Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biotin derivatives of methotrexate (biotin-SS-MTX) and folate (biotin-SS-folate), in which the functional components are joined by a dissociable disulfide-containing spacer, have been synthesized, purified by DEAE-Trisacryl chromatography, and characterized by HPLC, elemental analysis and mass spectrometry. These compounds provide a convenient means for the single-step purification of the folate transporters from L1210 cells. Parental L1210 murine leukemia cells, which contain only the microM transporter (the reduced folate/MTX transport protein) were treated with the N-hydroxysulfosuccinimide ester of biotin-SS-MTX, and a detergent extract of the plasma membranes was exposed to streptavidin-agarose beads to adsorb the labeled protein. Dithiothreitol cleavage of the disulfide linkage released the transporter, which migrated as a well-defined component (43 kDa) on SDS-PAGE gels; no other proteins were present. An L1210 subline (JF), obtained by adapting cells to grow on nanomolar concentrations of folate, contains both the microM transporter and the nM transporter (high-affinity folate binding protein). When these cells were treated with the N-hydroxysulfosuccimide ester of biotin-SS-folate and processed as described above, analysis on SDS-PAGE gels revealed the presence of two proteins, the microM transporter (43 kDa) and the nM transporter (39 kDa). Both transporters were characterized with respect to amino acid content; blocked N-termini precluded Edman sequencing. Treatment of the nM transporter with peptide:N-glycosidase F produced a smaller component (32 kDa); the microM transporter, conversely, was unchanged by this procedure. When the microM transporter in parental L1210 cells was labeled with fluorescein-MTX and then treated with phosphoinositol-specific phospholipase C (PI-PLC), no change in fluorescence was detected. Alternatively, when the nM transporter in the JF subline was labeled with fluorescein-folate and then treated with PI-PLC, complete loss of fluorescence was observed. These results indicate that the L1210 microM transporter is a non-glycosylated, integral membrane protein, while its nM counterpart is heavily glycosylated and anchored exofacially to the membrane by a glycosylphosphatidylinositol component.
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PMID:Multiple folate transport systems in L1210 cells. 132 5

Mast cells respond to clustering of the type I Fc epsilon receptor (Fc epsilon RI) on their membranes by mediator secretion. Recently, a marked enhancement of tyrosine phosphorylation on several proteins has been observed as a result of antigen-induced Fc epsilon RI aggregation on these cells. We report here that the phosphatidyl inositide specific phospholipase C gamma 1 (PLC gamma 1) is one of the prime proteins that undergoes tyrosine phosphorylation as a result of this stimulus. This was determined by immunoprecipitation of phosphotyrosine containing proteins from detergent lysates of rat mucosal mast cells (rat basophilic leukemia cells, subline 2H3; RBL-2H3) and Western blotting analysis of the separated components. A fast appearance of phosphorylated tyrosine residues on PLC gamma 1 was observed, reaching its maximal intensity at approximately 1-3 min after stimulation and declined afterwards to basal levels. Moreover, the phosphorylation depended on maintaining the aggregated Fc epsilon RI as did other cellular responses (e.g. phosphatidyl inositides hydrolysis and secretion). The time course of both Fc epsilon RI induced phospholipase C gamma 1 activation, as monitored by the formation of inositol phosphates, and of the secretory response of the cells followed that of the PLC gamma 1 phosphorylation. Furthermore, the tyrphostin AG490, a protein tyrosine kinase inhibitor, caused similar inhibition of the Fc epsilon RI-induced PLC gamma 1 phosphorylation, inositol phosphates formation, and mediator secretion. Significantly, no tyrosine phosphorylation of PLC gamma 1 was induced by the Ca2+ ionophore, ionomycin, even at doses that cause optimal secretory response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tyrosine phosphorylation of phospholipase C gamma 1 couples the Fc epsilon receptor mediated signal to mast cells secretion. 153 54

