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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ciliary neurotrophic factor (CNTF) signals via a tripartite receptor complex consisting of the glycosyl-phosphatidylinositol (GPI)-anchored CNTF receptor (CNTF-R), the leukaemia inhibitory factor receptor (LIF-R) and the interleukin-6 (IL-6) signal transducer gp130. We have recently reported that gp130 is endogenously expressed in the polarised epithelial model cell line Madin-Darby canine kidney (MDCK) and we have demonstrated a preferential basolateral localisation of this protein. In the present study we show that MDCK cells also express the LIF-R and respond to stimulation with human LIF by activation of tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT3), both however in an unpolarised fashion. This suggests that MDCK cells may be target cells for LIF. We have furthermore stably expressed the human CNTF-R in MDCK cells and by two different assays we found an apical localisation. Consistent with these findings, stimulation of CNTF-R-positive cells resulted only in an activation of STAT3 when CNTF was added apically. These data demonstrate that each subunit of the CNTF receptor complex has a distinct distribution in polarised cells which may reflect the different roles the respective cytokines play in vivo. Since it is currently believed that lipid rafts are involved in signal transduction as well as protein sorting we studied the association of the three receptor complex components with membrane rafts using different protocols. Whereas the CNTF-R cofractionated quantitatively with lipid rafts independently of the method used, gp130 and the LIF-R were found to associate with lipid rafts only partially when detergents were used for isolation. These findings could indicate that either the three receptor complex subunits are localised to the same kind of raft but with different affinities to the liquid-ordered environment, or that they are localised to different types of rafts. CNTF-, LIF-, and IL-6-dependent STAT3 activation was sensitive to the cholesterol-depleting drug methyl-beta-cyclodextrin (MCD) suggesting that the integrity of lipid rafts is important for IL-6-type cytokine-induced STAT activation.
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PMID:Polarity and lipid raft association of the components of the ciliary neurotrophic factor receptor complex in Madin-Darby canine kidney cells. 1505 6

IL-6 has been reported to play a central role in growth and survival of multiple myeloma (MM) cells. However, recently we have demonstrated that in the presence of bone marrow stromal cells, survival of MM cells becomes independent of the IL-6/gp130/STAT3 pathway questioning the singular role of IL-6 in MM. Therefore, it was the aim of this study to identify additional factors and signaling pathways that might contribute to the growth and survival of MM cells. We found that in addition to IL-6 a number of bone marrow derived cytokines such as LIF, VEGF, bFGF, MIP-1alpha, SDF-1alpha, IL-1beta, SCF and IL-3 activate the MAPK pathway and induce proliferation of MM.1S and RPMI-8226 MM cells. In addition, these cytokines independently phosphorylate the forkhead family member FKHR via PI3-K/AKT and support survival of primary human MM cells. Inhibition of these pathways induces apoptosis in MM cell lines and primary MM cells. Thus, we provide evidence that in addition to IL-6 a number of different factors trigger important growth-promoting pathways to support the proliferation and survival of MM cells. Therefore, blocking such pathways, rather than blocking a single factor, might be a promising approach for the development of novel treatment strategies in MM.
Leukemia 2004 Nov
PMID:PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. 1535 48

Intrinsic regulators of the pluripotency of mouse ES (embryonic stem) cells include the homeodomain proteins Oct4 and the recently identified Nanog. When overexpressed, Nanog displays the unique attribute of robustly sustaining ES cell self-renewal in the absence of the otherwise requisite extracellular stimulation by LIF (leukaemia inhibitory factor) and BMP (bone morphogenetic protein). Here, we review our current understanding of the function of Nanog in pluripotent stem cells both in vitro and in vivo.
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PMID:The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells. 1624 59

