Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparin, a glycosaminoglycan (GAG) derivative has been widely used as an anticoagulation agent for more than 50 years. This study was conducted to demonstrate that, due to their modulatory effect on cytokines, heparin and other GAGs can favor megakaryocytopoiesis both in vitro and in vivo in mice. In vitro addition of heparin and other GAGs (excepting keratane sulfate) into plasma clot cultures induces a significant increase in the number of megakaryocyte colonies. Optimal heparin and GAG concentrations for maximal effect are approximately 50-100 micrograms/ml. In agar culture without serum, all GAGs do not have this stimulating effect on megakaryocyte colonies. This would suggest that the GAG action depends on the presence of one or more plasma factors. Interactions between GAGs and cytokines such as IL3, IL6, G-SCF, GM-CSF, aFGF, TPO and EPO as well as PF4 and TGFB1 were also conducted. The results demonstrate that heparin and chondroitin sulfate significantly increases the action of TPO, IL6 and aFGF but not the action of IL3, G-SCF and EPO. Heparin and other GAGs can also neutralize PF4 and TGFB1 inhibitory action. In vivo, the effect of low-molecular-weight heparin (Fraxiparine) injected in normal mice treated with 5-fluorouracil increases megakaryocytopoiesis. The findings demonstrate that heparin and its derivatives have a potentializing effect on megakaryocytopoiesis and could be used as therapeutic agents in the treatment of thrombocytopenia.
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PMID:[Effects of heparin on megakaryocytopoiesis. From fundamental data to clinical applications]. 923 40

The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210bcr/abl. Relative to normal c-abl, p210bc1/abl has elevated tyrosine kinase activity that is essential for its transforming activity. We recently reported a prominent 62 kDa GAP-associated P-tyr protein and five additional consistent but less prominent P-tyr proteins as well as five more minor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin- normal blasts. The GAP-associated p62 protein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being characterized. In analyzing P-tyr proteins in primary lin- normal blasts in response to various hematopoietic cytokines, we found a striking similarity in the tyrosine phosphorylation of four major and three minor proteins after stimulation with c-kit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand, TPO, EPO) were much less active or stimulated phosphorylation of other proteins. KL/c-kit and bcr/abl have some similar activities including enhancing survival and expansion of hematopoietic progenitor cells, probably acting primarily on early progenitors at the time of lineage commitment rather than on self-renewing stem cells. Activation of growth factor receptors promote a cascade of protein phosphorylations that can ultimately result in a wide range of cellular responses. Sustained activation of discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instead causes a proliferative response; in other cell types, the converse is true. It may be postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders them especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical regulatory pathways, including c-kit. The affected pathways control and coordinate multiple diverse cell processes including proliferation, differentiation, maturation and apoptosis, processes that are normally tightly regulated and integrated. Perturbation of these key pathways in primitive progenitors would be expected to seriously disrupt orderly hematopoiesis and could also explain the multiple subtle pleiotropic biological abnormalities characteristically observed in later maturing CML compartments that we have collectively designated 'discordant maturation'. The true situation is undoubtedly very complex and involves interaction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical pathways in susceptible early progenitors that normally require KL or other factors for activation could explain most if not all features of the disease.
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PMID:New understanding of the pathogenesis of CML: a prototype of early neoplasia. 952 44

A novel variant cDNA from the human ST2 gene other than ST2 or ST2L was identified and tentatively named ST2V. Alternative splicing inserts a new exon which leads to a change in the C-terminal portion of ST2, causing it to gain a hydrophobic tail instead of losing the third immunoglobulin-like domain. ST2V is expressed in human leukemic cell line UT-7 and its sublines UT-7/GM, UT-7/EPO, and UT-7/TPO, in addition to human helper T cell line 5C10. The amount of ST2V mRNA is greatly diminished when UT-7/GM cells are induced to differentiate into either erythroblastic or megakaryoblastic phenotypes. The possible roles of the ST2V in growth and differentiation are intriguing.
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PMID:Presence and expression of a novel variant form of ST2 gene product in human leukemic cell line UT-7/GM. 1052 32

Anti-CD20 antibody is an established treatment for low-grade non-Hodgkin's lymphoma (NHL). Augmenting the expression of CD20 antigen on the tumor cells may increase the cell kill and therefore increase the effectiveness of the antibody. To study this, we incubated peripheral blood lymphocytes from CLL patients with the following cytokines: EPO, SCF, TNFalpha, TGFbeta, GMCSF, TPO, IL-1, IL-2, IL-3, IL-4, GCSF. CD20 expression was studied by flow cytometry at baseline, 24 and 72 h after exposure to these cytokines. Upregulation of CD20 antigen expression was observed with IL-4, TNFalpha and GMCSF.
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PMID:Effects of cytokines on CD20 antigen expression on tumor cells from patients with chronic lymphocytic leukemia. 1120 84

