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)

We have conducted functional studies of the enhancer elements of human T-cell leukemia virus type I (HTLV-I) using the human T-cell lines Jurkat and MOLT 4, which are negative for HTLV-I, and MT-2 and TL-Mor, which carry the proviral genome of HTLV-I. Two distinct elements have been implicated in function of the HTLV-I enhancer. One is the 21-base-pair (bp) core element that is responsible for trans-activation by the HTLV-I trans-activator p40tax and that has the ability to bind to cyclic-AMP responsive element binding factor (CREB)-like factor(s). The other is a region interposed between the 21-bp elements. In this study we demonstrate that a subfragment (C26) in the region between the 21-bp elements is involved in trans-activation by p40tax, possibly through binding to an NF-kappa B-like nuclear factor or factors. Formation of the protein-DNA complex with the C26 subfragment was positively affected by p40tax. The C26 element conferred partial responsiveness to p40tax when linked to one copy of the 21-bp element that, by itself, showed little activation in response to p40tax. However, the C26 element alone, even when repeated, could not be activated by p40tax, unlike other NF-kappa B-binding elements. In contrast, the C26 element itself was profoundly activated upon stimulation with 12-O-tetradecanoylphorbol-13-acetate. These findings therefore suggest that the HTLV-I enhancer contains multiple functional elements, including binding sites for at least CREB- and NF-kappa B-like factors, which synergistically cooperate in activation of the HTLV-I enhancer in response to p40tax. Our results also demonstrate that TPA-dependent activation of the HTLV-I enhancer may be mediated through the C26 element.
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PMID:Synergism between two distinct elements of the HTLV-I enhancer during activation by the trans-activator of HTLV-I. 193 34

Using the patch-clamp technique, we studied regulation of potassium channels by G protein activators in the histamine-secreting rat basophilic leukemia (RBL-2H3) cell line. These cells normally express inward rectifier K+ channels, with a macroscopic whole-cell conductance in normal Ringer ranging from 1 to 16 nS/cell. This conductance is stabilized by including ATP or GTP in the pipette solution. Intracellular dialysis with any of three different activators of G proteins (GTP gamma S, GppNHp, or AlF-4) completely inhibited the inward rectifier K+ conductance with a half-time for decline averaging approximately 300 s after "break-in" to achieve whole-cell recording. In addition, with a half-time averaging approximately 200 s, G protein activators induced the appearance of a novel time-independent outwardly rectifying K+ conductance, which reached a maximum of 1-14 nS. The induced K+ channels are distinct from inward rectifier channels, having a smaller single-channel conductance of approximately 8 pS in symmetrical 160 mM K+, and being more sensitive to block by quinidine, but less sensitive to block by Ba2+. The induced K+ channels were also highly permeable to Rb+ but not to Na+ or Cs+. The current was not activated by the second messengers Ca2+, inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, or by cyclic AMP-dependent phosphorylation. Pretreatment of cells with pertussis toxin (0.1 microgram/ml for 12-13 h) prevented this current's induction both by guanine nucleotides and aluminum fluoride, but had no effect on the decrease in inward rectifier conductance. Since GTP gamma S is known to stimulate secretion from patch-clamped rat peritoneal mast cells, it is conceivable that K+ channels become inserted into the plasma membrane from secretory granules. However, total membrane capacitance remained nearly constant during appearance of the K+ channels, suggesting that secretion induced by GTP gamma S was minimal. Furthermore, pertussis toxin had no effect on secretion triggered by antigen, and triggering of secretion before electrical recording failed to induce the outward K+ current. Finally, GTP gamma S activated the K+ channel in excised inside-out patches of membrane. We conclude that two different GTP-binding proteins differentially regulate two subsets of K+ channels, causing the inward rectifier to close and a novel K+ channel to open when activated.
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PMID:G protein control of potassium channel activity in a mast cell line. 210 71

Delta 9-tetrahydrocannabinol has been shown to induce incomplete maturation in ML2 human leukemia cell lines. We extend the observation of its induction of morphologic maturation to HL60 cells and of its induction of growth restriction to HL60 and K562 cells. We show that tetrahydrocannabinol reduces the cyclic AMP content of ML2 cells. Finally we demonstrate that this agent inhibits adenyl cyclase activity in ML2 cell membrane-enriched fractions. This finding in myeloid cells is compatible with one hypothesis of cannabinoid action in neuronal cells.
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PMID:Tetrahydrocannabinol inhibits adenyl cyclase in human leukemia cells. 215 51

To verify the clinical usefulness of extracellular cyclic nucleotide determinations as tumour markers in preneoplastic syndromes, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were monitored in 47 patients with refractory anaemia with excess of blasts (35 RAEB and 12 RAEBt), 20 of whom progressed to acute leukaemia during the observation period. The control group consisted of 45 healthy subjects matched for age and sex. In all groups of patients plasma cAMP levels were within the normal range, whereas plasma cGMP levels were significantly higher than those of normal subjects in both RAEB and RAEBt patients, and increased further when progression to acute leukaemia occurred. These data suggest that serial determinations of plasma cGMP may be useful to monitor the progression of the disease, though there is no evidence that cGMP values at diagnosis may have a prognostic significance.
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PMID:Plasma cyclic nucleotide levels in patients with refractory anaemia with excess of blasts. 215 84