The concept that bone marrow (BM)-derived cells participate in neural regeneration remains highly controversial and the identity of the specific cell type(s) involved remains unknown. We recently reported that the BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSCs), including neural TCSCs. Here, we report that these cells not only express neural lineage markers (beta-III-tubulin, Nestin, NeuN, and GFAP), but more importantly form neurospheres in vitro. These neural TCSCs are present in significant amounts in BM harvested from young mice but their abundance and responsiveness to gradients of motomorphogens, such as SDF-1, HGF, and LIF, decreases with age. FACS analysis, combined with analysis of neural markers at the mRNA and protein levels, revealed that these cells reside in the nonhematopoietic CXCR4+/Sca-1+/lin-/CD45 BM mononuclear cell fraction. Neural TCSCs are mobilized into the peripheral-blood following stroke and chemoattracted to the damaged neural tissue in an SDF-1-CXCR4-, HGF-c-Met-, and LIF-LIF-R-dependent manner. Based on these data, we hypothesize that the postnatal BM harbors a nonhematopoietic population of cells that express markers of neural TCSCs that may account for the beneficial effects of BM-derived cells in neural regeneration.
Leukemia 2006 Jan
PMID:Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke. 1627 36

This report describes the pH measurement of individual acidic organelles isolated from the human leukemia CCRF-CEM and CEM/C2 cells. These cells were allowed to endocytose fluorescein tetramethylrhodamine dextran (FRD), a ratiometric probe that has fluorescein as a pH-dependent fluorophore and tetramethylrhodamine as a pH-independent fluorophore. Isolated organelle fractions from these cells were then subjected to capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) analysis. The detection of individual organelle fluorescence at two different wavelengths, selected on the basis of the emission range of the FRD probe, gives a fluorescence intensity ratio used to calculate the pH from a calibration curve. This curve was constructed from CE-LIF measurements of individual liposomes loaded with several pH buffer standards. The respective median pH values are 5.1 +/- 0.2 in CEM/C2 cells and 6.1 +/- 0.4 in CCRF-CEM cells. These measurements compare well with pixel-based epifluorescence microscopy measurements of whole cells where the corresponding average pH values are 5.0 +/- 0.6 (n = 15) and 6.2 +/- 0.7 (n = 15). A pH comparison between the two cell types suggests that the lower pH in the CEM/C2 cells may be relevant to the protonation and sequestration of weak base anticancer drugs such as doxorubicin. The determination of the pH of individual vesicles, liposomes, and acidic organelles is a new resource for measuring and investigating the role of the acid-base properties of subcellular-size compartments.
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PMID:Individual acidic organelle pH measurements by capillary electrophoresis. 1644 56

By employing multiparameter sorting, we identified in murine bone marrow (BM) a homogenous population of rare (approximately 0.02% of BMMNC) Sca-1(+)lin(-)CD45- cells that express by RQ-PCR and immunohistochemistry markers of pluripotent stem cells (PSC) such as SSEA-1, Oct-4, Nanog and Rex-1. The direct electronmicroscopical analysis revealed that these cells are small (approximately 2-4 microm), posses large nuclei surrounded by a narrow rim of cytoplasm, and contain open-type chromatin (euchromatin) that is typical for embryonic stem cells. In vitro cultures these cells are able to differentiate into all three germ-layer lineages. The number of these cells is highest in BM from young (approximately 1-month-old) mice and decreases with age. It is also significantly diminished in short living DBA/2J mice as compared to long living B6 animals. These cells in vitro respond strongly to SDF-1, HGF/SF and LIF and express CXCR4, c-met and LIF-R, respectively, and since they adhere to fibroblasts they may be coisolated with BM adherent cells. We hypothesize that this population of Sca-1(+)lin(-)CD45- very small embryonic-like (VSEL) stem cells is deposited early during development in BM and could be a source of pluripotent stem cells for tissue/organ regeneration.
Leukemia 2006 May
PMID:A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. 1649 86

The basic helix-loop-helix protein Neurogenin3 specifies precursor cells of the endocrine pancreas during embryonic development, and is thought to be absent postnatally. We have studied Ngn3 expression during in vitro generation of beta-cells from adult rat exocrine pancreas tissue treated with epidermal growth factor and leukaemia inhibitory factor. This treatment induced a transient expression of both Ngn3 and its upstream activator hepatocyte nuclear factor 6. Inhibition of EGF and LIF signalling by pharmacological antagonists of the JAK2/STAT3 pathway, or knockdown of Ngn3 by RNA interference prevented the generation of new insulin-positive cells. This study demonstrates that in vitro growth factor stimulation can induce recapitulation of an embryonic endocrine differentiation pathway in adult dedifferentiated exocrine cells. This could prove to be important for understanding the mechanism of beta-cell regeneration and for therapeutic ex vivo neogenesis of beta cells.
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PMID:Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway. 1651 19

