Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel hematopoietic antigen was identified using a murine monoclonal antibody raised against KG-1 cells. This antigen, termed MKW, was also detected on the surface of the monocytic cell line U937, but not on the K562, ML1, or HL-60 cell lines. On normal hematopoietic cells, the antigen is expressed on the surface of monocytic and myelocytic cells and on a subpopulation of B-cells. During normal hematopoiesis, the surface expression of MKW is greatest and occurs very early on monocytic cells. Alternatively, in myeloid cells, surface expression occurs later and cell maturation is correlated with increased surface expression. When U937 cells are induced to differentiate, surface expression is transiently up-regulated. Surface expression of MKW, however, does not appear to be an activation antigen since activation of purified T- or B-cells failed to increase MKW on the cell surface. Leukemic blasts from 22 of 80 children (27%) with acute myeloblastic leukemia and from 29 of 225 children (13%) with acute lymphoblastic leukemia expressed MKW on the cell surface. Although surface expression of MKW was absent on T-cell lines, peripheral T-cells, and most B-cells, the antigen was identified in the cytoplasm of some B-cells, T-cells, and cell lines. Immunoprecipitation studies showed that MKW is a 52-kDa protein whether expressed on the cell surface or in the cytoplasm, and it appears to be nonglycosylated. Furthermore, studies with phosphatidylinositol-phospholipase C suggested that MKW is not attached to a glycolipid anchor. The biochemical characterization of MKW and its pattern of expression are distinct from any of the previously identified CD groups or published antigens. Since this unique antigen has prognostic significance in leukemia and appears to be associated with cell differentiation, its exact role in hematopoiesis should be investigated.
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PMID:MKW, a novel hematopoietic antigen. 132 77

Procoagulant activity of gastric cancer tissues and leukocytes obtained from various types of leukemia have been studied with special reference to TTP. The following results were obtained. Homogenates of APL leukocytes and gastric cancer tissues contained strong procoagulant activities, most of which have been identified as TTP since the activities were neutralized by a specific antibody against purified human placenta TTP, inactivated by the removal of phospholipid with heptane-butanol mixture, and inactivated by the addition of phospholipase C. The delipidated homogenates regained procoagulant activities by relipidation procedures. These results also confirmed that TTP from APL leukocytes and gastric cancer tissues have the same lipoprotein properties as those of TTP in normal tissues. Though slight proteolytic activity and fibrinolytic activity were demonstrated in the homogenate of gastric cancer tissues, it was noted that the TTP activity was different from these two activities by partial purification of TTP from gastric cancer tissues. The TTP activity of 9 homogenates of gastric cancer tissues was 301 +/- 289 (mean +/- SD) units per mg protein, being higher in homogenates of mucinous adenocarcinoma and signet-ring cell carcinoma than in those of tubular and poorly differentiated adenocarcinoma. The mean TTP activity of leukocyte homogenates from 14 patients with APL and one out of 4 patients with CML in blastic crisis was 81 +/- 76 units/10(7) cells. The TTP activity of the homogenates of leukocytes from 7 out of 18 patients with AML and another patient with CML in blastic crisis ranged from one to six units/10(7) cells with a mean of 3.3 +/- 1.2. The TTP activity of leukocyte homogenates from the other 11 cases of AML, two cases of CML in blastic crisis, 6 cases of CML, and one case each of ALL and CLL were less than one unit/10(7) cells. In leukemic patients, all cases with a value of more than 202 for the product of units of TTP activity per 10(7) cells and differential count (%) of leukemic cells in the bone marrow smear (MU value) were accompanied by DIC. The MU value of leukemic patients correlated well to the plasma fibrinogen and serum FDP levels. All patients with a MU value of more than 277 died of DIC when a sufficient amount of heparin was not administered. On the other hand, no DIC developed in any of the patients with a MU value of less than 90.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of tissue thromboplastin in the development of DIC accompanying neoplastic diseases. 666 48

We performed a flow cytometric analysis using monoclonal antibodies to decay accelerating factor (DAF) and CD59/membrane attack complex inhibitory factor (CD59/MACIF) in order to investigate the leukemic cells and erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria (PNH) who developed acute myelocytic leukemia. In May 1990, the leukemic cells comprised 70% of the mononuclear cells in the bone marrow and 76% of those in the peripheral blood. They consisted of a mixture of positive and negative populations, including single DAF-positive cells. In August 1990, almost 100% of the peripheral mononuclear cells were leukemic blasts, and these consisted of a single population with reduced DAF expression. Single-color flow cytometric analysis showed that the leukemic cells lacked CD59/MACIF, while control leukemic cells (n = 3) expressed both DAF and CD59/MACIF. Leukemic blasts from this patient and six control patients expressed lymphocyte function-associated antigen 3 and FcIII receptors (CD 16) both before and after treatment with phosphatidylinositol-specific phospholipase C. The patient's erythrocytes lacking DAF and CD59/MACIF expression corresponded to the proportion of complement-sensitive cells at the onset of acute leukemia. These DAF- and CD59/MACIF-deficient erythrocytes disappeared almost completely with progression of the leukemia. In conclusion, it appears that the expression of glycosylphosphatidylinositol-linked membrane proteins by leukemic cells was heterogeneous and discordant in our patient, and that the leukemic cells were derived from the PNH clone because of their deficiency of CD59/MACIF. It is also suggested that DAF could compete more effectively than CD59/MACIF for a limited number of anchor molecules available on the proliferating leukemic cells.
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PMID:Discordant and heterogeneous expression of GPI-anchored membrane proteins on leukemic cells in a patient with paroxysmal nocturnal hemoglobinuria. 768 3

