.doi.org/10.1007/s00125-005-0079-1.

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15

Vogiagis, D., and LA Salamonsen. "Review: The role of leukaemia inhibitory factor in the establishment of pregnancy." Journal of Endocrinology 160, no. 2 (February 1, 1999): 181–90. http://dx.doi.org/10.1677/joe.0.1600181.

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Leukaemia inhibitory factor (LIF) is a pleiotrophic cytokine required for blastocyst implantation in mice. Uterine expression of LIF and that of its receptors has been demonstrated in a number of mammalian species indicating that LIF may have widespread importance in the establishment of pregnancy. The variations in the reaction of the uterus in preparation for and during implantation are considerable between species and understanding the differences and similarities assists in the interpretation of how this cytokine functions. Recent studies suggest that reduced endometrial LIF contributes to human infertility. Studies also demonstrate a potential role in placentation and fetal development. Thus, LIF has become an important cytokine warranting further investigation in the human. It is anticipated that when the mechanisms underlying normal embryonic and endometrial development are elucidated, fertility and infertility will be more precisely understood and hence able to be effectively controlled.

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HEINRICH, Peter C., Iris BEHRMANN, Gerhard MÜLLER-NEWEN, Fred SCHAPER, and Lutz GRAEVE. "Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway1." Biochemical Journal 334, no. 2 (September 1, 1998): 297–314. http://dx.doi.org/10.1042/bj3340297.

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The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.

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Seeneevassen, Lornella, Julie Giraud, Silvia Molina-Castro, Elodie Sifré, Camille Tiffon, Clémentine Beauvoit, Cathy Staedel, et al. "Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer." Cancers 12, no. 8 (July 22, 2020): 2011. http://dx.doi.org/10.3390/cancers12082011.

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Cancer stem cells (CSCs) present chemo-resistance mechanisms contributing to tumour maintenance and recurrence, making their targeting of utmost importance in gastric cancer (GC) therapy. The Hippo pathway has been implicated in gastric CSC properties and was shown to be regulated by leukaemia inhibitory factor receptor (LIFR) and its ligand LIF in breast cancer. This study aimed to determine LIF’s effect on CSC properties in GC cell lines and patient-derived xenograft (PDX) cells, which remains unexplored. LIF’s treatment effect on CSC markers expression and tumoursphere formation was evaluated. The Hippo kinase inhibitor XMU-MP-1 and/or the JAK1 inhibitor Ruxolitinib were used to determine Hippo and canonical JAK/STAT pathway involvement in gastric CSCs’ response to LIF. Results indicate that LIF decreased tumorigenic and chemo-resistant CSCs, in both GC cell lines and PDX cells. In addition, LIF increased activation of LATS1/2 Hippo kinases, thereby decreasing downstream YAP/TAZ nuclear accumulation and TEAD transcriptional activity. LIF’s anti-CSC effect was reversed by XMU-MP-1 but not by Ruxolitinib treatment, highlighting the opposite effects of these two pathways downstream LIFR. In conclusion, LIF displays anti-CSC properties in GC, through Hippo kinases activation, and could in fine constitute a new CSCs-targeting strategy to help decrease relapse cases and bad prognosis in GC.

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Panni, M. K., J. Atkinson, and M. V. Sofroniew. "Leukaemia inhibitory factor prevents loss of p75-nerve growth factor receptor immunoreactivity in medial septal neurons following fimbria–fornix lesions." Neuroscience 89, no. 4 (April 1999): 1113–21. http://dx.doi.org/10.1016/s0306-4522(98)00385-6.

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19

THIEL, Stefan, Iris BEHRMANN, Andreas TIMMERMANN, Heike DAHMEN, Gerhard MÜLLER-NEWEN, Fred SCHAPER, Jan TAVERNIER, Vincent PITARD, Peter C. HEINRICH, and Lutz GRAEVE. "Identification of a Leu-Ile internalization motif within the cytoplasmic domain of the leukaemia inhibitory factor receptor." Biochemical Journal 339, no. 1 (April 1, 1999): 15. http://dx.doi.org/10.1042/0264-6021:3390015.

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HEINRICH, Peter C., Iris BEHRMANN, Serge HAAN, Heike M. HERMANNS, Gerhard MÜLLER-NEWEN, and Fred SCHAPER. "Principles of interleukin (IL)-6-type cytokine signalling and its regulation." Biochemical Journal 374, no. 1 (August 15, 2003): 1–20. http://dx.doi.org/10.1042/bj20030407.

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The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.

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Gardiner, Natalie J., William B. J. Cafferty, Sarah E. Slack, and Stephen W. N. Thompson. "Expression of gp130 and leukaemia inhibitory factor receptor subunits in adult rat sensory neurones: regulation by nerve injury." Journal of Neurochemistry 83, no. 1 (September 18, 2002): 100–109. http://dx.doi.org/10.1046/j.1471-4159.2002.01101.x.