Suppressor of cytokine signaling (SOCS) is a new family of proteins produced in cells. It may play an important role in classic negative feedback loop to regulate cytokine signal transduction. SOCS-1 was observed and confirmed firstly. Expression of SOCS-1 can inhibit cytokine signal transduction of some cytokines, such as IL-6, LIF, OSM, INF-gamma, GH, and so on, many immune responses are regulated by them in vivo. Abnormal expression of SOCS-1 is closely related to some human diseases. It plays an important role in the development of leukemia, rheumatoid arthritis, liver cirrhosis and liver cancer. In this review, the advances of research on the relationship between SOCS-1 and cytokine, and its correlation with some diseases were summarized.
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PMID:[Progress of study on suppressor of cytokine signaling-1 - review]. 1749 65

The blood-brain barrier (BBB), a communicating interface for inflammation, transports cytokines through its endothelial cells. This study shows how tumor necrosis factor alpha (TNF) regulates the expression of the leukemia inhibitor factor receptor (LIFR) gp190 in RBE4 cells. The high expression of LIFR was rapidly downregulated by the proinflammatory agents lipopolysaccharide, TNF, and LIF. Downregulation by TNF affected LIFR endocytosis and lysosomal degradation, preceding decreased LIFR mRNA. Lysosomal inhibitors reversed the rapid disappearance of LIFR, whereas inhibition of the ubiquitin-proteasome pathway did not. Rather, blockade of proteasome activity, as well as inhibition of NFkappaB activation, reduced the basal expression of LIFR. Thus, NFkappaB activity and proteasome degradation of IkappaB stabilized LIFR and prevented its rapid lysosomal degradation. By a non-NFkappaB-mediated mechanism, TNF facilitated LIFR degradation and reduced LIFR activation indicated by pStat3. The novel opposite effects of proteasomes and lysosomes in controlling receptor expression shows the functional implications and interactions of circulating inflammatory cytokines in acutely modulating BBB activity.
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PMID:Opposing effects of proteasomes and lysosomes on LIFR: modulation by TNF. 1787 91

The activation of receptor complexes containing glycoprotein 130 (gp130) identifies the interleukin (IL)-6 cytokine family. We examined members of this family for their expression and activity in hair follicles. Quantitative polymerase chain reaction using mRNA derived from microdissected, anagen-stage human hair follicles and comparison to non-follicular skin epithelium revealed higher levels of IL-6 (15.5-fold) and oncostatin M (OSM, 3.4-fold) in hair follicles. In contrast, expression of all mRNAs coding for IL-6 cytokine family receptors was reduced. Immunohistology suggested expression of OSM, gp130, leukaemia inhibitory factor receptor (LIFr) and IL-11r in the hair follicle root sheaths and dermal papilla, while IL-11, IL-6r and OSMr were expressed in root sheaths alone. IL-6 was expressed in the dermal papilla while cardiotrophin-1 (CT-1) and LIF were not observed. OSM and to a lesser extent CT-1 exhibited a dose-dependent growth inhibition capacity on human hair follicles in vitro. OSM and CT-1 incubated with agarose beads and injected subcutaneously at 1 mug per mouse into telogen skin of 65-day-old mice revealed no capacity to induce anagen hair growth. In contrast, injection of 65-day-old mice in which anagen had been induced by hair plucking revealed a moderate hair growth inhibitory capacity for OSM, but no significant effect for CT-1. The data identify OSM as a modulator of hair follicle growth and suggest other family members may also have some degree of hair growth inhibitory effect. In principle, increased expression of some IL-6 cytokine family members in cutaneous inflammation might contribute to the promotion of hair loss.
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PMID:Interleukin-6 cytokine family member oncostatin M is a hair-follicle-expressed factor with hair growth inhibitory properties. 1797 74


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