We investigated the effect of bacterial lipopolysaccharide (LPS) on phospholipid (PL) turnover in human monocytic leukaemia U937 cells. Cells were pre-labelled with [3H]choline, [14C]ethanolamine and [3H]inositol for 24 h. By monitoring the radiolabel association with cellular PL, the data indicated that LPS (10 micrograms/ml) drastically altered the catabolism of choline-containing PL; it induced their breakdown by 50% within 20 min. The reutilization of choline or its phosphates for PL synthesis was also suggested as a result of regaining radiolabel in the next 40 min. Choline-containing PL then underwent a second degradation after 60 min; 50% decline in radiolabel was detected at 120 min. In contrast, LPS did not induce the breakdown of phosphatidylethanolamine and phosphatidylinositol through phospholipase C/phospholipase D (PLC/PLD). No significant redistribution of the radiolabel in PL was detected in any cases during chasing. The data clearly indicate that LPS stimulates phosphatidylcholine breakdown, implying that the liberation of phosphatidic acid or diacylglycerol via PLC/PLD reaction may be relevant to the initiation of LPS-induced monocytic activation.
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PMID:Bacterial lipopolysaccharide induces phosphatidylcholine breakdown in human leukaemia monocytic U937 cells. 162 16

Phosphatidylinositol-specific phospholipase C (PI-PLC) is an enzyme that has the capacity to release glycosyl-phosphatidyl inositol (G-PI)-anchored proteins from the cells surface. Pretreatment of the human T-cell leukemia cell line Molt-4 with PI-PLC resulted in a decrease in the susceptibility to lysis by natural killer (NK) cells. Treatment of the erythroleukemia cell line K562 with PI-PLC had no effect on its NK susceptibility. PI-PLC-treated and untreated Molt-4 bound equally well to lymphocytes in target-binding studies with effector cell preparations enriched for NK cells. Susceptibility to cytolytic granules isolated from rat LGL tumor cells remained the same after treatment of Molt-4 or K562 with PI-PLC. Combined treatment of Molt-4 with PI-PLC and rlFN-alpha or rlFN-gamma resulted in additive reductions of the NK susceptibility, suggesting that PI-PLC and interferons act on different mechanisms to protect cells from NK lysis. When expression of a number of antigens on Molt-4 and K562 was analyzed in flow cytometry, only the expression of CD58 was reduced after PI-PLC treatment. The susceptibility of Con A blasts to MLR derived cytotoxic T-cells was not altered by treatment with phospholipase. These data suggest that PI-PLC treatment reduces the capacity of some target cells to activate NK cells upon contract. The mechanism behind this phenomenon is presently unclear.
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PMID:Phospholipase C treatment of certain human target cells reduces their susceptibility to NK lysis without affecting binding or sensitivity to lytic granules. 170 25

The interactions between haemopoietic progenitor cells and marrow stromal cells that are essential for the regulation of normal haemopoiesis are defective in chronic phase chronic myeloid leukaemia (CML). The presence of primitive progenitor cells (blast colony-forming cells, Bl-CFC) in the blood of patients with CML is reflected by their reduced capacity to bind to marrow derived stromal layers in vitro. Whereas normal bone marrow Bl-CFC bind irreversibly to cultured stromal layers (and none are found in normal blood), the Bl-CFC in CML bind transiently and then detach. The normal cell adhesion mechanism is partially sensitive to treatment with phosphatidylinositol-specific phospholipase C (Pl-PLC), indicating the participation of a phosphatidylinositol (Pl)-linked structure; however, when CML cells were treated with Pl-PLC it had no effect on progenitor binding. Two other Pl-linked structures, decay-accelerating factor (DAF) and lymphocyte function associated antigen-3 (LFA-3) were normally expressed on CD34 positive CML cells and normally susceptible to Pl-PLC treatment. The treatment of normal cells with Pl-PLC, to mimic the situation in CML, resulted in the indiscriminate and inefficient binding of Bl-CFC to stroma. Moreover, treatment of the normal cells with 5637 conditioned medium (CM), which contains haemopoietic growth factors, also reduced the binding capacity of normal Bl-CFC; 5637CM treatment did not alter the expression of DAF. It is proposed that a Pl-linked cell adhesion molecule (CAM) is deficient in CML as a consequence of the constitutive activation of ABL kinase whilst, in normal cells, CAMs attached in this manner are responsible for efficient adhesion to stroma and are regulated by growth factors.
Leukemia 1991 Aug
PMID:Deficiency of a phosphatidylinositol-anchored cell adhesion molecule influences haemopoietic progenitor binding to marrow stroma in chronic myeloid leukaemia. 171 60

