Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombopoietin or thrombocytopoiesis-stimulating factor (TSF) is known to be the natural stimulator of megakaryocytopoiesis and, thus, stimulates thrombocytopoiesis. In the past 15 years, new assay technology and sources of the hormone have made possible partial characterization of the molecule and clarification of the biologic role of thrombopoietin. Experiments describing the biology and characterization of TSF are reviewed. In addition, a brief history of the molecule, its biology, and the effects of thrombopoietin on both thrombocytopoiesis and megakaryocytopoiesis are discussed, including the effects of thrombopoietin on platelet counts, platelet sizes, and incorporation of isotopes. In the discussion of thrombopoietin's control of megakaryocytopoiesis there is specific information showing that thrombopoietin stimulates an increase in megakaryocyte size and number, DNA content, endomitosis, and maturation. Thrombopoietin also increases the number of early precursor cells of the megakaryocytic series, that is, small acetyl-cholinesterase-positive cells. New information is given on the chemistry of thrombopoietin, along with present assays and the relationship of thrombopoietin to interleukin-6. The clinical aspects of thrombopoietin, with detailed descriptions of several disease states in which decreases and excesses of the hormone have been found, are presented. The potential uses of thrombopoietin in clinical medicine are reviewed. In the near future, it appears that successful gene cloning of the hormone will be achieved, which will allow production of large amounts of recombinant thrombopoietin. The pure material will be helpful in clarifying the hormone's mode of action. Thrombopoietin will no doubt prove to be useful in treating patients with various hematologic disorders, such as patients undergoing bone marrow transplantation, chemotherapy, or radiotherapy, and other patients with various types of marrow hypoplasia.
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PMID:Thrombopoietin. Its biology, clinical aspects, and possibilities. 155 Feb 68

Mechanisms triggering the commitment of pluripotent bone marrow stem cells to differentiated lineages such as mononuclear macrophages or multinucleated megakaryocytes are still unknown, although several lines of evidence suggested correlation between cholinergic signaling and hematopoietic differentiation. We now present cloning of a cDNA coding for CHED (cholinesterase-related cell division controller), a human homolog of the Schizosaccharomyces pombe cell division cycle 2 (cdc2)-like kinases, universal controllers of the mitotic cell cycle. Library screening, RNA blot hybridization, and direct PCR amplification of cDNA reverse-transcribed from cellular mRNA revealed that CHED mRNA is expressed in multiple tissues, including bone marrow. The CHED protein includes the consensus ATP binding and phosphorylation domains characteristic of kinases, displays 34-42% identically aligned amino acid residues with other cdc2-related kinases, and is considerably longer at its amino and carboxyl termini. An antisense oligodeoxynucleotide designed to interrupt CHED's expression (AS-CHED) significantly reduced the ratio between CHED mRNA and actin mRNA within 1 hr of its addition to cultures, a reduction that persisted for 4 days. AS-CHED treatment selectively inhibited megakaryocyte development in murine bone marrow cultures but did not prevent other hematopoietic pathways, as evidenced by increasing numbers of mononuclear cells. An oligodeoxynucleotide blocking production of the acetylcholine-hydrolyzing enzyme, butyrylcholinesterase, displayed a similar inhibition of megakaryocytopoiesis. In contrast, an oligodeoxynucleotide blocking production of the human 2Hs cdc2 homolog interfered with production of the human 2Hs cdc2 homolog interfered with cellular proliferation without altering the cell-type composition of these cultures. Therefore, these findings strengthen the link between cholinergic signaling and cell division control in hematopoiesis and implicate both CHED and cholinesterases in this differentiation process.
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PMID:Cloning and antisense oligodeoxynucleotide inhibition of a human homolog of cdc2 required in hematopoiesis. 173 28

A cloned human cDNA for cholinesterase (ChE) was used as a probe for in situ hybridization to spread lymphocyte chromosomes to map the structural human CHE genes to distinct chromosomal regions. The recent genetic linkage assignment of the CHE1 locus of the CHE gene to chromosome 3q was confirmed and further refined to 3q21-q26, close to the genes coding for transferrin (TF) and transferrin receptor (TFRC). The CHE1 allele localizes to a 3q region that is commonly mutated and then associated with abnormal megakaryocyte proliferation in acute myelodysplastic anomalies. In view of earlier findings that ChE inhibitors induce megakaryocytopoiesis in culture, this localization may indicate that ChEs are involved in regulating the differentiation of megakaryocytes. A second site for ChEcDNA hybridization was found on chromosome 16p11-q23, demonstrating that the CHE2 locus of the cholinesterase gene, which directs the production of the common C5 variant of serum ChE, also codes for a structural subunit of the enzyme and is localized on the same chromosome with the haptoglobin (HP) gene, both genes being found on the long arm of chromosome 16. The finding of two sites for ChEcDNA hybridization suggests that the two loci coding for human ChEs may include nonidentical sequences responsible for the biochemical differences between ChE variants.
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PMID:Human cholinesterase genes localized by hybridization to chromosomes 3 and 16. 369 76

