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

A growth factor-like activity for erythroid cells (erythroid-potentiating activity) is produced by the T-cells infected with human T-cell leukemia virus type 2 (HTLV-2) (Gasson, J. C., Golde, D. W., Kaufman, S. E., Westbrook, C. A., Hewick, R. M., Kaufmann, R. J., Wong, G. G., Temple, P. A., Leary, A. C., Brown, E. L., Orr, E. C., and Clark, S. C. (1985) Nature 315, 768-771) and is reportedly identical with tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) (Docherty, A. J. P., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., Harris, T. J. R., Murphy, G., and Reynolds, J. J. (1985) Nature 318, 66-69). We found that adult T-cell leukemia cell lines infected with HTLV-1 also express high levels of a TIMP-1 transcript. A viral transactivator of HTLV-1, Tax1, in a human T-cell line (Jurkat), was sufficient to stimulate transcription of the TIMP-1 gene. Deletion and mutation analysis of the TIMP-1 gene promoter showed that the AP-1 binding site in the 38-base pair sequence conserved between the human and mouse genes was essential for activation by Tax1. The transactivator of HTLV-2 also stimulated the promoter through the same cis-element. The reported growth-promoting activity of TIMP-1 against erythroid cells and potentially against HTLV-1-infected T-cells may modulate the clinical course of adult T-cell leukemia.
 ...
PMID:Tax proteins of human T-cell leukemia virus type 1 and 2 induce expression of the gene encoding erythroid-potentiating activity (tissue inhibitor of metalloproteinases-1, TIMP-1). 819 27

The human CGL-1/cytotoxic serine protease B gene (CSP-B; also known as granzyme B) is transcriptionally activated during cytotoxic T-lymphocyte maturation. Activation can be mimicked in the PEER T-cell leukemia cell line by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) and N6-2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (bt2cAMP). In this report, we show that a consensus AP-1 element and a consensus cAMP response element (CRE) located 5' to the CSP-B transcriptional start site are both required for transcriptional activation of the CPS-B promoter in TPA + bt2cAMP-stimulated PEER cells. A 94-bp fragment containing both elements activates a heterologous promoter in an orientation-independent fashion. Several single nucleotide substitutions in the AP-1 site abolish activity of the 94-bp fragment. Several point mutations in the consensus CRE substantially reduce promoter activity, but one CRE mutation increases activity fourfold. Replacement of the CRE with a second copy of the AP-1 site results in a level of transcriptional activity comparable with that of the wild-type sequence, but replacement of the AP-1 site with a CRE abolishes activity. Neither the AP-1 site nor the CRE can be effectively replaced with an SP-1 site. Deletions between the AP-1 site and the CRE retain full activity only if helical spacing is preserved, suggesting that synergism between these two elements is either the result of cooperative binding of factors to the DNA or of cooperative binding of DNA-bound factors to another protein.
 ...
PMID:Consensus AP-1 and CRE motifs upstream from the human cytotoxic serine protease B (CSP-B/CGL-1) gene synergize to activate transcription. 821 27

We have shown that Tax1 of human T-cell leukemia virus type 1 stimulates the expression of several cellular immediate-early genes (M. Fujii, T. Niki, T. Mori, T. Matsuda, M. Matsui, N. Nomura, and M. Seiki, Oncogene 6:1023-1029, 1991). In this study, the 5'-flanking region of the human fra-1 gene, which is a Tax1-inducible fos-related gene, was isolated and Tax1 or serum-responsive cis elements were analyzed to obtain further insight into the mechanism of Tax1 action. The 62-bp sequence starting 46 nucleotides upstream from the translation initiation site showed 71% homology with the sequence surrounding the TATA box of the c-fos promoter. Regulatory motifs identified in the c-fos promoter, such as an Ets-binding site, E boxes, a CArG box, c-fos AP-1 sites, and two retinoblastoma control elements, were also found upstream of the c-fos homology region. A 502-bp fragment containing these motifs mediated transcriptional activation by Tax1 or by serum in a transient transfection assay. Three independent Tax1-responsive regions (TRRs) were identified, and mutations in each revealed that one of the retinoblastoma control elements in TRR1 and the c-fos AP-1 sites in TRR2 and TRR3 were essential for the activation. Although TRR2 contains a CArG box-like sequence, it was a weak binding site for p67SRF, if it bound at all, and was not required for activation. All three TRRs could also mediate the signals stimulated by serum. Thus, Tax1 appears to activate fra-1 gene expression by means of a part of the cellular machinery similar to that which mediates growth signals.
 ...
PMID:Human T-cell leukemia virus type 1 Tax activates transcription of the human fra-1 gene through multiple cis elements responsive to transmembrane signals. 823 Apr 24