Two peaks of phosphoinositide-specific phospholipase C (PI-PLC) activity were resolved when guinea pig uterus cytosolic proteins were chromatographed on a DEAE-Sepharose column. The first peak of enzyme activity eluting from the DEAE-Sepharose column (PI-PLC I) was further purified to homogeneity, whereas the second peak of enzyme activity was enriched 300-fold. PI-PLC I migrated as a 62-kDa protein on sodium dodecyl sulfate-polyacrylamide gels. Antibodies prepared against PI-PLC I failed to react with PI-PLC II. PI-PLC I hydrolyzed all three phosphoinositides, exhibiting a greater Vmax for phosphatidylinositol 4,5-bisphosphate greater than phosphatidylinositol 4-phosphate greater than phosphatidylinositol. Hydrolysis of phosphatidylinositol was calcium-dependent, whereas significant hydrolysis of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate occurred in the presence of 2.5 mM EGTA. At physiological concentrations of calcium, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate were the preferred substrates. Antibodies specific for PI-PLC I reacted with a 62-kDa protein in both the cytosol and membrane fractions from guinea pig uterus. Quantitation of the immunoblots revealed that 25% of the 62-kDa protein was membrane-associated, whereas only 5% of the total enzyme activity was membrane-associated. Approximately 20% of the membrane-bound phospholipase C activity and immunoreactive material were loosely bound, whereas the remainder required detergent extraction for complete solubilization. The 62-kDa protein associated with the membrane fractions did not bind lectin affinity columns, suggesting that it was not glycosylated. PI-PLC I was identified as a phosphoprotein in [32P]orthophosphate-labeled rat basophilic leukemia (RBL-1) cells by two-dimensional gel electrophoresis followed by immunoblotting. In untreated cells, 32P-labeled PI-PLC I was found in the cytosolic fraction. Treatment of RBL-1 cells with those phorbol esters which are known to activate the Ca2+/phospholipid-dependent enzyme protein kinase C, resulted in a time-dependent increase in the phosphorylation of both membrane-bound and cytosolic PI-PLC I. Thus, in RBL-1 cells, protein kinase C may play an important role in the regulation of phospholipase C through protein phosphorylation.
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PMID:Purification and characterization of a phosphoinositide-specific phospholipase C from guinea pig uterus. Phosphorylation by protein kinase C in vivo. 282 Sep 80

Subunit specific radioimmunoassay for aldolase isozymes were developed for the quantification of human aldolase A and B. Aldolase B immunoreactivities were predominantly high in adult normal liver, while aldolase A was distinctly low. Aldolase A was high, while aldolase B was low in neonatal liver compared with the adult liver. Aldolase A immunoreactivities were almost the same as those of aldolase B in fetal liver (28 weeks). Aldolase A was predominantly found in human hepatoma tissues, whereas aldolase B was distinctly low in the same hepatoma tissues. With regard to human hepatoma cell lines, aldolase A was also predominantly found in HepG2 and PLC/PRF/5 cell lines, whereas aldolase B levels were extremely low. Almost the same results were obtained from mRNA expression of aldolase A and B in human hepatoma cell lines by the method of northern hybridization. Effects of various reagents on differentiation of hepatoma cell lines were investigated. Neither Dimethyl Sulfoxide (DMSO) and 12-O-Tetradecanoylphorbol-13-acetate (TPA), which are known to be the inducers of differentiation of human leukemia cell lines such as HL-60, nor Transforming Growth Factor-beta 1 (TGF-beta 1) and Hepatocyte Growth Factor (HGF), which are known to be growth inhibitors, could cause the differentiation of hepatoma cell lines in the alteration of aldolase isozymes. The same data were shown in mRNA expression of aldolase isozymes. These results suggest that aldolase A immunoreactivities and mRNA expression are both predominantly high in hepatoma cell lines, and the reagents such as DMSO, TPA, TGF-beta 1 and HGF which tried to differentiate the hepatoma cell lines used in this study were not effective in the alteration of aldolase isozymes.
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PMID:[Immunoreactivities and messenger RNA expression of aldolase A and B in human hepatoma cell lines]. 786 61