1. To investigate the possibility that cholinesterase inhibitors may cause adverse hematopoietic effects, we employed antisense oligodeoxynucleotides selectively inhibiting butyrylcholinesterase gene expression (AS-BCHE). Complementary sense (S) oligonucleotides served as controls. 2. In primary bone marrow cell cultures grown with interleukin 3 (IL-3), AS-BCHE but not S-BCHE reduced growth of megakaryocyte colony-forming units (CFU-MK) in a dose-dependent manner at the micromolar range. 3. In cultures grown with IL-3, transferrin, and erythropoietin (Epo), cell counts increased up to twofold, yet colony counts (CFU-GEMM) remained unchanged under AS-BCHE treatment. 4. Electrophoretic measurements of DNA ladder as an apoptotic index revealed that the above oligonucleotide effects were not due to nonspecific induction of programmed cell death. 5. Differential cell counts demonstrated increased myeloidogenesis and reduced levels of early megakaryocytes in CFU-GEMM under AS-BCHE, suggesting requirement of the BuChE protein for megakaryopoiesis. 6. In vivo injection of AS-BCHE reduced BCHE mRNA levels in both young and mature megakaryocytes for as long as 20 days, as shown by in situ hybridization. 7. Ex vivo growth of primary bone marrow cells revealed a twofold reduction in CFU-MK colonies grown from the AS-BCHE- but not the S-BCHE-injected mice, 15 days posttreatment. 8. These findings demonstrate that deficient butyrylcholinesterase expression, and hence interference with this enzyme's activity through treatment with or exposure to cholinesterase inhibitors, may cause hematopoietic differences in treated patients.
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PMID:Antisense inhibition of butyrylcholinesterase gene expression predicts adverse hematopoietic consequences to cholinesterase inhibitors. 762 7

Megakaryocytopoiesis and platelet production can be assessed with reasonable accuracy by quantitative and functional analyses of circulating platelets. The evaluation of megakaryocytopoiesis in culture has remained unsatisfactory, particularly because platelet production is rarely observed. In mouse culture systems, megakaryocytes have been identified almost entirely by measurements of acetyl cholinesterase, size, and ploidy without concomitant assessment of maturation based on such criteria as the formation of granules, demarcation membranes, and cytoplasmic fragmentation. The availability of various thrombopoietic cytokines, in particular thrombopoietin (TPO), and their imminent clinical use has made a more detailed understanding of their effect on differentiation and maturation of the MK lineage more urgent. Therefore, ultrastructural analyses were performed on megakaryocyte-depleted serum-free mouse bone marrow cultures in the presence of TPO alone, TPO plus other cytokines, or under conditions in which TPO and/or other cytokines were blocked with neutralizing agents. These studies show that, while cytokines that use the gp130 receptor subunit may function synergistically with TPO, in the absence of TPO, such cultures do not yield morphologically recognizable MK. On the other hand, TPO alone is able to drive MK to full maturation as evidenced by the generation of granules, demarcation membranes, and cytoplasmic fragmentation into platelets.
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PMID:Effect of thrombopoietin on the development of megakaryocytes and platelets: an ultrastructural analysis. 878 18

The effect of malignant tumor growth on host's megakaryocytopoiesis and platelet production was studied in mice bearing transplantable Dalton's lymphoma. Tumor growth was paralleled by thrombocytosis, neutrophilia, and anemia. Platelet 51Cr half-life was normal but incorporation of 75Selenomethionine into circulating platelets was significantly enhanced in the tumor bearers suggesting stimulated thrombopoiesis while platelet life span remained unchanged. Megakaryocytes and their precursors, the small acetyl cholinesterase positive cells, were found in increased numbers in the bone marrow (BM) and particularly in the spleen where five to eight-fold rise was observed at the log phase of tumor growth. In addition, a remarkable increase in the number of megakaryocyte progenitors (CFU-MK and MK CFU-S) was observed both in the BM and spleen. Stimulation of these progenitors was more pronounced in the spleen than in the marrow, and the change was noticeable even from the third day of tumor bearing. Therefore, the results suggest that thrombocytosis associated with the growth of this experimental lymphoma was due to accelerated platelet production following stimulated megakaryocytopoiesis especially in the spleen.
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PMID:Stimulation of megakaryocytopoiesis and platelet production during growth of an experimental lymphoma. 1127 30

Using thrombopoietin (TPO), as selective pressure, several TPO-dependent clones were isolated from the murine multipotential IL-3-dependent cell line 32D. Four of them were fully characterized. They depended on TPO for survival and proliferation and, although retaining the capacity to grow in IL-3, did not respond to either EPO, G-CSF or GM-CSF. 32D TPO cells were heterogeneous in morphology and ranged from small cells, with a DNA content nearly tetraploid and a modal chromosome no. 66, to cells 50-75 microm in diameter containing multiple (up to 5-6) interconnected nuclei with a clear megakaryocyte (Mk) morphology by electron microscopy. Cell sorter isolation and single cell cloning experiments indicated that the small cells were those capable to proliferate in TPO and to generate the larger ones over time. 32D TPO cells expressed Mk-specific markers by FACS (CD41, CD61 and 2D5) and RT-PCR (acetyl cholinesterase E and platelet factor 4) and their unique profile, by gene array analysis, included expression of urokinase plasminogen activator surface receptor (CD87 or uPAR), plasminogen activator inhibitor and coagulation factor II (thrombin) receptor (Cf2r). In addition, by quantitative RT-PCR, 32D TPO clones expressed levels of Gata1 similar to those expressed by freshly isolated Mks (DeltaCt approximately 4.7 in both cases). In conclusion, the 32D TPO subclones described here are among the few pure Mk cell lines isolated so far and, for their unique properties, may prove themselves as a useful model to study Mk differentiation.
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PMID:Isolation of TPO-dependent subclones from the multipotent 32D cell line. 1605 57