The Jun protein binds DNA and regulates transcription as a component of the AP-1 transcription factor complex. In its oncogenic form, Jun can transform cells in culture and cause tumors in animals. Both trans-activation and transformation require several functional domains of Jun, including an amino-terminal trans-activation domain. In this study, properties of Jun required for trans-activation and transformation were explored by replacing the trans-activation domains of c-Jun and its oncogenic counterpart, v-Jun, with the constitutively active trans-activation domain from the herpes simplex virus VP16 protein. The VP16-v-Jun chimera retained similar oncogenic properties to its parent, v-Jun. The VP16-c-Jun chimera, however, was considerably more oncogenic than c-Jun. Substitutions of a phenylalanine in the VP16 domain of the VP16-c-Jun chimera diminished or abolished transformation. Each of the chimeras bound to the AP-1 consensus recognition sequence from the collagenase promoter or from the human T-cell leukemia virus type I long terminal repeat in vitro. None of the VP16-Jun chimeras efficiently stimulated transcription from the collagenase promoter or an artificial promoter containing the human T-cell leukemia virus type I element in vivo. These results demonstrate that the Jun trans-activation domain can be replaced by a heterologous trans-activation domain with retention of oncogenic activity. However, this oncogenic activity is not reflected in the trans-activating properties of the chimeras.
 ...
PMID:Chimeras of herpes simplex viral VP16 and jun are oncogenic. 824 Oct 24

Protein kinase C (PKC)-activating phorbol esters are known to induce the expression of several genes in monocytic cells. As the effect of serine-threonine kinases, such as PKC, is often counteracted by specific protein phosphatases, we have now examined the role of phosphatases in the regulation of the phorbol ester (PMA)-induced interleukin-1 beta (IL-1 beta) gene expression in the THP-1 monocytic leukaemia cell line. Okadaic acid (OA) is a potent tumour promoter, the function of which is based on its activity to inhibit the serine/threonine specific phosphatases 1 and 2A (PP1 and PP2A, respectively). Thus, it mimicks or potentiates the action of PKC activators in several cell types. Our data demonstrate that alone OA induced a very weak expression of IL-1 beta mRNA, but it strongly enhanced the PMA-induced IL-1 beta expression. To analyse the site of action of OA, the cells were transiently transfected with a chloramphenicol acetyl transferase (CAT)-reporter plasmid containing the AP-1 binding site as the enhancer. Alone, OA was a weak inducer of CAT-activity in these cells, but again it strongly enhanced the PMA-induced response. Similar data were obtained with cells transfected with a reporter plasmid containing the PMA-responsive element (containing a putative AP-1 binding site) of the IL-1 beta gene. Thus, these data indicate that the PMA-induced AP-1 enhancer activity, which is required for the expression of the IL-1 beta gene, is controlled in these cells by PP1 and/or PP2A. As OA did not synergize with PMA in the induction of expression of genes encoding the AP-1 proteins (c-fos, c-jun, junB), it is likely that OA potentiates the AP-1 enhancer activity by its effect on protein phosphorylation.
 ...
PMID:Okadaic acid, a phosphatase inhibitor, enhances the phorbol ester-induced interleukin-1 beta expression via an AP-1-mediated mechanism. 825 16

Skeletal myoblasts undergo terminal differentiation when maintained under low-mitogen conditions. We have examined the expression of c-jun, one of the growth-factor-inducible immediate-early genes, during myogenic differentiation of L6 myoblasts. The steady-state levels of c-jun mRNA, c-Jun polypeptide, and activator protein 1 binding activity were not markedly altered in L6 cells undergoing myogenic differentiation. Although expression of c-jun is induced by serum mitogens in fibroblasts and other cell lines, addition of high serum to proliferating myoblasts resulted in the activation of another immediate early gene junB, but not c-jun mRNA expression. These results indicate that regulation of c-jun may differ from that of other immediate early genes in L6 cells. Manipulation of myogenesis by exposing L6 cells to dimethyl sulfoxide also suggested that expression of myogenin and muscle differentiation could occur in the presence of high levels of c-Jun. Furthermore, expression of c-jun from Moloney murine leukaemia viral long-terminal repeat in transfected L6 cells confirmed that constitutive expression of c-jun does not interfere with myogenesis in L6 myoblasts. Therefore, regulation of c-jun expression in rat L6 cells differs from that in the mouse C2 cell line.
 ...
PMID:Expression of the protooncogene c-jun is maintained during myogenic differentiation in rat L6 myoblasts. 827 67