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Denizot, Yves, Valérie Lorgeot, Elisabeth Cornu, and Nathalie Nathan. "PLASMA LEUKAEMIA INHIBITORY FACTOR, INTERLUEKIN 6 AND SOLUBLE INTERLEUKIN 6 RECEPTOR LEVELS DURING CARDIOPULMONARY BYPASS WITH EXTRACORPOREAL CIRCULATION." Cytokine 10, no. 4 (April 1998): 303–6. http://dx.doi.org/10.1006/cyto.1997.0285.

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Heymann, Dominique, Anne Godard, Sylvie Raher, Nadia Bentouimou, Frédéric Blanchard, Michel Chérel, Marie-Martine Hallet, and Yannick Jacques. "Leukaemia inhibitory factor (LIF) and oncostatin M (OSM) high affinity binding require additional receptor subunits besides GP130 and GP190." Cytokine 8, no. 3 (March 1996): 197–205. http://dx.doi.org/10.1006/cyto.1996.0028.

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van Eijk, M. J. T., J. Mandelbaum, J. Salat-Baroux, J. Belaisch-Allart, M. Plachot, A. M. Junca, and C. L. Mummery. "Preimplantation embryology: Expression of leukaemia inhibitory factor receptor subunits LIFRβ and gp 130 in human oocytes and preimplantation embryos." Molecular Human Reproduction 2, no. 5 (1996): 355–60. http://dx.doi.org/10.1093/molehr/2.5.355.

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Abir, R. "Immunocytochemical detection and RT-PCR expression of leukaemia inhibitory factor and its receptor in human fetal and adult ovaries." Molecular Human Reproduction 10, no. 5 (March 25, 2004): 313–19. http://dx.doi.org/10.1093/molehr/gah047.

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K. Bhanumathy, Kalpana, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald, and Vincenzo Giambra. "Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia." Cancers 13, no. 2 (January 7, 2021): 184. http://dx.doi.org/10.3390/cancers13020184.

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Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

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K. Bhanumathy, Kalpana, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald, and Vincenzo Giambra. "Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia." Cancers 13, no. 2 (January 7, 2021): 184. http://dx.doi.org/10.3390/cancers13020184.

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Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

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Reddy, M. A., B. S. Yang, X. Yue, C. J. Barnett, I. L. Ross, M. J. Sweet, D. A. Hume, and M. C. Ostrowski. "Opposing actions of c-ets/PU.1 and c-myb protooncogene products in regulating the macrophage-specific promoters of the human and mouse colony-stimulating factor-1 receptor (c-fms) genes." Journal of Experimental Medicine 180, no. 6 (December 1, 1994): 2309–19. http://dx.doi.org/10.1084/jem.180.6.2309.

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The receptor for macrophage colony stimulating factor (CSF-1), the c-fms gene product, is a key determinant in the differentiation of monocytic phagocytes. Dissection of the human and mouse c-fms proximal promoters revealed opposing roles for nuclear protooncogenes in the transcriptional regulation of this gene. On the one hand, c-ets-1, c-ets-2, and the macrophage-specific factor PU.1, but not the ets-factor PEA3, trans-activated the c-fms proximal promoter. On the other hand c-myb repressed proximal promoter activity in macrophages and blocked the action of c-ets-1 and c-ets-2. Basal c-fms promoter activity was almost undetectable in the M1 leukaemia line, which expressed high levels of c-myb, but was activated as cells differentiated in response to leukemia inhibitory factor and expressed c-fms mRNA. The repressor function of c-myb depended on the COOH-terminal domain of the protein. We propose that ets-factors are necessary for the tissue-restricted expression of c-fms and that c-myb acts to ensure correct temporal expression of c-fms during myeloid differentiation.

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Gough, NM, RL Williams, DJ Hilton, S. Pease, TA Willson, J. Stahl, DP Gearing, NA Nicola, and D. Metcalf. "LIF: a molecule with divergent actions on myeloid leukaemic cells and embryonic stem cells." Reproduction, Fertility and Development 1, no. 4 (1989): 281. http://dx.doi.org/10.1071/rd9890281.

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We have previously characterized, purified and cloned a novel murine and human regulator [leukaemia inhibitory factor, LIF] which induces the differentiation of certain murine and human myeloid leukaemic cells. Recently we have shown that there are specific LIF receptors on murine embryonic stem [ES] and embryonal carcinoma [EC] cells and that purified recombinant LIF can substitute for feeder cells and crude sources of differentiation inhibiting activity [DIA] [such as BRL-cell-conditioned medium] in the maintenance of ES cells in a pluripotential state in vitro. Furthermore, ES cells maintained in culture in recombinant LIF for a prolonged period can give rise to germline chimaeric mice. Thus, based on a number of biochemical and biological similarities, it is likely that LIF and DIA are the same molecule. The identification of LIF as a molecule, necessary and sufficient for the maintenance of ES cells in culture, should have a profound impact on the use of these cells for genetic manipulations.