The expression of a membrane-associated folate receptor (FR) was elevated in spleen samples from patients with chronic (CML) and acute (AML) myelogenous leukemias compared with normal spleen. Contrary to earlier reports, antibodies to a purified FR from placenta cross-reacted quantitatively with this protein in solution radioimmunoassays. Similar to FR-alpha (KB cells) and FR-beta (placenta), the protein was released from the membrane by phosphatidylinositol-specific phospholipase C, indicating a glycosylphosphatidylinositol (GPI) membrane anchor. Screening of a cDNA library from CML spleen with a heterologous murine FR cDNA and also amplification of FR cDNAs from spleen and bone marrow in CML, AML, chronic lymphocytic leukemia (CLL), and acute lymphocytic leukemia (ALL) by polymerase chain reaction (PCR) using degenerate oligonucleotides yielded cDNA clones representing FR-beta, a novel FR (type gamma), and an aberrant transcript of FR-gamma with a 2 base pair deletion resulting in a truncated 104-residue polypeptide; FR-alpha was not detected in these tissues. The cDNA for FR-gamma predicts a 243-residue polypeptide with an amino acid sequence homology of 71% and 79% with FR-alpha and FR-beta, respectively, a 23-residue amino-terminal signal peptide, and 3 potential sites for N-linked glycosylation. Transfection of COS-1 cells with the cDNA for FR-gamma resulted in low expression of a [3H]folic acid binding protein on the cell surface that was GPI-anchored. PCR analysis of total RNA from a number of normal and malignant tissues and cell lines indicated a limited tissue specificity of FR-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. 811 Jul 52

The RET proto-oncogene product is a receptor tyrosine kinase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), in which a novel glycosyl-phosphatidylinositol (PI)-linked protein (termed GDNFR-alpha) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-alpha in purified normal hematolymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malignancies encompassing different lineages and differentiation stages. Relatively low amounts of RET mRNA were found in early CD34+ hematopoietic progenitors, but RET transcripts appeared to increase after myelomonocytic maturation. No expression of RET was found in peripheral blood and tissue B and T lymphocytes. Analysis of human myelomonocytic cell lines was overall consistent with results obtained on purified normal cells. Accordingly, RET expression was mainly confined to acute myeloid leukemias (AMLs) displaying either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) phenotypes, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically detected in B-cell tumors, whereas, among T-cell malignancies, RET transcripts were mainly detected in cells of postthymic and mature T-cell phenotype. RET broad detection in primary tumors was not paralleled by the mutual expression of GDNFR-alpha, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-alpha transcripts, in the absence of RET mRNA, were found in normal bone marrow stromal cells (BMSC), in BM fibroblasts, and in two osteoblast cell lines previously described to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phospholipase C cleavage, GDNF efficiently bound RET-expressing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.
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PMID:Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. 910 13

In this study, we have investigated the expression of phospholipase C-beta2 during the course of granulocytic differentiation of normal and malignant progenitors. As a model system, we used the NB4 cell line, a reliable in vitro model for the study of acute promyelocytic leukemia (APL), a variety of acute myeloid leukemia (AML) that responds to pharmacological doses of all trans-retinoic acid (ATRA) by differentiating in a neutrophil-like manner. We found that PLC-beta2, virtually absent in untreated NB4 cells, was strongly up-regulated after ATRA-induced granulocytic differentiation. Remarkably, using primary blasts purified from bone marrow of patients affected by APL successfully induced to remission by treatment with ATRA, we showed a striking correlation between the amount of PLC-beta2 expression and the responsiveness of APL blasts to the differentiative activity of ATRA. An increase of PLC-beta2 expression also characterized the cytokine-induced granulocytic differentiation of CD34+ normal hematopoietic progenitors. Taken together, these data show that PLC-beta2 represents a sensitive and reliable marker of neutrophil maturation of normal and malignant myeloid progenitors. Moreover, PLC-beta2 levels can predict the in vivo responsiveness to ATRA of APL patients.
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PMID:Selective up-regulation of phospholipase C-beta2 during granulocytic differentiation of normal and leukemic hematopoietic progenitors. 1205 Jan 80

