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)

Pharmacologic differentiation of the promyelocytic leukemia HL60 is associated with an increase in cellular tyrosine phosphatase activity. We asked (a) if this increase might, at least in part, be due to changes in a transmembranous protein-tyrosine phosphatase, CD45; and (b) if CD45 changes similarly in other differentiating leukemias. Differentiation of HL60, several chronic myelogenous leukemias, a monocytic leukemia (THP-1), and a monoblastoid leukemia (U-937) could be induced by phorbol ester, 1,25-dihydroxy vitamin D3, dimethyl sulfoxide, or cyclic AMP analogues. This differentiation was associated with a marked increase in (a) total cellular tyrosine phosphatase activity (2-4-fold as measured by the ability to dephosphorylate a tyrosine-phosphorylated peptide); (b) CD45-specific tyrosine phosphatase activity (2-4-fold); (c) CD45 cell surface expression by flow cytometry (2-5-fold); (d) synthesis of both exon B-dependent M(r) 205,000 and exon ABC- M(r) 185,000 CD45 proteins, as revealed by immunoprecipitation with antisera specific for CD45 isoforms. Both isoforms have enhanced electrophoretic mobility when isolated from the differentiated cells. This enhanced mobility did not appear to be due to decreased stoichiometry of CD45 phosphorylation on serine/threonine residues. Interestingly, 12-O-tetradecanoylphorbol-13-acetate transiently reduced CD45 protein-tyrosine phosphatase activity in the chronic myelogenous leukemia cell RWLeu4 without altering the CD45 amount (as measured by cell surface immunofluorescence). Modulation of CD45 tyrosine phosphatase activity (and protein levels) may play a role in differentiation or in maintaining cells in a nonproliferative state or may represent a phenotypic marker of differentiation.
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PMID:Differentiation-induced changes in protein-tyrosine phosphatase activity and commensurate expression of CD45 in human leukemia cell lines. 153 52

smg p21A and -B (smg p21s) are ras p21-like small GTP-binding proteins (G proteins) with the same putative effector domain as ras p21s. Both smg p21A mRNA and smg p21B mRNA were detected in CMK, a human megakaryocytic leukemia cell line, and their levels were markedly elevated by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which caused the differentiation of this cell line into more mature megakaryocytes. The smg p21 protein molecules also increased during the TPA-induced differentiation of CMK cells. The mRNA level of glycoprotein IIb (GPIIb), a typical marker of the megakaryocytes, was increased by this treatment, but the time course of the increase in the smg p21 mRNA levels as more rapid than that of the increase in the GPIIb mRNA level. Ha-ras p21 mRNA was undetectable, but both Ki- and N-ras p21 mRNAs were detected in CMK cells and their levels were also increased during TPA-induced differentiation of CMK cells, although to a lesser extent than those of smg p21 mRNAs. Protein kinase C inhibitors inhibited the basal and TPA-induced smg p21A mRNA level, but cyclic AMP-elevating prostaglandin E1 or Ca(2+)-mobilizing ionomycin did not inhibit them. Cycloheximide enhanced the basal and TPA-induced smg p21A mRNA levels. Actinomycin D blocked the TPA-induced smg p21A mRNA levels, but showed no detectable effect on the elevated smg p21A mRNA level which was induced by pretreatment with TPA. A dramatic increase in the smg p21 mRNA levels was also observed in other leukemia cell lines during TPA-induced differentiation. These results suggest that TPA stimulated expression of the smg p21A gene, presumably through the action of protein kinase C at the transcriptional level rather than at the post-transcriptional level, in hematopoietic leukemia cells.
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PMID:Induction of smg p21/rap1A p21/krev-1 p21 gene expression during phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line. 154 53