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Lei, T., ZQ Yang, T. Xia, L. Gan, XD Chen, JH Yuan, and Y. Zhu. "Stage-specific Expression of Leukaemia Inhibitory Factor and its Receptor in Rabbit Pre-implantation Embryo and Uterine Epithelium During Early Pregnancy." Reproduction in Domestic Animals 39, no. 1 (February 2004): 13–18. http://dx.doi.org/10.1046/j.1439-0531.2003.00469.x.

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Mohamet, L., J. K. Heath, and S. J. Kimber. "Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist." REPRODUCTION 138, no. 5 (November 2009): 827–36. http://dx.doi.org/10.1530/rep-09-0113.

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Uteri of Lif null mice do not support embryo implantation. Since deletion of some genes often prevents the survival of null mice to adulthood, we have used a proven inhibitor of leukaemia inhibitory factor (LIF) signalling to identify the precise window of time during which LIF is required in vivo, and assessed the cellular expression of several LIF-associated targets. On day 4 of pregnancy, mice were injected with hLIF-05 (inhibitor) into the uterine lumen, with corresponding volumes of PBS (vehicle) injected into the contralateral horn. On days 5 and 6, the number of implantation sites was recorded and the uteri processed for immunohistochemistry. Blockade of LIF on day 4 reduced embryo implantation by 50% (P≤0.0001) and was effective maximally between 0930 and 1230 h. Antagonism of LIF signalling was evidenced by a lack of phosphorylated STAT3 in the luminal epithelium (LE). Amphiregulin was absent from the LE on day 4 evening and H-type-1 antigen expression was retained in the LE on day 5 in inhibited uteri. Interleukin-1α and oncostatin M expression were reduced in the stroma on day 6, following LIF inhibition. Unexpectedly, PTGS2 expression in stroma was unaffected by LIF inhibition in vivo, in contrast to Lif null mice. In summary, this suggests that LIF signalling is effective for implantation during a discrete time window on day 4 and antagonism of LIF signalling recapitulates many features exhibited in Lif null uteri. The data presented validates the use of antagonists to investigate tissue specific and temporal cytokine signalling in reproductive function.

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Eckert, J. "mRNA expression of leukaemia inhibitory factor (LIF) and its receptor subunits glycoprotein 130 and LIF-receptor-beta in bovine embryos derived in vitro or in vivo." Molecular Human Reproduction 4, no. 10 (October 1, 1998): 957–65. http://dx.doi.org/10.1093/molehr/4.10.957.

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Kojima, Kenji, Hideharu Kanzaki, Masazumi Iwai, Hiroshi Hatayama, Mariko Fujimoto, Shinji Narukawa, Toshihiro Higuchi, Yoshiyuki Kaneko, Takahide Mori, and Jun Fujita. "Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts." Molecular Human Reproduction 1, no. 5 (1995): 249–53. http://dx.doi.org/10.1093/molehr/1.5.249.

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HAMMACHER, Annet, John WIJDENES, Douglas J. HILTON, Nicos A. NICOLA, Richard J. SIMPSON, and Judith E. LAYTON. "Ligand-specific utilization of the extracellular membrane-proximal region of the gp130-related signalling receptors." Biochemical Journal 345, no. 1 (December 17, 1999): 25–32. http://dx.doi.org/10.1042/bj3450025.

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The receptor gp130 is used by the interleukin-6 (IL-6)-type cytokines, which include IL-6 and leukaemia-inhibitory factor (LIF). To investigate the role of the three extracellular membrane-proximal fibronectin-type-III-like (FNIII) modules of gp130 and the related receptor for granulocyte colony-stimulating factor (G-CSFR) in cytokine signal transduction we have transfected into murine myeloid M1-UR21 cells the chimaera (GR-FNIII)gp130, which contains the membrane-proximal FNIII modules of the G-CSFR on a gp130 backbone, and its complement, the chimaera (gp130-FNIII)GR. Whereas the binding affinities of 125I-labelled IL-6 to (GR-FNIII)gp130, or of 125I-Tyr1,3-G-CSF to (gp130-FNIII)GR, were similar to wild-type gp130 and wild-type G-CSFR, respectively, 125I-LIF failed to bind with high affinity to (GR-FNIII)gp130. In assays measuring differentiation the (gp130-FNIII)GR cells were fully responsive to G-CSF, whereas the (GR-FNIII)gp130 cells responded fully to the agonistic anti-gp130 monoclonal antibody (mAb) B-S12, but not to IL-6 or LIF. Neutralizing mAbs that recognize the membrane-proximal FNIII modules of gp130 or the G-CSFR differentially interfered with signalling by B-S12, LIF and G-CSF. The data suggest that B-S12 and G-CSF induce the correct orientation or conformation for signalling by the wild-type and chimaeric homodimeric receptors, that the membrane-proximal region of gp130 is important for the correct formation of the signalling IL-6-IL-6 receptor-gp130 complex and that this region is also involved in LIF-dependent receptor heterodimerization and signalling.

