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)

Interleukin-6 (IL-6) activation of the immediate-early gene junB has been shown to require both a tyrosine kinase and an unknown 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7)-sensitive pathway. Here we report the identification and characterization of an IL-6 immediate-early response element in the junB promoter (designated JRE-IL6) in HepG2 cells. The JRE-IL6 element, located at -149 to -124, contains two DNA motifs, an Ets-binding site (EBS) (CAGGAAGC) and a CRE-like site (TGACGCGA). Functional studies using variously mutated JRE-IL6 elements showed that both motifs were necessary and sufficient for IL-6 response of the promoter. The EBS of the JRE-IL6 element (JEBS) appears to bind a protein in the Ets family or a related protein which could also form a major complex with the EBSs of the murine sarcoma virus long terminal repeat or human T-cell leukemia virus type 1 long terminal repeat. The CRE-like site appears to weakly bind multiple CREB-ATF family proteins. Despite the similarity in the structure between the JRE-IL6 element and the polyomavirus enhancer PyPEA3, composed of an EBS and an AP1-binding site and known to be activated by a variety of oncogene signals, JRE-IL6 could not be activated by activated Ha-Ras, Raf-1, or 12-O-tetradecanoylphorbol-13-acetate. We show that IL-6 activates JRE-IL6 through an H7-sensitive pathway that does not involve protein kinase C, cyclic AMP-dependent kinase, Ca(2+)- or calmodulin-dependent kinases, Ras, Raf-1, or NF-IL6 (C/EBP beta). The combination of JEBS and the CRE-like site appears to form the basis for the selective and efficient response of JRE-IL6 to IL-6 signals, but not to signals generated by activated Ha-Ras, Raf-1, or protein kinase C.
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PMID:Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. 838 18

Among various myeloid leukemias which were induced by X rays in C3H/He mice (Seki et al., Radiat. Res. 127, 146-149, 1991), the three most frequent types were analyzed for myeloperoxidase, c-myc, c-myb, and c-fos mRNAs. It was shown by in situ hybridization that all the component cells were positive for myeloperoxidase mRNA in granulocytic leukemia, whereas only half the cells were positive in myelomonocytic leukemia and none in monocytic leukemia. Granulocytic leukemia was also characterized by a persistently heightened expression of c-fos, while the other two types of leukemia showed negligibly low expression of the c-fos message. By contrast, both c-myc and c-myb were expressed to a similar extent in all three types of leukemia. When fresh granulocytic leukemia cells were transferred to culture in a medium containing 0.5% fetal calf serum, c-fos mRNA was decreased rapidly during incubation. The decay of c-fos mRNA was inhibited by cycloheximide markedly but was not changed significantly by actinomycin D. In the culture containing 10% fetal calf serum, the rate of decay of c-fos mRNA was slowed down significantly. Addition of dibutyryl cyclic AMP rapidly restored the c-fos expression and kept it elevated for at least 2 h in the cultured granulocytic leukemia cells. Phorbol ester (TPA) and calcium ionophore A23187 also caused a rapid but transient c-fos expression. A transient c-fos expression was inducible by TPA in the other two types of leukemia cells and in the granulocytic leukemia cells. The results suggest that the persistent expression of c-fos is distinguished from its transient expression and is characteristic for granulocytic leukemia cells as it is for normal mature granulocytes.
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PMID:Constitutive overexpression of the c-fos gene in radiation-induced granulocytic leukemia in mice. 839 29

To gain insight into the developmentally regulated expression of the mouse TCR V delta-gene segments, we have investigated the role of the 5' promoter region of the V delta 1-gene. Transient transfection assays showed that a construct encompassing 267 nucleotides upstream from the mapped transcriptional start site was capable of driving promoter activity when transfected into V delta 1+ T cells. The inclusion of an additional 459-bp 5' segment to this construct did not affect promoter activity. However, a deletion of 222 5' nucleotides from the same construct dramatically decreased promoter activity. In vivo genomic footprinting localized several protein-DNA interactions to the stretch of DNA shown to have transcriptional activity. A computer analysis revealed that the segments of DNA participating in these protein-DNA interactions were identical to the previously described cyclic AMP response element (CRE), E box, and leukemia virus E26 cis-acting elements. Transient transfection assays performed with -267 bp constructs containing mutations at each of the localized cis-acting elements revealed that the CRE, E box, and Ets elements work together in driving promoter activity and that the CRE and Ets elements are the most important for driving transcription. Gel mobility shift analyses showed that each of these cis-acting elements is capable of binding specific nuclear factors present in V delta 1-expressing cells. These data indicate that multiple transcription factors acting in concert are responsible for V delta 1 gene expression.
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PMID:Multiple cis-acting elements are required for proper transcription of the mouse V delta 1 T cell receptor promoter. 841 20

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.
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PMID:Gout, uric acid and purine metabolism in paediatric nephrology. 843 71

