Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Treatment of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient human promyelocytic leukemia (HL-60) cells with 6-thioguanine results in growth inhibition and cell differentiation. 6-Thioguanine is a substrate for the tRNA modification enzyme tRNA-guanine ribosyltransferase, which normally catalyzes the exchange of queuine for guanine in position 1 of the anticodon of tRNAs for asparagine, aspartic acid, histidine, and tyrosine. During the early stages of HGPRT-deficient HL-60 cell differentiation induced by 6-thioguanine, there was a transient decrease in the queuine content of tRNA, and changes in the isoacceptor profiles of tRNA(His) indicate that 6-thioguanine was incorporated into the tRNA in place of queuine. Reversing this structural change in the tRNA anticodon by addition of excess exogenous queuine reversed the 6-thioguanine-induced growth inhibition and differentiation. Similar results were obtained when 8-azaguanine (another inhibitor of queuine modification of tRNA that can be incorporated into the anticodon) replaced 6-thioguanine as the inducing agent. The data suggest a primary role for the change in queuine modification of tRNA in mediating the differentiation of HGPRT-deficient HL-60 cells induced by guanine analogs.
Mol Cell Biol 1987 Oct
PMID:Guanine analog-induced differentiation of human promyelocytic leukemia cells and changes in queuine modification of tRNA. 347 81

We studied the expression of the genes encoding the A and B chains of platelet-derived growth factor (PDGF) in a number of human leukemia cell lines. Steady-state expression of the A-chain RNA was seen only in the promonocytic leukemia cell line U937 and in the T-cell leukemia cell line MOLT-4. It has previously been reported that both PDGF A and PDGF B genes are induced during megakaryoblastic differentiation of the K562 erythroleukemia cells and transiently during monocytic differentiation of the promyelocytic leukemia cell line HL-60 and U937 cells. In this study we show that PDGF A RNA expression was induced in HL-60 and Jurkat T-cell leukemia cells and increased in U937 and MOLT-4 cells after a 1- to 2-h stimulation with an 8 pM concentration of transforming growth factor beta (TGF-beta). PDGF A RNA remained at a constant, elevated level for at least 24 h in U937 cells, but returned to undetectable levels within 12 h in HL-60 cells. No PDGF A expression was induced by TGF-beta in K562 cells or in lung carcinoma cells (A549). Interestingly, essentially no PDGF B-chain (c-sis proto-oncogene) RNA was expressed simultaneously with PDGF A. In the presence of TGF-beta and protein synthesis inhibitors, PDGF A RNA was superinduced at least 20-fold in the U937 and HL-60 cells. PDGF A expression was accompanied by secretion of immunoprecipitable PDGF to the culture medium of HL-60 and U937 cells. The phorbol ester tumor promoter tetradecanoyl phorbol acetate also increased PDGF A expression with similar kinetics, but with a mechanism distinct from that of TGF-beta. These results suggest a role for TGF-beta in the differential regulation of expression of the PDGF genes.
Mol Cell Biol 1987 Oct
PMID:Regulation of platelet-derived growth factor gene expression by transforming growth factor beta and phorbol ester in human leukemia cell lines. 347 82

The lipid-soluble folate antagonist, 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e (piritrexim; BW301U), induced misincorporation of dUMP in human B (SB)- and T (MOLT-4)-lymphoblastoid cells, and in human promyelocytic leukemia cells (HL-60). Analysis by alkaline sucrose gradients and alkaline elution indicated that 3H-DNA that had been labeled for 15 min distributed into progressively smaller DNA fragment sizes in a drug concentration-dependent manner from 0 microM to 50 microM piritrexim. This phenomenon was observed regardless of the labeled nucleotide precursor employed for detection of newly synthesized DNA [( 3H]deoxyuridine, [3H]deoxyadenosine, or [3H]deoxycytidine). In contrast, formaldehyde denaturation and sedimentation of DNA in neutral denaturing sucrose gradients released only 3-4% of the newly synthesized DNA as 3S-6S fragments (80-200 nucleotides), whereas the remaining population of newly synthesized DNA pelleted to the bottom of the tube. Failure to detect DNA fragmentation under neutral conditions to the extent observed under alkaline conditions indicated the presence of apurinic and apyrimidinic sites in DNA--lesions which would be expected in DNA undergoing excision-repair of misincorporated dUMP. Cytotoxicity resulting from dUMP misincorporation was consistent with the enhanced toxicity of piritrexim which was observed when HL-60 cells or MOLT-4 cells were exposed concurrently to exogenous deoxyuridine. Deoxyuridine-enhanced toxicity was demonstrated to be concentration dependent for both cell lines when piritrexim concentrations were marginally toxic. The cytotoxic effect of dUMP misincorporation was further substantiated by the observation that MOLT-4 cells treated with 0.5 microM piritrexim alone eventually developed resistance to the drug, whereas treatment with both piritrexim and 10 microM deoxyuridine prevented the selection of piritrexim-resistant cells.
Mol Pharmacol 1986 Dec
PMID:Drug concentration-dependent DNA lesions are induced by the lipid-soluble antifolate, piritrexim (BW301U). 349 Dec 87