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Krüttgen, A., J. Grötzinger, G. Kurapkat, J. Weis, R. Simon, M. Thier, M. Schröder, et al. "Human ciliary neurotrophic factor: a structure-function analysis." Biochemical Journal 309, no. 1 (July 1, 1995): 215–20. http://dx.doi.org/10.1042/bj3090215.

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Ciliary neurotrophic factor (CNTF) promotes survival in vitro and in vivo of several neuronal cell types including sensory and motor neurons. The primary structure of CNTF suggests it to be a cytosolic protein with strong similarity to the alpha-helical cytokine family which is characterized by a bundle of four anti-parallel helices. CNTF exerts its activity via complexation with CNTF receptor (CNTF-R). This complex consists of a CNTF-binding protein (CNTF-R) and two proteins important for signal transduction [gp130 and leukaemia inhibitory factor receptor (LIF-R)]. We have shortened the cDNA coding for CNTF at both the 5′ and the 3′ end and expressed the truncated proteins in bacteria. Biological activities of the protein preparations were determined by their ability to induce proliferation of BAF/3 cells that were stably transfected with CNTF-R, gp130 and LIF-R cDNAs. CNTF proteins with 14 amino acid residues removed from the N-terminus were biologically active whereas the removal of 23 amino acids resulted in an inactive protein. In addition, 18 amino acid residues could be removed from the C-terminus of the CNTF protein without apparent loss of bioactivity, but further truncation at the C-terminus yielded biologically inactive proteins. The introduction of two point mutations into the CNTF protein at a site that presumably interacts with one of the two signal-transducing proteins resulted in a CNTF mutant with no measurable bioactivity. In addition, a model of the three-dimensional structure of human CNTF was constructed using the recently established structural co-ordinates of the related cytokine, granulocyte colony-stimulating factor. CD spectra of CNTF together with our mutational analysis and our three-dimensional model fully support the view that CNTF belongs to the family of alpha-helical cytokines. It is expected that our results will facilitate the rational design of CNTF mutants with agonistic or antagonistic properties.

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Eswari, S., G. Sai Kumar, and G. Taru Sharma. "Expression of mRNA encoding leukaemia inhibitory factor (LIF) and its receptor (LIFRβ) in buffalo preimplantation embryos produced in vitro: markers of successful embryo implantation." Zygote 21, no. 2 (August 14, 2012): 203–13. http://dx.doi.org/10.1017/s0967199412000172.

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SummaryThe objective of this study was to evaluate the effect of supplementation of recombinant leukaemia inhibitory factor (LIF) in culture media on blastocyst development, total cell number and blastocyst hatching rates and the reverse transcription-polymerase chain reaction analysis of preimplantation buffalo embryos to determine whether they contain the LIF-encoding mRNA and its beta receptor (LIFRβ) genes in different stages of preimplantation buffalo embryos. Cumulus–oocyte complexes retrieved from slaughterhouse buffalo ovaries were matured in vitro and fertilized using frozen buffalo semen. After 18 h of co-incubation with sperm, the presumptive zygotes were cultured in modified synthetic oviductal fluid without (control) or with rhLIF (100 ng/ml). There was no significant difference in the overall cleavage rate up to morula stage however the development of blastocysts, hatching rate and total cell numbers were significantly higher in the LIF-treated group than control. Transcripts for LIFRβ were detected from immature, in vitro-matured oocytes and in the embryos up to blastocyst stage, while transcripts for the LIF were detected from 8–16-cell stage up to blastocyst, which indicated that embryo-derived LIF can act in an autocrine manner on differentiation process and blastocyst formation. This study indicated that the addition of LIF to the embryo culture medium improved development of blastocysts, functional (hatching) and morphological (number of cells) quality of the blastocysts produced in vitro. The stage-specific expression pattern of LIF and LIFRβ mRNA transcripts in buffalo embryos indicated that LIF might play an important role in the preimplantation development and subsequent implantation of buffalo embryos.