The human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) is inducible both by the retroviral tax gene product and by cyclic AMP in the murine thymoma S49 cell line. The cis-acting sequences that control transcriptional induction by tax and by cyclic AMP are in close proximity within the HTLV-I promoter. By using a protein kinase A (PKA)-deficient S49 mutant cell line, the response of the viral promoter to cyclic AMP was shown to depend on PKA, whereas the response to tax did not require the activity of this enzyme. Transactivation of the HTLV-I LTR by tax, however, decreased in PKA-deficient and adenylate cyclase-deficient cells. The evidence presented supports largely independent mechanisms of promoter induction by cyclic AMP and tax but also suggests a role for PKA-mediated phosphorylation in the regulation of HTLV-I LTR-driven gene expression by tax.
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PMID:Role of protein kinase A in tax transactivation of the human T-cell leukemia virus type I long terminal repeat. 215 76

We examined the role of augmented formation of intracellular cyclic AMP (cAMP) in the mediation of stromal cell growth factor production that occurs constitutively or upon cytokine stimulation. Clonal murine marrow adherent cell lines were stimulated under serum-free conditions by interleukin-1 (IL-1) or lipopolysaccharide (LPS) and one (+/+ -1.LDA11) was found to produce low quantities of granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF identity was confirmed by the ability of supernatants from stromal cells to promote proliferation of the factor-dependent cell line FDC-P1, neutralization of this activity by antiserum to GM-CSF, and by Northern blot analysis. However, optimal concentrations of IL-1 and tumor necrosis factor-alpha (TNF-alpha), in combination, led to synergistic (greater than 5-fold higher quantity) GM-CSF production compared with either stimulus alone in the +/+ -1. LDA11 cell line, capable of GM-CSF production after only single stimulation with IL-1 or LPS. In addition, synergistic stimulation by IL-1 and TNF-alpha led to equivalent high amounts of GM-CSF in another cell line incapable of GM-CSF production after induction with only IL-1 or LPS. Any of several means to raise intracellular cAMP levels, including addition of 8-bromo-cyclic AMP (8Br cAMP) (0.25-1mM), pertussis toxin (20-100 ng/ml), or addition of prostaglandin E1 (PGE1) (1 microM), failed to stimulate GM-CSF production alone and strongly inhibited GM-CSF production in stromal cells stimulated by IL-1, LPS, or the synergistic combination of IL-1 and TNF-alpha. In addition, PGE1 and pertussis intoxication were agonists of adenylate cyclase in membranes of marrow adherent cells, whereas IL-1 and LPS were not. The role for regulators of intracellular cAMP was specific because any of the cAMP agonists alone, or in the presence of cytokine stimulators of stromal cells, strongly enhanced IL-6 production, an event known to be cAMP-responsive. Thus, acute formation of intracellular cAMP is a negative regulator of stromal cell GM-CSF production mediated by cytokines, but positively regulates IL-6 production and may be an important determinant of cytokine-directed marrow microenvironmental function. These findings on the requirement for augmentation versus inhibition of cytokine-mediated production of hemopoietic growth factors might be applied to an analysis of marrow stromal cell heterogeneity.
Leukemia 1990 Jul
PMID:Role for cyclic AMP in the postreceptor control of cytokine-stimulated stromal cell growth factor production. 216 2

Vanadate, at concentrations between 0.5 and 2 mM, rapidly decreased the basal level of P-enolpyruvate carboxykinase (GTP) (EC 4.1.1.32) mRNA and blocked the dibutyryl cyclic AMP (Bt2cAMP)-induced increase in enzyme mRNA in both FTO-2B and H4IIE rat hepatoma cells. The concentration of vanadate necessary to inhibit the expression of this gene was similar to that required for the vanadate-mediated activation of the insulin receptor tyrosine kinase. To determine whether vanadate could inhibit PEPCK gene transcription, a series of chimeric genes containing several deletions in the P-enolypyruvate carboxykinase promoter between -550 and -68 was linked to the structural genes for either amino-3-glycosyl phosphotransferase (neo) or chloramphenicol acetyltransferase and introduced into hepatoma cells using three methods: (a) infection with a Moloney murine leukemia virus-based retrovirus, (b) transfection and stable selection for neo expression, or (c) transient expression of chloroamphenicol acetyltransferase. In FTO-2B hepatoma cells infected with retrovirus, vanadate rapidly (within 1 h) inhibited transcription of the PEPCK-neo gene and blocked induction of gene expression caused by the addition of either Bt2cAMP or dexamethasone to the cells. Vanadate was not a general transcription inhibitor since, it like insulin, stimulated the expression of the c-fos gene. Also, the inhibitory effect of vanadate was rapidly reversible in FTO-2B cells since PEPCK gene expression could be stimulated by Bt2cAMP and dexamethasone after removal of vanadate. A series of 5' deletions in the P-enolpyruvate carboxykinase promoter (-550 to +73) was ligated to the structural gene for neo and stably transfected into hepatoma cells. Sequences responsive to vanadate were detected between -109 and -68. This result was confirmed using H4IIE hepatoma cells transiently expressing the PEPCK-CAT gene. The most likely target for vanadate in that region of the P-enolpyruvate carboxykinase promoter is cAMP regulatory element 1 which maps from -91 to -84. A comparison of the inhibitory effects of insulin and vanadate in this system indicated a major difference in the site of action of these two compounds on PEPCK gene transcription.
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PMID:Vanadate inhibits expression of the gene for phosphoenolpyruvate carboxykinase (GTP) in rat hepatoma cells. 216 40