We have examined the actions of a novel xanthine derivative, propentofylline (HWA 285), that has been shown to protect against ischemic brain damage in rats and gerbils, on adenosine receptors (A1 and A2), and on adenosine transporters using several techniques, cells and tissues. Propentofylline and its hydroxylated metabolite A 72 0287 were about 20 times less potent than theophylline in displacing A1-agonist binding to membranes from rat cortex, and A1-antagonist binding to whole DDT, MF-2 smooth muscle cells. A1-agonist binding to adenosine A1-receptors in several brain structures was inhibited in a concentration-dependent manner by A 72 0287 and propentofylline as judged by quantitative autoradiography (IC50-values 300-600 microM in eg striatum and in cortex layer IV). In two functional assays, A1-receptor mediated effects were blocked by propentofylline. A1-receptor-mediated inhibition of cyclic AMP accumulation was virtually abolished by 100 microM propentofylline. The A1-receptor-mediated inhibition of evoked acetylcholine release was also reduced by propentofylline, but in this case the effect is not due exclusively to adenosine receptor antagonism but also to another action since the presynaptic inhibitory effect of carbachol was also inhibited. Adenosine A2-receptors were also antagonized by propentofylline as judged by a concentration-dependent antagonism of A2-agonist-induced cAMP accumulation in human T-leukemia cells (possessing putative A2b-receptors; pA2-value 180 microM compared to 0.26 microM for 8-cpt), and in PC-12 cells (possessing putative A2a-receptors, Ki-value 365 microM). Finally, adenosine transporters were affected by propentofylline and A 72 0287. Thus, [3H]-nitrobenzylthioinosine-binding to guinea-pig cardiac membranes was blocked by propentofylline or A 72 0287 (Ki 270 microM). The present results show that propentofylline and its hydroxylated metabolite can influence adenosine mechanisms in a multitude of ways. How these different actions may contribute to the ability of propentofylline to reduce the magnitude of ischemic damage is discussed.
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PMID:Further evidence that propentofylline (HWA 285) influences both adenosine receptors and adenosine transport. 162 77

We investigated actin polymerization and the increase of cytosolic free calcium concentration ([Ca2+]i) in a human eosinophilic leukemia cell line, EoL-1, in response to stimulation with chemotactic factors; we also investigated the effect of dibutyryl cyclic AMP (dbcAMP) on the responses. EoL-1 cells under normal culture conditions did not show either actin polymerization or an increase in [Ca2+]i when stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP). Expression of formyl peptide receptors was not detectable on untreated EoL-1 cells, either. Dibutyryl cAMP induced the expression of formyl peptide receptors and the responsiveness to fMLP. The responsiveness of EoL-1 cells to the complement fragment C5a and platelet-activating factor (PAF) was also induced or enhanced by dbcAMP. The growth of EoL-1 cells was decreased and the proportion of cells in the G0/G1 phase of the cell cycle was increased by the treatment of EoL-1 cells with dbcAMP. The proportion of eosinophilic granule-containing cells and the content of eosinophil cationic protein (ECP) in EoL-1 cells was also increased when they were stimulated with dbcAMP for a longer period. The responsiveness of EoL-1 cells to fMLP, C5a, and PAF was shown to be regulated independently. EoL-1 cells and dbcAMP seem to be useful for examining chemotactic receptor expression and its signal transduction mechanisms.
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PMID:Dibutyryl cyclic AMP induces formyl peptide receptor expression and chemotactic responses in a human eosinophilic cell line, EoL-1. 165 Dec 53