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Wånggren, K., P. G. Lalitkumar, F. Hambiliki, B. Ståbi, K. Gemzell-Danielsson, and A. Stavreus-Evers. "Leukaemia inhibitory factor receptor and gp130 in the human Fallopian tube and endometrium before and after mifepristone treatment and in the human preimplantation embryo." MHR: Basic science of reproductive medicine 13, no. 6 (April 12, 2007): 391–97. http://dx.doi.org/10.1093/molehr/gam013.

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38

de Ruijter-Villani, M., C. Deelen, and T. A. E. Stout. "Expression of leukaemia inhibitory factor at the conceptus–maternal interface during preimplantation development and in the endometrium during the oestrous cycle in the mare." Reproduction, Fertility and Development 28, no. 10 (2016): 1642. http://dx.doi.org/10.1071/rd14334.

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Leukaemia inhibitory factor (LIF) plays a critical role in blastocyst development and implantation in several species. The present study investigated mRNA and protein expression for LIF, as well as the low-affinity LIF receptor (LIFR) and interleukin-6 signal transducer (IL6ST), in equine endometrium, trophoblast and histotroph during early pregnancy and in the endometrium during the oestrous cycle. Endometrial LIF mRNA expression was upregulated after Day 21 of pregnancy, whereas LIF immunoreactivity increased in the endometrium on Day 28. Expression of LIF mRNA in the yolk sac membrane increased from Day 21 of pregnancy, whereas LIF immunoreactivity increased from Day 28 in the trophoblast. LIFR and IL6ST mRNA was expressed in the endometrium during both the oestrous cycle and early pregnancy and, although LIFR and IL6ST protein were localised to the glandular epithelium during the cycle and first 14 days of pregnancy, from Day 21 they were located in the luminal epithelium. Trophoblast expression of LIFR and IL6ST increased as pregnancy proceeded. In conclusion, LIF expression increased at the conceptus–maternal interface during capsule attenuation. Because contemporaneous upregulation of both LIFR and IL6ST was also observed in the trophoblast, we propose that LIF plays an important role in the development of endometrial receptivity for trophoblast growth, apposition and adhesion in mares.

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Verma, Arjun, Nishant Banait, Pradeep Suryawanshi, and Reema Garegrat. "Neonatal Schwartz-Jampel syndrome type II: a rare case of peripheral origin of neonatal hypertonia." BMJ Case Reports 14, no. 7 (July 2021): e240397. http://dx.doi.org/10.1136/bcr-2020-240397.

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Neonatal Schwartz-Jampel syndrome type II is a rare and severe form of genetic disorder. Different from the classical appearance in infancy, neonatal presentation involves respiratory and feeding difficulties, along with characteristic pursed appearance of the mouth, myotonia, skeletal dysplasia and severe fatal hyperthermia. The clinical spectrum of this syndrome is so wide that it easily baffles with more common differentials. In this case report, a neonate born to third-degree consanguineous marriage with previous two abortions presented with respiratory difficulty, severe hyperthermia and feeding difficulty, which were daunting challenges to manage due to being refractory to standard line of management. Severe myotonia and gross dysmorphism were challenging dots to connect. Targeted exome sequencing was a ray of hope, which revealed homozygous mutation in the leukaemia inhibitory factor receptor gene on chromosome 5p13, confirming the genetic diagnosis for a fairly common spectrum of symptoms. The neonate later developed pneumoperitoneum and succumbed to underlying severe neonatal illness.

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Saha, Piyali, Ghungroo Saraswat, Pratip Chakraborty, Sayani Banerjee, Bikas C. Pal, and Syed N. Kabir. "Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage." REPRODUCTION 144, no. 5 (November 2012): 633–45. http://dx.doi.org/10.1530/rep-11-0423.

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The tubers ofPueraria tuberosahave folkloric repute as emmenagogue. The n-BuOH fraction of the ethanolic extract of tubers exhibits significant antifertility activity in laboratory animals. The present investigation explored the active principle(s) of the tuber extract with reference to contragestive effects in rats and probed the possible mechanism of action. Bioactivity-guided fractionation identified puerarin as the major constituent that exerted pregnancy-terminating effects. Oral administration of puerarin at ≥300 mg/kg per day for days (D) 1–2 post-coitus resulted in complete implantation failure. Serum oestradiol levels during D2–D5 and progesterone (P4) level on D5 remained unaffected, but the endometrial expression of oestrogen receptor α (ERα) and ERβ was adversely modulated that disrupted the implantation-specific characteristic endometrial oestrogenic milieu. The eventual consequence was loss of endometrial receptivity characterised by down-regulation of the uterine expression of P4receptor (PR) and attenuation of endometrial expression of leukaemia inhibitory factor, vascular endothelial growth factor and cyclo-oxygenase-2, the three important signalling molecules involved in the process of implantation. Light microscopic examination of the embryos demonstrated no untoward effect of puerarin on the development of embryos until D4, but D5 blastocysts underwent gross morphological distortion. The findings taken together are interpreted to suggest that puerarin adversely impacts the uterine expression of ER and PR that disrupts the implantation-conducive uterine milieu and prevents implantation. In conclusion, puerarin may be envisaged as a prospective molecule that merits further exploration for the development of non-steroidal post-coital contraceptive for women.