Myeloid differentiation is a highly regulated process governed by various cytokines, such as EPO, TPO, G-CSF, IL-3, IL-5 and GM-CSF. These cytokines act in part through activation of the STAT transcription factor family. In particular, various isoforms of STAT3 and STAT5 are activated during myeloid differentiation in a cell-type and maturation-state dependent fashion. In vitro studies have shown that STAT proteins are essential for cytokine-regulated processes such as cellular proliferation, differentiation as well as survival. Similarly, various STAT knock-outs have highlighted the role of STATs in myeloid differentiation in vivo. STATs also appear to play an important role in various myeloid malignancies, which are characterized by arrested maturation and cytokine-independent proliferation of myeloid progenitors. Constitutive activation of STAT3 and/or STAT5 resulting in enhanced transcription of anti-apoptotic- cell-cycle progression genes is likely to contribute to the pathogenesis of various myeloid leukemia's. Oncogene (2000).
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PMID:The role of STATs in myeloid differentiation and leukemia. 1085 Oct 50

Megakaryocytopoiesis is a complex network regulated by different megakaryocyte (MK)-stimulating factors (i.e., thrombopoietin [TPO], stem cell factor [SCF], interleukin 3 [IL-3], IL-6, IL-11 and GM-CSF). Although all of these factors can affect human and murine megakaryocytopoiesis at different levels of MK development, the effect on very primitive hematopoietic stem cells (HSC) is not well understood. We have further characterized the in vitro biological activity of recombinant murine TPO, SCF and IL-3 on the maturation and proliferation of MK progenitors from different murine primitive hematopoietic cells in a fibrin clot system under serum-free conditions. Neither TPO nor SCF alone induced MK colony formation (CFU-MK) from Lin- Sca+ cells. However, isolated large and mature MKs were observed in the presence of TPO. In contrast, IL-3 exerted a potent effect on CFU-MK formation from Lin- Sca+ cells. On this population of HSC, a significant increase of large MK colonies with mature MK were obtained under those conditions in which TPO was combined with IL-3 or SCF plus IL-3. Similar results were obtained with murine bone marrow cells enriched by primitive progenitors from day 3 post-5-fluorouracil treated mice (5-FUBMC). In contrast, TPO-sensitive precursors were detected in fetal liver cells (FLC). These cells differentiate and proliferate to MK progenitors in the presence of TPO. A significant increase in the number of CFU-MK was induced when TPO was combined with either IL-3 or SCF. On these populations of primitive hematopoietic progenitors, IL-3 induced both the proliferation and differentiation of MK progenitors. Because erythropoietin and TPO share similarities between their molecules and their receptors, we studied whether these growth factors may modulate megakaryocytopoiesis from FLC. Flow cytometry analysis of FLC expressing erythroid markers demonstrated that these cells expressed c-Mpl receptor. In our in vitro studies, although EPO by itself did not induce MK colonies from FLC, it enhanced the proliferative activity of TPO. High ploidy and proplatelet-shedding MK were observed in Lin- Sca+ cells, 5-FUBMC and FLC stimulated with TPO alone or in combination with other MK-stimulating factors. Based on these observations, we propose that TPO, IL-3 and SCF constitute early MK-acting factors with differential proliferative and differentiative activities on murine stem cells. TPO by itself does not appear to be involved in the proliferation of MK progenitors from bone marrow HSC. TPO appears to induce in these cells the commitment toward MK differentiation. However, this growth factor may enhance the proliferative activity of IL-3. IL-3 is an early MK-stimulating factor able to induce in vitro the proliferation and differentiation of MK progenitors from HSC.
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PMID:Megakaryocytopoiesis in vitro: from the stem cells' perspective. 1101 17

Several cytokines stimulating hematopoiesis, mainly lineage restricted, are already widely used in supportive care to correct myelosuppression or anaemia (GM-CSF, G-CSF, EPO). The new growth factor are tested in preclinical or clinical studies to abrogate other anti-cancer therapy side-effects (thrombocytopenia, mucositis etc.). IL-3 has been shown to have only limited effect on neutrophils and platelets production respectively. IL-6 and IL-11 have been tested to improve thrombocytopenia and mucositis (IL-11). Thrombopoetin (TPO, c-mpl) is tested in clinical trials and shows very strong effect on platelet counts. Stem cell factor (SCF) has shown to improve progenitor cell mobilisation, particularly in combination with other cytokines. The new promising factor, FLT-3 ligand, combines effect on hematopoiesis with effect on dendritic cells generation. The new group of synthetic cytokines (daniplestim, myelopoetin, promegapoetin and progenipoetin) is now tested in preclinical and clinical studies. Mucositis could be influenced by new keratinocyte growth factor (KGF), which is now in phase I trials.
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PMID:[New cytokines and their role in supportive care]. 1104 87