The c-jun proto-oncogene belongs to the family of immediate early response genes and is inducible by serum growth factors and Tumor Necrosis Factor (TNF). In the present study we have addressed the role of c-jun for the mitogenic response of primary acute myelogenous leukemia (AML) blasts to TNF-alpha. Our data indicate that TNF-alpha treatment of these cells is associated with transcriptional activation of c-jun and accumulation of c-jun mRNA. In order to elucidate the role of c-jun for TNF-mediated growth stimulation, an antisense (AS) oligomer directed towards the translation initiation site of c-jun was instrumental. Uptake studies of oligonucleotides showed that incorporation of oligomers was maximal at 4 hours. Oligodeoxynucleotides remained stable in these cells for up to 24 hours. Treatment of AML blasts with the AS oligonucleotide resulted in intracellular duplex formation followed by efficient translation blockade of c-jun/AP-1. In contrast, sense (S) and none-sense (NS) oligodeoxynucleotides failed to form intracellular duplexes and also did not interfere with translation of c-jun/AP-1, suggesting specific elimination of c-jun/AP-1 by the AS oligomer. AML blasts cultured in the presence of AS to c-jun, but not of S or NS, failed to proliferatively respond to TNF-alpha stimulation. Taken together, our results indicate that activation of c-jun/AP-1 plays a pivotal role in the signaling cascade initiated by TNF which leads to a proliferative response of its target cells.
Leukemia 1993 Aug
PMID:The mitogenic response of AML blasts to tumor necrosis factor-alpha requires functional c-jun/AP-1. 836 Dec 27

Anthracycline antitumor drugs, particularly aclacinomycin (ACM) have been shown to be potent inducers of erythroid differentiation in human leukemic K562 cells. Here we report that such an event is associated with an overexpression of the erythroid-specific transcription factors GATA-1 and NFE-2. Using the electrophoretic mobility shift assay, during differentiation over 3 days of culture, we have observed an increase in the binding either of GATA-1 to the promoter of the gamma-globin gene (region -201 to -156) or NFE-2 to the promotor of the porphobilinogen deaminase gene (region -170 to -142). Both events were paralleled by a recruitment of hemoglobinized cells and a stimulation of heme synthesis. Enhanced binding capacity of GATA-1 was confirmed by an increase in its mRNAs. Moreover, GATA-1 and NFE-2 overexpression has been shown to be specific of the differentiating effect of the drug and not of its growth inhibitory effect. In contrast, no change was observed in the binding of the ubiquitous factors OTF-1 and AP-1, except on day 3, where AP-1 decreased. Although ACM is a DNA-intercalating agent, it did not directly affect transcription factors binding to their cis-sequences as assessed by the preincubation of the oligonucleotides probes with increasing concentrations of ACM. Taken together, these results strongly suggest that ACM could exert their erythroid-differentiating activity by modulating the expression of transcription factors which specifically regulate the transcription of erythroid genes.
Leukemia 1993 Mar
PMID:Increased expression of GATA-1 and NFE-2 erythroid-specific transcription factors during aclacinomycin-mediated differentiation of human erythroleukemic cells. 844 49

A novel cellular gene, SFA-2, was isolated by differential hybridization of a cDNA library, using probes obtained from an adult T-cell leukemia cell line in comparison with normal CD4+ T cells and MOLT-4 cell line. The mRNA of the SFA-2 gene is approximately 0.9-kb in size and encodes a protein of 125 amino acids, containing a basic region-leucine zipper DNA-binding domain. The N-terminal region of SFA-2 is rich in serine and contains a consensus sequence for casein kinase II phosphorylation. The SFA-2 gene was strongly expressed in mature T and B lymphocytes, and was up-regulated after transformation by human T-cell leukemia virus type I. The SFA-2 did not homodimerize efficiently but formed heterodimer preferentially with c-Jun. The SFA-2/c-Jun heterodimer bound preferentially to the AP-1 and CRE sites.
 ...
PMID:SFA-2, a novel bZIP transcription factor induced by human T-cell leukemia virus type I, is highly expressed in mature lymphocytes. 863 63

The promyelocyte (PML)-retinoic acid receptor alpha (RARalpha) fusion gene results from a t(15;17) chromosome translocation in acute promyelocytic leukaemia. We have analysed the oncogenic potential of the human fusion PML-RARalpha product in chicken using retrovirus vectors. We show that PML-RARalpha transforms very early haematopoietic progenitor cells in vitro and induces acute leukaemias. Neither PML nor RARalpha domains alone achieve such a transformation. The PML-RARalpha viruses recovered from the transformed cells carry two point mutations in the PML domain, one of which alters both the pattern of intracellular localization of the fusion protein and its functional interference with AP-1, thus defining an essential domain in PML for oncogenic transformation.
 ...
PMID:A retrovirus carrying the promyelocyte-retinoic acid receptor PML-RARalpha fusion gene transforms haematopoietic progenitors in vitro and induces acute leukaemias. 865 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>