Granulocyte-colony stimulating factor (G-CSF) is a member of colony stimulating factors which regulate the proliferation and differentiation of hematopoietic progenitor cells. A full-length cDNA clone coding human G-CSF was used as a hybridization probe to detect homologous sequence in human-mouse somatic cell hybrids, flow-sorted human chromosomes, and in situ human metaphase chromosomes. The results indicate that the gene encoding human G-CSF is on the q21-q22 region of chromosome 17, which is involved in translocation of t(15;17) (q23;21) in human acute promyelocytic leukemia.
Somat Cell Mol Genet 1987 Nov
PMID:Human gene coding for granulocyte-colony stimulating factor is assigned to the q21-q22 region of chromosome 17. 349 71

Tuftsin induced tumor necrosis activity was investigated. The activity was found in mice serum several days after i.p. injection of tuftsin. Further experiments with adhering peritoneal and spleen cells indicated that macrophages were the source of the observed activity. The same effect was observed when promyelocytic leukemia cells (HL60) were stimulated with different concentrations of the peptide. These showed yet another possible mechanism for tuftsin antineoplastic activity.
Mol Cell Biochem 1987 Jun
PMID:Tuftsin induced tumor necrosis activity. 362 9

The human germ-line position of c-erb-A, the cellular counterpart of v-erb-A, has been determined by in situ molecular hybridization of a 3H-labeled c-onc gene probe to meiotic pachytene chromosomes. Both v-erb-A and v-erb-B are the v-onc genes that are associated with induction of sarcoma and erythroblastosis in chicken by the avian erythroblastosis virus, a rapidly transforming RNA tumor virus. The position of c-erb-A, determined here to be at 17q21.33-q22, is in the same region of chromosome 17 in which a nonrandom break occurs in the generation of t(15;17), a translocation commonly seen in acute promyelocytic leukemia.
Somat Cell Mol Genet 1985 Jan
PMID:Germ-line chromosomal localization of human C-Erb-A oncogene. 385 34

The effect of the cyclopentenyl adenosine analog neplanocin A (NPC) on cell growth and differentiation was examined in the human promyelocytic leukemia cell line HL-60. Continuous exposure of HL-60 cells to 0.1-3.3 microM NPC resulted in a progressive reduction in cell growth which was accompanied by an increase in differentiation to cells with a myelocyte and neutrophil morphology. The latter effect was expressed as an increase in the capacity of cells to reduce nitro blue tetrazolium and reached a level of 40% of the total cell population. Preceding the phenotypic changes was the preferential inhibition of RNA and DNA methylation in comparison to inhibition of their synthesis which coincided with the formation of a metabolite of NPC with the chromatographic characteristics of S-adenosyl-L-methionine (AdoMet). In addition, c-myc mRNA expression, which is amplified in HL-60 cells, was markedly reduced following NPC treatment. These results indicate that NPC is an effective inhibitor of RNA and DNA methylation resulting from its conversion to an analog of AdoMet, and that these effects appear to be responsible for reduced c-myc RNA expression and the induction of myeloid differentiation in this cell line.
Mol Pharmacol 1985 Jul
PMID:Effect of neplanocin A on differentiation, nucleic acid methylation, and c-myc mRNA expression in human promyelocytic leukemia cells. 386 Jul 29