The Tax protein from human T-cell leukemia virus type I (HTLV-I) is a 40-kDa phosphoprotein capable of activating transcription from its own long terminal repeat (LTR), as well as increasing the transcription of cellular genes. Transcriptional activation of the HTLV-I LTR has been demonstrated via a cyclic-AMP-responsive element within the 21-bp Tax-responsive elements of the LTR. Phorbol esters also upregulate expression via the LTR. Since phosphorylation of Tax may play a role in these processes, we investigated the relative effects of kinase-stimulating agents on 32P incorporation into Tax. Our studies demonstrated that the phorbol ester 4 beta-phorbol-12 beta-myristate-13 alpha-acetate greatly stimulated Tax phosphorylation in a time- and dose-dependent manner. In contrast, 8-bromoadenosine 3'-5'-cyclic monophosphate induced little stimulation of Tax phosphorylation. Tax phosphorylation occurred only on serine residues and was mapped to a single tryptic fragment in both Tax-producing human lymphocytes and mouse fibroblast cells.
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PMID:Phorbol esters modulate the phosphorylation of human T-cell leukemia virus type I Tax. 851 Feb 30

We have examined whether activation of MAP kinases [or extracellular signal-regulated kinases (ERKs)] is required for the survival of rat sympathetic neurons by comparing the actions of three survival factors whose survival-promoting actions can be blocked by neutralizing Fab fragments to p21 ras (Nobes and Tolkovsky, 1995, Eur. J. Neurosci., 7, 344-350), nerve growth factor (NGF), the cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF), and the cyclic AMP analogue 4-(8-chlorophenylthio)cAMP (CPTcAMP). NGF-induced survival was accompanied by an intense (15- to 30-fold) and steady (> 24 h) activation of p44 and p42 ERKs which waned rapidly (t1/2 approximately 30 min) upon NGF withdrawal. However, concentrations of NGF that induced a weak (4- to 5-fold) stimulation of the ERKs were not sufficient to maintain long-term survival. Moreover, prolonged and intense stimulation of the ERKs by NGF for up to 15.5 h was unable to confer long-term survival, since withdrawal of NGF after this time resulted in neuronal death that was kinetically indistinguishable from the death of neurons that had not been exposed to NGF. By contrast, CNTF and LIF continued to support survival for up to 3 days after eliciting only transient (< 30 min and 1 h respectively) activation of p44 and p42 ERKs, while CPTcAMP induced survival for several days without any measurable activation of the ERKs. Taken together, these data suggest that ERK activation per se is neither necessary nor sufficient for survival and that alternative pathways exist for effecting long-term survival of rat sympathetic neurons.
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PMID:Activation of p44 and p42 MAP kinases is not essential for the survival of rat sympathetic neurons. 854 72

1 The ability of various prostaglandins (PGs) to inhibit monocyte chemotaxis induced by monocyte chemoattractant protein-1 (MCP-1) was investigated with a human monocytic leukaemia cell line, THP-1. Moreover, to investigate the mechanism of the inhibitory action of PGs the involvement of either intracellular adenosine 3': 5'-cyclic monosphosphate (cyclic AMP) accumulation or intracellular Ca2+ mobilization was studied. 2 TEI-6122, a synthetic 7-thia-PGE1 derivative, inhibited chemotaxis of THP-1 cells induced by MCP-1 with an IC50 of 1.5 pM. Its inhibitory activity was 1000 fold more than that of PGE1 and PGE2 (IC50 = 2.8 nM and 0.9 nM, respectively), which were more potent than other PGs such as PGA1, PGA2, PGF2 alpha and PGI2 (IC50 > or = 1 microM). 3 With respect to the effect on intracellular cyclic AMP accumulation in THP-1 cells, TEI-6122 was as potent as PGE1 and PGE2, which were approximately 100 to 1000 fold more potent than the other PGs such as PGA1, PGA2 and PGI2. The minimum concentration of TEI-6122 required to increase intracellular cyclic AMP accumulation in THP-1 cells was 1 nM. 4 TEI-6122 and PGE1 (4 microM) transiently increased intracellular calcium levels in THP-1 cells. When added prior to MCP-1, both PGs partially suppressed the increased in Ca2+ caused by this cytokine. There were no significant differences between the activity of TEI-6122 and PGE1 in either respect. 5 It is concluded that TEI-6122, a synthetic 7-thia-PGE1 derivative is a much more potent inhibitor of MCP-1-induced THP-1 cell chemotaxis than PGEI and PGE2 which are the best inhibitors among the natural PGs tested, while neither intracellular cyclic AMP accumulation nor effects on Ca2+ mobilization account for the extremely potent inhibitory activity of TEI-6122. Thus, either a novel PGE2 receptor (EPreceptor) or a novel intracellular signal transduction system may be involved in the extremely potent chemotaxis inhibitory activity of TEI-6122.
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PMID:The effect of a synthetic 7-thiaprostaglandin E1 derivative, TEI-6122, on monocyte chemoattractant protein-1 induced chemotaxis in THP-1 cells. 856 63