Up-regulation of folate receptor (FR) type-beta in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-beta in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-beta lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent in FR-beta from AML cells from patient marrow, which bound folate. From flow cytometric analysis of 78 AML bone marrow specimens of different subtypes, 68% expressed FR-beta, most of which were also CD34+. In model cell lines that are FR - (KG-1a, L1210, and Chinese hamster ovary [CHO]) or FR + (KG-1, L1210 JF, and recombinant CHO-FR-beta), selective FR-mediated binding and cytotoxicity was obtained using folate-coated liposomes encapsulating fluorescent calcein (f-L-calcein) and doxorubicin (f-L-DOX), respectively, which could be blocked by 1 mM free folic acid. In the FR-beta-expressing KG-1 human AML cells, treatment with ATRA further increased this specificity. In mouse ascites leukemia models generated using L1210JF or KG-1 cells, increased median survival times were obtained with f-L-DOX treatment compared to nontargeted L-DOX. In the KG-1 model, ATRA treatment increased the cure rate with f-L-DOX from 10% to 60%. The above combined data from our 2 laboratories further support the feasibility and potential usefulness of selective ATRA-facilitated liposomal drug delivery in FR-beta + AMLs.
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PMID:Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. 1209 53

Myelodysplastic syndrome (MDS) is an adult hematological disease that evolves into acute myeloid leukemia (AML) in about 30% of the cases. The availability of a highly specific probe moved us to perform in patients affected with MDS/AML, associated with normal karyotype, painting and fluorescence in situ hybridization (FISH) analysis aimed to check the inositide-specific phospholipase C (PI-PLC) beta1 gene, a player in the control of some checkpoints of the cell cycle. Here we present a preliminary observation in which FISH analysis disclosed in a small group of MDS/AML patients with normal karyotype the monoallelic deletion of the PI-PLCbeta1 gene. On the contrary, PI-PLC beta4, another gene coding for a signaling molecule, located on 20p12.3 at a distance as far as less than 1Mb from PI-PLCbeta1, is unaffected in MDS patients with the deletion of PI-PLC beta1 gene, hinting at an interstitial deletion. The MDS patients, bearing the deletion, rapidly evolved to AML. The data suggest the possible involvement of PI-PLCbeta1 in the progression of the disease and pave the way for a larger investigation aimed at identifying a possible high-risk group among MDS patients with a normal karyotype.
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PMID:Inositide-specific phospholipase c beta1 gene deletion in the progression of myelodysplastic syndrome to acute myeloid leukemia. 1642 63

During the past years, several independent laboratories have highlighted the presence of nuclear signaling pathways based on lipid hydrolysis, which are not a mere duplication of those occurring at the plasma membrane. Among the enzymes of the cycle, nuclear phosphoinositide-specific phospholipase C (PI-PLC) has been analyzed quite extensively. In this context, PI-PLCbeta1 appears to play a key role as a check point in the G1 phase of the cell cycle. It has also been shown that its activation and/or up-regulation is upon the control of type 1 insulin-like growth factor receptor (IGF-R) in both mouse fibroblast and myoblasts, suggesting that its signaling activity is essential for the normal behavior of the cell, at least in culture. The recent discovery of a possible involvement of the deletion of PI-PLCbeta1 gene in the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML) in humans strengthens the contention that nuclear PI-PLC signaling is essential for physiological processes such as cell growth and differentiation. Even though PI-PLCbeta1 is present and does not translocate to eukaryotic nuclei, this organelle, even though only in some conditions contains also PI-PLCgamma1 which acts not only as a PI-PLC but also as guanine nucleotide exchange factor (GEF) for PI 3-kinase enhancer (PIKE) and is somehow linked to PI 3-kinase (PI3K) activity. Also members of PI-PLCdelta family are shuttling from the nucleus to the cytoplasm and return and are possibly involved in the control of cell growth. We must also take into account the presence in the nucleus of other phospholipases such as phospholipase A2 (PLA2) and phospholipase D (PLD), which also exert a signaling activity upon external stimuli. On the whole this review highlights the latest development in the PI-PLC cycle in the nucleus, which in terms of activation, regulation and down-stream targets differs substantially from that located at the plasma membrane.
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PMID:Nuclear phospholipase C: involvement in signal transduction. 1589 48

A distinct polyphosphoinositide cycle is present in the nucleus, and growing evidence suggests its importance in DNA replication, gene transcription, and apoptosis. Even though it was initially thought that nuclear inositol lipids would function as a source for second messengers, recent findings strongly indicate that lipids present in the nucleus also fulfil other roles. The scope of this review is to highlight the most intriguing advances made in the field over the last few years, such as the possibility that nuclear phosphatidylinositol (4,5) bisphosphate is involved in maintaining chromatin in a transcriptionally active conformation, the new emerging roles for intranuclear phosphatidylinositol (3,4,5) trisphosphate and phosphoinositide 3-kinase, and the evidence which suggests a tight relationship between a decreased level of nuclear phosphoinositide specific phospholipase C-beta1 and the evolution of myelodisplastic syndrome into acute myeloid leukemia.
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PMID:Nuclear inositol lipid metabolism: more than just second messenger generation? 1608 39


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