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Kogan, Inna, Dafna Chap, Ron Hoffman, Elena Axelman, Benjamin Brenner, and Yona Nadir. "JAK-2 V617F mutation increases heparanase procoagulant activity." Thrombosis and Haemostasis 115, no. 01 (January 2016): 73–80. http://dx.doi.org/10.1160/th15-04-0320.

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SummaryPatients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.

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ALTHOFF, Katja, Jürgen MÜLLBERG, Dorthe AASLAND, Nicole VOLTZ, Karl-Josef KALLEN, Joachim GRÖTZINGER, and Stefan ROSE-JOHN. "Recognition sequences and structural elements contribute to shedding susceptibility of membrane proteins." Biochemical Journal 353, no. 3 (January 25, 2001): 663–72. http://dx.doi.org/10.1042/bj3530663.

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Although regulated ectodomain shedding affects a large panel of structurally and functionally unrelated proteins, little is known about the mechanisms controlling this process. Despite a lack of sequence similarities around cleavage sites, most proteins are shed in response to the stimulation of protein kinase C by phorbol esters. The signal-transducing receptor subunit gp130 is not a substrate of the regulated shedding machinery. We generated several chimaeric proteins of gp130 and the proteins tumour necrosis factor α (TNF-α), transforming growth factor α (TGF-α) and interleukin 6 receptor (IL-6R), which are known to be subject to shedding. By exchanging small peptide sequences of gp130 for cleavage-site peptides of TNF-α, TGF-α and IL-6R we showed that these short sequences conferred susceptibility to spontaneous and phorbol-ester-induced shedding of gp130. Importantly, these chimaeric gp130 proteins were functional, as shown by the phosphorylation of gp130 and the activation of signal transduction and activators of transcription 3 (‘STAT3’) on stimulation with cytokine. To investigate minimal requirements for shedding, truncated cleavage-site peptides of IL-6R were inserted into gp130. The resulting chimaeras were susceptible to shedding and showed the same cleavage pattern as observed in the chimaeras containing the complete IL-6R cleavage site. Surprisingly, we could also generate cleavable chimaeras by exchanging the juxtamembrane sequence of gp130 for the corresponding region of leukaemia inhibitory factor (‘LIF’) receptor, a protein that like gp130 is not subject to regulated or spontaneous shedding. Thus it seems that there is no minimal consensus shedding sequence. We speculate that structural changes allow the access of the protease to a membrane-proximal region, leading to shedding of the protein.

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Modrić, T., A. A. Kowalski, M. L. Green, R. C. M. Simmen, and F. A. Simmen. "Pregnancy-dependent Expression of Leukaemia Inhibitory Factor (LIF), LIF Receptor-β and Interleukin-6 (IL-6) Messenger Ribonucleic Acids in the Porcine Female Reproductive Tract." Placenta 21, no. 4 (May 2000): 345–53. http://dx.doi.org/10.1053/plac.1999.0493.

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Charnock-Jones, D. S., A. M. Sharkey, P. Fenwick, and S. K. Smith. "Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time." Reproduction 101, no. 2 (July 1, 1994): 421–26. http://dx.doi.org/10.1530/jrf.0.1010421.

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Gouin, François, Séverine Couillaud, Mireille Cottrel, Anne Godard, Norbert Passuti, and Dominique Heymann. "PRESENCE OF LEUKAEMIA INHIBITORY FACTOR (LIF) AND LIF-RECEPTOR CHAIN (gp190) IN OSTEOCLAST-LIKE CELLS CULTURED FROM HUMAN GIANT CELL TUMOUR OF BONE. ULTRASTRUCTURAL DISTRIBUTION." Cytokine 11, no. 4 (April 1999): 282–89. http://dx.doi.org/10.1006/cyto.1998.0429.

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46

Aasland, Dorthe, Birgit Oppmann, Joachim Grötzinger, Stefan Rose-John, and Karl-Josef Kallen. "The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex 1 1Edited by M. Yaniv." Journal of Molecular Biology 315, no. 4 (January 2002): 637–46. http://dx.doi.org/10.1006/jmbi.2001.5282.