Site-selective cyclic AMP (cAMP) analogues have been shown to inhibit growth and induce differentiation in several human leukemia cell lines. However, detailed studies of the effects exerted by cAMP analogues on cell cycle kinetics have been lacking. We have examined the effects of 8-Cl-cAMP and N6-benzyl-cAMP on the cell cycle kinetics of the HL-60 human promyelocytic leukemia cell line. A cell cycle study was performed by univariate DNA analysis after 24-72 h of treatment with noncytotoxic concentrations of 8-Cl-cAMP and N6-benzyl-cAMP capable of inducing 50-60% growth inhibition in these cells. HL-60 cells treated with 5 microM 8-Cl-cAMP showed no significant change in the cell distribution in the cycle as compared to the untreated control cells, whereas the treatment with 10 microM N6-benzyl-cAMP transiently increased the percentage of cells in the G0/G1 phase after 48 h, followed by a partial recovery at 72 h. Combined treatment with low doses of 8-Cl-cAMP and N6-benzyl-cAMP, each of which alone produced 20% growth inhibition, exerted a growth inhibitory effect of 65% and delayed increase of the G0/G1 phase by 72 h. To better understand the cell cycle effects induced by 8-Cl-cAMP, flow cytometric analysis of bromodeoxyuridine incorporation was also performed. 8-Cl-cAMP treatment exhibited a slowing down of the cell cycle; thus, the delayed appearance of the G0/G1 cell accumulation after combined treatment could be due to this effect of 8-Cl-cAMP on the HL-60 cell cycle. At a toxic dose, 8-Cl-cAMP brought about a G2M block, whereas N6-benzyl-cAMP brought about an increase of the G0/G1 compartment. G2M block produced by toxic doses of 8-Cl-cAMP was not related to its adenosine metabolite since 8-Cl-adenosine did not produce any specific block in the cell cycle. Our results show, for the first time, that these site-selective cAMP analogues could affect cell cycle kinetics at different points. These data may provide the basis for combination treatments involving cAMP analogues and other agents in the treatment of human leukemia.
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PMID:Effects of 8-chloroadenosine 3',5'-monophosphate and N6-benzyl-cyclic adenosine 5'-monophosphate on cell cycle kinetics of HL-60 leukemia cells. 165 83

To evaluate its toxicity and clinical efficacy in children with relapsed or refractory leukemia, we performed a phase I trial of 2-chloro-2'-deoxy-adenosine (2-chlorodeoxyadenosine; 2-CDA) given as a continuous 5-day infusion at doses of 3 to 10.7 mg/m2/d. In this study of 31 children with acute leukemia, the only dose-limiting toxicity was myelosuppression. At the highest dose level, three of seven patients developed fatal systemic bacterial or fungal infections. At dose levels above 6.2 mg/m2/d, significant oncolytic responses occurred in all patients. In addition, there was a significant correlation between both the responsiveness by cell type and dose of 2-CDA, such that more oncolytic responses were noted in acute myeloid leukemia (AML) patients than acute lymphoblastic leukemia (ALL) patients (P = .02). Although this was a phase I trial in heavily pretreated patients with refractory disease, two AML patients treated at 5.2 and 10.7 mg/m2/d, respectively, had complete hematologic responses, and one patient treated at 10.7 mg/m2/d had a partial response. In addition, there was a dose-response relationship in all patients with improved cytoreduction of peripheral blast cells at higher doses of 2-CDA. In vitro evaluation of 2-CDA uptake and anabolism by leukemic blast cells from 22 patients demonstrated that 2-chloro-2'-deoxyadenosine (Cld-AMP) and 2-chloro-2'-deoxyadenosine 5'-striphosphate (CldATP) reached concentrations close to steady-state levels within 1 hour. Intracellular nucleotide disappearance rates were high with half-lives of 1.29 and 2.47 hours for CldAMP and CldATP, respectively. This suggests that continuous infusion is necessary to maintain the desired plasma concentration. The results of this study confirm the antileukemic activity of 2-CDA and the lack of prohibitive nonhematologic toxicity. Phase II trials in patients with AML and ALL are warranted.
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PMID:A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. 167 75