Human promyelocytic leukemia (HL-60) cells were induced by 1,25-dihydroxyvitamin D3 (calcitriol) to differentiate and examined using a panel of monoclonal antibodies (MoAbs) and functional assays. Although morphologically and histochemically these cells appeared to be of the monocyte-macrophage phenotype, there was a decline in Fc receptors for IgGl and no induction of class II HLA antigens. There was, however, dramatic induction of the antigen detected by the myeloid-specific MoAb AML-2-23. These data suggest that the phenotypic changes induced by calcitriol in HL-60 cells are consistent with myelomonocytic differentiation in that the resultant cells possess characteristics of both monocytes (morphology, non-specific esterase staining, high levels of AML-2-23 reactivity) and granulocytes (PMN 29 binding, decreased Fc receptors for IgGl, absence of class II HLA antigens). Perhaps more important, the ability of calcitriol-treated cells to perform antibody-dependent cellular cytotoxicity and phagocytosis was markedly augmented. Lysis of antibody-coated erythrocytes by HL-60 cells increased from 5% in controls to 30-35% with calcitriol treatment for 4 days. This enhanced effector cell function was seen despite a decline in Fc receptors measured by cytofluorography. These data suggest that calcitriol may be involved in both differential and functional activation of myeloid cells.
Mol Immunol 1985 May
PMID:1,25-Dihydroxyvitamin D3 induces a myelomonocytic phenotype with enhanced effector cell function in the HL-60 promyelocytic leukemia cell line. 386 Jul 30

Cells from 95 patients with acute leukemia were studied by cytochemistry, light microscopy, and transmission electron microscopy (TEM), and were classified according to the French-American-British (FAB) guidelines. This group included 63 patients with acute nonlymphocytic leukemia (ANLL) de novo, 18 with acute lymphocytic leukemia (ALL), and 14 with ANLL as a second malignancy. In addition, 13 cases of chronic myelocytic leukemia in blast crisis were studied. Ultrastructural examination resulted in reclassification of 6 cases of ANLL de novo; two of these were reclassified from M2 (myeloblastic leukemia with maturation) to M3 variant (microgranular variant of hypergranular promyelocytic leukemia). The classification of the cases of CML in blast crisis was identical by light microscopy and TEM. IN 1 case of myeloblastic crisis, however, basophilic granules were demonstrated by TEM but were not appreciated by light microscopy. Classification of the cases of secondary leukemia was possible by light microscopy and cytochemistry in all 14 cases, but was often difficult since the cytochemical reactions were usually less intense than in de novo ANLL. This was particularly true in those cases classified as M1, and in such cases, TEM was required to confirm the diagnosis.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982
PMID:Ultrastructural characterization of de novo and secondary leukemias. 612 30

Human myeloid leukemia cell lines ML-1, ML-2, ML-3, promyelocytic leukemia cell line HL-60 and histiocytic lymphoma cell line U-937 were induced to differentiate by 0.5-10 ng/ml (0.8-16 nM) 12-O-tetradecanoylphorbol-13-acetate (TPA). After 48-72 h of induction, changes of the morphology, cytochemistry and of the antigenic phenotype of induced and control cells were studied using a panel of monoclonal antibodies against granulocytic, monocytic, HLA-ABC and HLA-DR antigens in indirect immunofluorescence. Cells of the TPA-treated cultures acquired morphological, cytochemical and antigenic markers of monocytes/macrophages, as surface adherence, alpha-naphthyl acetate esterase (alpha-NE) and acid phosphatase activity and the expression of monocytic antigens detected with monoclonal antibodies 63D3, FMC 17, B 44.1, B 52.1 and anti-Mol. During differentiation in vitro induced by TPA, also loss of HLA-DR antigens and diminution of antigen of cell activation were detected with antibodies L 243 and 4F2. The expression of granulocytic antigens was only slightly diminished and the expression of HLA-ABC antigens was not changed by TPA-treatment. There were differences in the percentage of cells induced to differentiate among the lines of different origin and even among the lines ML-1, ML-2 and ML-3, established from a single patient with acute myeloid leukemia. After treatment of cultures with 5 ng/ml TPA for 72 h DNA synthesis was inhibited to 60-80%.
 ...
PMID:Differentiation of human myeloid leukemia cell lines induced by tumor-promoting phorbol ester (TPA). I. Changes of the morphology, cytochemistry and the surface differentiation antigens analyzed with monoclonal antibodies. 634 16


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