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47

Kojima, Kenji, Hideharu Kanzak, Masazumi Iwai, Hiroshi Hatayama, Mariko Fujimoto, Shinji Narukawa, Toshihiro Higuchi, Yoshiyuki Kaneko, Takahide Mori, and Jun Fujita. "Molecular interactions during pregnancy: Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts." Human Reproduction 10, no. 7 (July 1995): 1907–11. http://dx.doi.org/10.1093/oxfordjournals.humrep.a136205.

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Kumar, Rahul, Raquel Pereira, Julian Niemann, Costanza Zanetti, Alex Azimpour, Melanie Meister, Parimala Sonika Godavarthy, and Daniela S. Krause. "The Role of the Lipid Raft-Associated Protein Flotillin-2 during Development and Progression of Myeloid Leukaemia." Blood 134, Supplement_1 (November 13, 2019): 2921. http://dx.doi.org/10.1182/blood-2019-122670.

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Introduction The role of the bone marrow (BM) microenvironment (BMM) for the regulation of leukaemic stem cells (LSC) and their respective interplay is slowly being elucidated, but knowledge about how membrane structures or adhesion molecules on leukaemia cells may, specifically, interact with the BMM leading to regulation of leukemia cell maintenance and proliferation is limited. Flotillin (flot)-1 and -2 are highly conserved, ubiquitously expressed proteins localised in lipid microdomains in cellular membranes. These dynamic microdomains can serve as platforms for signal transduction, endocytosis and interactions with the actin cytoskeleton, as well as cell adhesion. Hypothesis As flotillins in the leukaemia cell membrane are associated with adhesion molecules known to be involved in the engraftment of leukaemia-initiating cells (LIC), we hypothesized that flotillins may play a role in LIC engraftment in the BMM. Results Using the murine retroviral transduction/transplantation model of BCR-ABL1-driven chronic myeloid leukaemia (CML) we observed a significant prolongation of survival of recipients of BCR-ABL1+, flot-2-deficient bone marrow compared to the respective control. The homing of BCR-ABL1+LIC to wild-type recipient bone marrow was reduced. Consistent with the known association of flotillins in the cell membrane with P-selectin glycoprotein ligand-1, a selectin ligand similar to CD44, both of which are known to be involved in the engraftment of CML LIC (Krause DS et al., Nat Med, 2006, and Krause DS et al., Blood, 2014), we demonstrated that flot-2 physically interacts and co-localizes with CD44. Flot-2-deficiency led to a significant reduction of the expression of CD44 and an impairment of the cytoskeleton in BCR-ABL1+ cells, as well as impaired migration. Further, Cdc42, a member of the Rho-GTPase family,was differentially distributed in wildtype versus flotillin-2-deficient BCR-ABL1+ LSC and may have compromised activity. Consistently, intrafemoral transplantation of flot-2-deficient CML-initiating cells or coexpression of CD44 in flot-2-deficient bone marrow ,rescued' or restored the CML-like disease. In contrast, in an MLL-AF9-driven model of acute myeloid leukemia (AML) a similar prolongation of survival or reduced homing of AML-initiating cells were not observed. However, expression of CD44, known to play a role for engraftment in this disease (Jin L et al., Nat Med, 2006), in AML-initiating cells was similarly reduced and migration, adhesion and the cytoskeleton was similarly compromised.We demonstrated that this might be due to compensatory upregulation of C-X-C chemokine receptor type 4 (CXCR-4), the receptor for stromal-derived factor (SDF)-1a. Conclusions In summary, these data suggest that lipid raft molecules, particularly flotillins, play a previously unknown and possibly leukaemia-specific role in CML progression via modification of the levels and function of CD44 and possible regulation of Cdc42. Disclosures Kumar: European Patent No. 16187926.7: Other: USE OF FIBRONECTIN OR ILK INHIBITORS FOR USE IN THE TREATMENT OF LEUKEMIA; Merck: Research Funding. Krause:Merck KGaA: Research Funding; Patent: Patents & Royalties: European Patents No. 16187926.7-1401, EP18184430.9-.

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Guo, Donglin, Fang Zhou, Dongdong Chen, Hongxiang Xie, Ting Wang, Haibo Wang, Guoying Xu, Haiping Wen, and Zhou Hong. "Involvement of IRAKs and TRAFs in anti-β2GPI/β2GPI-induced tissue factor expression in THP-1 cells." Thrombosis and Haemostasis 106, no. 12 (2011): 1158–69. http://dx.doi.org/10.1160/th11-04-0229.