Expression of the human c-fos proto-oncogene is activated in trans by the Tax protein encoded by human T-cell leukemia virus type-1 (HTLV-1). Indeed, we show here that a HeLa clone stably transfected by Tax expresses Fos at a high level. We also show that multiple elements of the human c-fos promoter, i.e. the v-sis conditioned medium inducible element (SIE), the dyad symmetry element (DSE) necessary for growth factor induction, the octanucleotide direct repeat element (DR), and the cyclic AMP response element (CRE) centred at -60, can all mediate Tax transactivation. In the DSE, the 10bp central core that binds the serum response factor (SRF) is, by itself, sufficient to mediate Tax transactivation. Moreover, a CRE-binding protein is involved in Tax activation through the CRE-60 element. Since Fos is a transregulator of cellular genes, our results suggest that the oncoprotein plays a crucial role in T-cell transformation by HTLV-1 in conjunction with other Tax-inducible genes.
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PMID:Four regulatory elements in the human c-fos promoter mediate transactivation by HTLV-1 Tax protein. 182 66

The adenovirus E1A protein and tax protein (Tax) of human T-cell leukemia virus-1 (HTLV-1) are transcriptional regulators that do not bind to DNA directly. The ATF sites/CRE (cyclic AMP response element) of the adenovirus E4 promoter and the long terminal repeat of HTLV-1 have been shown to be required for E1A and Tax inducibility, respectively. Using the c-Myb-CRE-BP1 fusion protein, it was shown that CRE-BP1, which could bind to the ATF sites/CRE, mediated the E1A-induced trans-activation. For this activation, the N-terminal portion of CRE-BP1, which contained the putative metal finger structure, was essential but not sufficient. In contrast, the trans-activation induced by HTLV-1 Tax was not mediated by CRE-BP1. These results strongly suggested that E1A activates transcription through interaction with CRE-BP1, but another CRE-binding protein participates in the Tax-induced trans-activation.
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PMID:Cyclic AMP response element-binding protein, CRE-BP1, mediates the E1A-induced but not the Tax-induced trans-activation. 182 68

One of the gene products of human T-cell leukemia virus type I (HTLV-I), p40tax, activates its own viral transcription in trans through tax-responsive enhancers in viral long terminal repeats. Five species of cDNA clones for proteins that bind to the tax-responsive enhancer element in HTLV-I were isolated from the Jurkat cell library. The beta-galactosidase fusion protein prepared from the lysogen of a clone specifically recognized the cyclic AMP-responsive element in HTLV-I enhancer. The nucleotide sequence of a full-length cDNA clone (TAXREB67) had a coding capacity of 351 amino acids, which contained a basic motif followed by a leucine zipper structure near the carboxy terminus. Its mRNA was detected in human cell lines, including HTLV-I-infected or noninfected hematopoietic cell lines. The mRNA level in Jurkat cells was decreased temporarily by increasing cyclic AMP concentration but increased by increasing Ca2+ concentration. Polyclonal antibodies against the fusion protein specifically recognized a 52-kDa protein in Jurkat cells. Analyses of the function of this protein and its interactions with other cellular factors will be useful to help understand the regulatory mechanism through tax-responsive enhancers in HTLV-I.
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PMID:Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I. 184 61

A unique oncofetal protein (OFP) previously identified in rat fetal tissue and rat and human solid tumors, is now shown to be present in rat and human leukemia cells by use of a monoclonal antibody-based assay. Using a highly specific anti-rat OFP monoclonal antibody OFP has been unquivocally immunolocalized to the cytoplasm of the rat leukemia cells. The factor is rapidly released to the circulation as 50 and 55 kD species which share the immunological determinants. When leukemia cells are transplanted to normal rats, OFP increases in the circulation in a biphasic manner which may be due to immune clearance since circulating anti-OFP antibodies have been demonstrated. Induction of differentiation in the human HL-60 leukemia cell line by 13-cis-retinoic acid caused a down regulation of OFP synthesis, both intra- and extra-cellular levels dropping to essentially zero. Induction of differentiation with dibutyryl cyclic AMP caused a cessation of secretion of OFP, with a marked increase in its intracellular concentration, a condition resembling the retention in fetal cells. Leukemia cells add to a growing list of tumors previously shown to produce OFP, suggesting that OFP is intimately involved in some facet of tumorigenesis.
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PMID:Expression of an oncofetal protein (OFP) in rat and human leukemia cells. 186 29


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