A series of new water soluble sugar and non-sugar containing platinum(II) complexes was synthesized and evaluated for effects of the sugar moiety on water solubility, anti-tumor activity, and acute leukopenia. When tested in vivo against the murine P388 and L1210 leukemias at LD10/maximally effective doses, the compound cis-[(gluconylamino)malonato-O,O'](1R,2R-cyclohexanediami ne-N,N')platinum (II), R,RG-AMP produced comparable or superior anti-tumor activity to cisplatin, carboplatin, and tetraplatin. Efficacy was also demonstrated for the L1210/DDP (cisplatin-resistant) leukemia. Further, R,R-G-AMP is non-nephrotoxic and produces less leukopenia than cisplatin, carboplatin, and tetraplatin.
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PMID:Murine anti-tumor activity of new water soluble platinum(II) complexes with reduced toxicity. 229 75

The long terminal repeat (LTR) of the human T-cell leukemia virus type I (HTLV-I) contains an imperfect repeat of 21 nucleotides which governs the response to the virus trans-activator protein tax and to cyclic AMP. In a murine thymocyte cell line defective in the catalytic subunit of protein kinase A, the response of the HTLV-I LTR to cyclic AMP is abolished and the response to tax is substantially diminished. This report shows that a factor present in nuclear extracts of wild-type cells binds to the HTLV-I 21-nucleotide sequence and that this binding activity is missing from the extracts of protein kinase A-defective cells. Treatment of nuclear extracts of protein kinase A-defective cells with the bovine protein kinase A catalytic subunit restores the binding activity, whereas treatment of wild-type nuclear extracts with a protein phosphatase destroys the binding activity. The binding factor is referred to as protein kinase A-dependent factor (PKAF). These results indicate that in murine thymocytes the response of the HTLV-I LTR to cyclic AMP depends upon the binding of a phosphorylated protein to the 21-nucleotide repeat sequence and that the response to tax is partially dependent upon binding of the phosphorylated protein. The results suggest a model in which the phosphorylation of a transcription factor by protein kinase A regulates HTLV-I gene expression.
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PMID:Protein kinase A-dependent binding of a nuclear factor to the 21-base-pair repeat of the human T-cell leukemia virus type I long terminal repeat. 230 43

Intracellular ribonucleotide pools were analyzed by HPLC with leukemic blasts obtained from 20 children, including 13 untreated ALL, 5 relapsed ALL, and 2 lymphomas with hematological relapse. Nucleotide pools were, in general, found more expanded among relapsed cases. Also, the larger mono and diphosphate ribonucleotide levels found in relapsed cells, for instance adenine nucleotide pools, were significantly larger among the relapsed patients, as measured 216.97 +/- 53.30 nmol/10(8) cells, in contrast to 109.70 +/- 39.54 nmol/10(8) cells with untreated children (p less than 0.005). Furthermore, AMP and ADP occupied only 18% of the total adenine pool in untreated children, but 34% in relapsed children. The similar pattern of nucleotide pools was observed in guanine, cytidine, and uridine nucleotide pools. Inosine mono phosphates were measured 5.07 +/- 6.02 nmol/10(8) cells with untreated ALL, and 3.55 +/- 1.44 nmol/10(8) cells with relapsed ALL, but thymidine mono phosphates, as a key pyrimidine nucleotide of salvage pathway, were larger (p less than 0.01) among with relapsed patients measuring 31.47 +/- 8.11 nmol/10(8) cells as compared with that of untreated ALL, 11.19 +/- 12.84 nmol/10(8) cells. The present results may suggest that there is a difference in nucleotide metabolism between untreated and relapsed leukemic cells, and nucleotide profiles provide more accurate information of leukemia chemotherapy.
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PMID:Intracellular ribonucleotide pools of lymphoblastic leukemic cells in untreated and relapsed ALL children. 230 21


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