This review is a short synopsis of the roles cytokines play during fetal life, initiation of labor, and in neonatal immunity and diseases. Hematopoietic growth factors regulate the maturation of progenitors in fetal and neonatal hematopoietic organs. Cytokines act as extra-hematopoietic growth factors, modulators of feto-maternal tolerance and are involved in selective apoptosis during tissue remodeling. Inter-regulation of cytokine networks is critical for normal function and maturation of neonatal host defenses. Antigen specific immunity develops later in life and neonates initially depend on natural (innate) immunity. Cytokines regulate innate immunity and connect it with antigen specific adaptive immunity. Some cytokines have already found a place in routine NICU therapy (EPO and G-CSF), while diagnostic and therapeutic uses of others are under investigation (TPO, TNF-alpha, etc.).
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PMID:Cytokines and neonates. 1114 89

The molecular pathogenesis of ET and PV is unknown, although the relatively indolent clinical course observed in most patients suggests that the defect may be subtle and difficult to establish. Clonality analysis using X-chromosome inactivation patterns in females on purified CD34+ cells have confirmed that a defect is present in the hematopoietic stem cell. However, at least in ET, a significant proportion of patients have polyclonal hemopoiesis, and this presumably reflects the heterogeneous nature of the disorder(s). Attention has focussed on the potential disruption of the physiological regulators EPO and TPO and their respective receptors. In familial disorders, pathological mutations have been identified in some, but by no means all, cases: EPO receptor mutations in PFCP, TPO mutations in FT and, conversely, TPO receptor (c-mpl) mutations in CAMT. Equivalent ligand or receptor mutations have not been detected in ET or PV patients. However, there is evidence to suggest that c-mpl expression may be dysregulated, with low or absent c-mpl mRNA or protein reported in ET and/or PV patients. At present it is not clear whether this is the cause or consequence of the paradoxically normal/increased TPO levels found with both primary and secondary thrombocytosis. In vitro culture analysis has demonstrated both cytokine independence and hyper-sensitivity as a generalised feature of progenitor cells from many patients, but differences exist depending on the assays used and there is little understanding of the mechanism(s) underlying these responses. Two genes have recently been identified with increased mRNA expression in PV granulocytes: PRV-1, a novel cell surface receptor closely related to the uPAR/Ly6/CD59/snake toxin family of proteins, and NFI-B, a member of the nuclear factor I family which may be associated with TGF-beta resistance. Investigation of their regulation and biological effects may assist in determining the pathobiology of these elusive disorders.
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PMID:Basic sciences of the myeloproliferative diseases: pathogenic mechanisms of ET and PV. 1243 Sep 42

The megakaryoblastic leukemia cell line MOLM-16 was established at relapse from the peripheral blood of a 77-year-old Japanese woman with minimally differentiated acute myeloid leukemia (AML-M0). Immunophenotyping of the fresh leukemic cells revealed a myeloid/NK precursor phenotype being positive for CD7, CD13, CD33, CD34, and CD56. In addition, megakaryocyte-associated antigens CD41 and CD61 were found to be positive. The established cell line designated MOLM-16 was proliferatively responsive to the treatment with various cytokines including EPO, GM-CSF, IL-3, PIXY-321, and TPO. MOLM-16 revealed characteristics of the megakaryocytic lineage in terms of immunophenotyping being positive for CD9, CD31, CD36, CD41, CD61, CD62P, CD63, CD110, CD151, thrombospondin, von Willebrand factor (vWf), and fibrinogen. Electron microscopic analysis showed positivity for ultrastructural platelet peroxidase in the nuclear envelope. The karyotype analysis of MOLM-16 revealed various numerical and structural abnormalities including t(6;8)(q21;q24.3), t(9;18)(q13;q21) and marker chromosomes. The extensive immunological, cytogenetic and functional characterization of MOLM-16 suggests that this cell line may represent a scientifically significant in vitro model which could facilitate the evaluation of megakaryocytic differentiation.
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PMID:Megakaryoblastic leukemia cell line MOLM-16 derived from minimally differentiated acute leukemia with myeloid/NK precursor phenotype. 1252 22


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