The human c-erbA beta protooncogene encodes a thyroid hormone receptor (comprising a hormone-binding domain and a DNA-binding domain) which modulates expression of specific genes, such as cell differentiation genes. Using the reverse transcription and polymerase chain reaction (RT-PCR) assay, significant expression of the c-erbA beta gene was detected in the SiHa, CaSki, HeLa cervical carcinoma; Hep3B, PLC/PRF/5, Mahlavu hepatocellular carcinoma; HT-1080 fibrosarcoma cell lines; as well as in normal MRC-5 embryo lung and FS-4 foreskin fibroblast cell lines. However, the Molt-4 leukaemia and Raji Burkitt's lymphoma cell lines exhibited very low levels of c-erbA beta expression. Single-strand conformation polymorphism analysis and direct sequencing of PCR products of the c-erbA beta hormone-binding domain cDNAs of these cell lines revealed identical sequences, but differed from the published human placental c-erbA beta sequence by five single base disparities. Sequencing of an aberrant fragment fortuitously amplified from the HT-1080 cDNA library demonstrated concordance with the cDNA of pregnancy-specific glycoprotein 4, which is related to the tumour marker, carcinoembryonic antigen.
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PMID:The c-erbA beta thyroid hormone receptor. Expression and cDNA sequence analysis of the hormone-binding domain in human cancer cell lines. 791 62

Constitutive activation of BCR-ABL tyrosine kinase fusion protein has been shown to be an essential step in the pathogenesis of Philadelphia chromosome (Ph)-positive leukemias. We studied the tyrosine phosphorylated proteins which might be involved in the signaling pathway p185BCR-ABL using a Ph-positive acute lymphoblastic leukemia cell line. p185BCR-ABL but not p145c-abl was constitutively phosphorylated on tyrosine in this cell line. p21ras GTPase-activating protein (GAP) was physically associated with p185BCR-ABL, but not with p145c-abl, and GAP-associated proteins p62/p190 were found to be tyrosine-phosphorylated. Furthermore, p185BCR-ABL was also physically associated with phospholipase C-gamma 1 (PLC-gamma) and phosphatidylinositol 3'-kinase (P13-kinase). Concomitantly, both PLC-gamma and p85 subunit of P13-kinase are tyrosine-phosphorylated in the cells with p185BCR-ABL. These data suggest that GAP, GAP-associated proteins, PLC-gamma, and P13-kinase may participate in downstream signaling for p185BCR-ABL tyrosine kinase.
Leukemia 1994 Jan
PMID:Potential molecules implicated in downstream signaling pathways of p185BCR-ABL in Ph+ ALL involve GTPase-activating protein, phospholipase C-gamma 1, and phosphatidylinositol 3'-kinase. 828 76

Fusariosis, a rare infectious disease of the immunocompromised host, is relatively resistant to amphotericin B (AmB) or other antifungal agents. We describe a 5-year follow-up of a 40 year old woman with T-type acute lymphoblastic leukemia who following chemotherapy developed prolonged high fever, chills, night sweats, and severe weakness. Liver function tests were impaired and abdominal computerized tomography (CT) showed multiple lesions in the liver and abnormal structure of the spleen. A laparotomy revealed multiple granulomas containing Fusarium sp. in the liver, and the spleen was heavily infiltrated by the same fungus. The patient failed to respond to the conventional AmB dosage form (Fungizone) even after a total dose of 3.0 g was given, and developed significant renal impairment. AmB was complexed (in a mole ratio of 1:16) with a mixture of the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (mixed in 7:3 mole ratio). The resulting drug complex, AmB-PLC, was then administered (1-4 mg/kg/day, total dose 4.2 g) and subsequently the patient was cured of all symptoms of fusariosis. There were only mild side effects and no nephrotoxicity was evident. On the contrary, marked improvement of the renal function tests occurred during AmB-PLC treatment. Eight months later, she developed a spinal lesion with dense consistency in L5 and S1, and after receiving another course of AmB-PLC (3.1 g) she recovered completely. In a 2 year follow-up period the patient had no further relapse of the fungal disease. Subsequent chemotherapy given for relapse of the leukemia was followed by a new fungal infection, which was treated with AmB-cholesteryl sulfate complex (Amphocil).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Disseminated visceral fusariosis treated with amphotericin B-phospholipid complex. 834 74


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