To achieve a better understanding of the mechanism of transactivation by Tax of human T-cell leukemia virus type 1 Tax-responsive element 1 (TRE-1), we developed a genetic approach with Saccharomyces cerevisiae. We constructed a yeast reporter strain containing the lacZ gene under the control of the CYC1 promoter associated with three copies of TRE-1. Expression of either the cyclic AMP response element-binding protein (CREB) or CREB fused to the GAL4 activation domain (GAD) in this strain did not modify the expression of the reporter gene. Tax alone was also inactive. However, expression of the reporter gene was induced by coexpression of Tax and CREB. This effect was stronger with the GAD-CREB fusion protein. Analysis of different CREB mutants with this genetic system indicated that the C-terminal 92 amino acid residues, which include the basic domain and the leucine zipper, are necessary and sufficient to mediate transactivation by Tax. To identify cellular proteins binding to TRE-1 in a Tax-dependent manner, this strain was also used to screen a library of human cDNAs fused to GAD. Of five positive clones isolated from 0.75 x 10(6) yeast colonies, four were members of the CREB/activating transcription factor (ATF) family: CREB, two isoforms of the cyclic AMP-responsive element modulator (CREM), and ATF-1. Interestingly, these three proteins can be phosphorylated by protein kinase A and thus form a particular subgroup within the CREB/ATF family. Expression of ATF-2 in S. cerevisiae did not activate TRE-1 in the presence of Tax. This shows that in a eukaryotic nucleus, Tax specifically interacts with the basic domain-leucine zipper region of ATF-1, CREB, and CREM. The fifth clone identified in this screening corresponded to the Ku autoantigen p70 subunit. When fused to GAD, the C-terminal region of Ku was able to activate transcription via TRE-1 but this activation was not dependent on Tax.
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PMID:Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors. 862 84

The amount of the heterotrimeric G protein subunit G (alpha S) decreases after the induction of human myeloblastic leukemia HL-60 cells to become granulocyte-like cells in the presence of retinoic acid (RA). Compared to untreated control cells, HL-60 cells expressed decreased levels of G (alpha S) protein and mRNA levels after addition of RA to the cultures as shown by immunoblot and Northern blot analysis. The reduction of the G (alpha S) protein in HL-60 cells by antisense RNA expression was associated with (i) decreased cell doubling time; (ii) induction of a granulocyte-like phenotype; (iii) and expression of a surface marker characteristic of myeloid differentiation. Expression of a constitutively active mutant G (alpha S) (Q227L) in HL-60 cells blocked RA-induced differentiation. In contrast, treatment with forskolin, prostaglandin E2, or 8-bromo-cyclic AMP, which increase intracellular cyclic AMP (cAMP) levels, did not inhibit the RA-mediated differentiation process. No changes in cAMP levels occurred in response to RA. The present study provides insights into the involvement of G (alpha S) protein in growth regulation during differentiation of the human myeloid cell line HL-60. These data suggest that in HL-60 human myeloid cells RA-mediated decrease of G (alpha S) plays a critical role in the regulation of differentiation which is independent of intracellular cAMP.
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PMID:Retinoic acid-mediated decrease of G (alpha S) protein expression: involvement of G (alpha S) in the differentiation of HL-60 myeloid cells. 863 3

Under resting conditions, steady-state [Ca] in agonist-sensitive Ca stores reflects a balance between active uptake (usually mediated by a thapsigargin-sensitive Ca-ATPase of the SERCA family) and passive efflux of Ca. Even though this pump-leak cycle appears to be a common property of Ca-storing organelles, little is known about the nature of the leak pathway. Ca homeostasis in thapsigargin-sensitive internal Ca stores of single permeabilized BHK-21 fibroblasts was examined using digital image processing of compartmentalized mag-fura-2 (a low-affinity Ca indicator). It is shown here that the leak of Ca from internal stores is regulated specifically by the cytosolic ATP concentration. The rate of leak was 3.6 times slower in 0.375 mM[ATP] than in 4 mM [ATP] (Na or Mg salt). These effects were observed in the presence of 0 Ca/EGTA, thapsigargin, heparin, and ruthenium red, and therefore appear to be independent of the Ca-ATPase, the InsP(3) receptor and the ryanodine receptor. The ATP-stimulated leak was seen in a variety of cell types, including rat basophilic leukemia cells and mouse pancreatic acinar cells. Other nucleotides (ADP, GTP, CTP, and UTP) and nonhydrolyzable ATP analogs (AMP-PNP and ATPgammaS) did not reproduce the action of ATP. Changes in cellular metabolism and ensuing alterations in [ATP] will be expected to influence the filling state of internal Ca stores through effects on the passive leak pathway, potentially leading to modulation of Ca signaling and organellar function.
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PMID:ATP regulates calcium leak from agonist-sensitive internal calcium stores. 864 63


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