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SummaryOur previous study has shown that Toll-like receptor 4 (TLR4) and its signalling pathway contribute to anti-β2-glycoprotein I/β2-glycoprotein I (anti-β2GPI/β2GPI)-induced tissue factor (TF) expression in human acute monocytic leukaemia cell line THP-1 and annexin A2 (ANX2) is involved in this pathway. However, its downstream molecules have not been well explored. In this study, we have established that interleukin-1 receptor-associated kinases (IRAKs) and tumour necrosis factor receptor-associated factors (TRAFs) are crucial downstream molecules of anti-β2GPI/β2GPI-induced TLR4 signaling pathway in THP-1 cells and explored the potential mechanisms of their self-regulation. Treatment of THP-1 cells with anti-β2GPI/β2GPI complex induced IRAKs and TRAFs expression and activation. Anti-β2GPI/β2GPI complex firstly induced expression of IRAK4 and IRAK1, then IRAK1 phosphorylation and last IRAK3 upregulation. In addition, anti-β2GPI/β2GPI complex simultaneously and acutely enhanced mRNA levels of TRAF6, TRAF4 and zinc finger protein A20 (A20), while chronically increased A20 protein level. Moreover, anti-β2GPI/β2GPI complex-induced IRAKs and TRAFs expression and activation were attenuated by knockdown of ANX2 by infection with ANX2-specific RNA interference lentiviruses (LV-RNAi-ANX2) or by treatment with paclitaxel, which inhibits TLR4 as an antagonist of myeloid differentiation protein 2 (MD-2) ligand. Furthermore, both IRAK1/4 inhibitor and a specific proteasome inhibitor MG-132 could attenuate TRAFs expression as well as TF expression induced by anti-β2GPI/β2GPI complex. In conclusion, our results indicate that IRAKs and TRAFs play important roles in anti-β2GPI/β2GPI-stimulated TLR4/TF signaling pathway in THP-1 cells and contribute to the pathological processes of antiphospholipid syndrome (APS).

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Platzbecker, Uwe, Nicole Georgi, Christian Thiede, Gerhard Ehninger, and Thomas Illmer. "The Role of Expression of FLICE and FLICE-Inhibitory Protein Isoforms in Acute Myeloid Leukemia." Blood 106, no. 11 (November 16, 2005): 2758. http://dx.doi.org/10.1182/blood.v106.11.2758.2758.

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Abstract One possibility of the execution of cell death is due to the interaction of ligands with their specific death receptors. The death-receptor pathway via FAS, tumor-necrosis factor receptor 1 (TNF-R1) and TNF-related apoptosis inducing ligand (TRAIL)-receptors has been shown to be involved in apoptosis induction by cytotoxic agents in acute myeloid leukaemia (AML). Upon ligation the primary executioner of these pathways is named FLICE (caspase 8). The FLICE-inhibitory-protein (FLIP) consists of two isoforms (FLIP long and FLIP short) and can be recruited to the death inducing signaling complex (DISC) thus preventing the generation of active FLICE. Therefore, both proteins might be important regulators of cell death in AML. First, we determined the expression of FLIPL and FLIPS as well as of the caspase-8 isoforms a/c and b/d by quantitative Taqman-PCR in samples of 149 AML patients at diagnosis. The patients were treated within the AML SHG 96 trial. The median age of the patients was 56 years. The expression levels of all isoforms was not associated with known prognostic factors including cytogenetic risk groups and FLT-3 ITD status. There was a positive correlation between FLIPL and FLIPS (p<0.001) and caspase-8 a/c and b/d (p<0.001) expression, respectively. Additionally, we found a correlation between the expression of both isoforms of caspase-8 with those of FLIPL (p<0.001) but not of FLIPS (p=0.5). We did not observe any association between expression levels of both genes and remission rate, disease-free or overall survival in the entire population. Since we observed a coregulation of caspase-8 and FLIP in AML samples we asked whether a selective deregulation of this balance might change the sensitivity of cell to apoptotic stimuli including chemotherapeutic agents. In a validated model system of HeLa cells we were able to selectively downregulate the expression rate of FLIP on the cDNA and protein level to about 20% of baseline employing a siRNA strategy. As compared to non-silencing control and determined by the MTT assay FLIP siRNA application resulted in reduced viability of HeLa cells (baseline non silence: 100%, FLIP siRNA: 65% [±4]) which was further enhanced (20 % [±3]) by the addition of TRAIL (3 ng/ml). In contrast, silencing of caspase 8 did not influence the viability of HeLa cells. Moreover the addition of commonly used drugs in AML treatment (daunorubicin; etoposide, Ara-C) to HeLa cells after siRNA against FLIP induced an additive cytotoxic effect which was higher as compared to cells treated with siRNA against caspase 8 or non-silencing control. In conclusion upregulation of proapoptotic caspase-8 in AML patient samples seems to be counteracted by parallel expression of the inhibitor protein FLIP. Shifting the balance between FLIP and caspase 8 may alter the sensitivity profile of malignant cells. Whether this approach might be able to overcome resistance of primary leukemic cells needs to be determined.

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Journal articles on the topic 'Leukaemia Inhibitory Factor Receptor'

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