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)

The ETS family proteins have a conserved DNA-binding domain and act as transcription factors. Three domains have been recently defined in human ETS-1 proteins and their role could depend upon the nature of alternative transcripts according to whether they possess or lack DNA binding and/or transcriptional activation domain and also point mutation that could affect these important domains. Expression of ETS-1 gene is very complex and is controlled at several levels: the initiation of transcription, alternative splicing, post-translational modification, and protein stability. As a selection apparently exists for ETS-1 gene activation in hematopoietic cells, we investigated a relation between quantitative and qualitative ETS-1 expression and leukemogenesis. Using Northern blot, polymerase chain reaction (PCR), and single strand conformation polymorphism (SSCP) methods, we analyzed quantitative and qualitative ETS-1 expression in a variety of hematological pathologies and cell lines of different origin. Two ETS-1 transcripts of 6.8 and 2.7 kb, resulting from differential polyadenylation site utilization and exhibiting different stability, were observed. We identified, in a great number of patients, the four alternative ETS-1 products, but the relative extent significance of the four transcripts was very different from one patient to another. A non-conservative mutation observed in one case of T-cell acute lymphoblastic leukemia (T-ALL) and in the ETS-1 transactivation domain raised the question of suppressor activity for some ETS-1 products, as it is now known that activators and repressors can be encoded by the same gene and consistently co-expressed in vivo.
Leukemia 1993 Nov
PMID:Quantitative and qualitative variation of ETS-1 transcripts in hematologic malignancies. 823 Dec 46

Earlier work demonstrated that the Myb-Ets fusion protein of E26 avian leukemia virus induces the proliferation of multipotent hematopoietic progenitors (MEPs). These progenitors differentiate spontaneously at low frequencies along the erythroid lineage, and following the introduction of kinase/ras-type oncogenes or treatment with TPA, they are induced to differentiate along the myelomonocytic and eosinophilic lineages. Here, we show that the ts1.1 mutant of E26 encodes an Ets DNA-binding domain that is both defective and thermolabile for binding of specific DNA sequences. Correlating with this, ts1.1 MEP colonies transformed at the permissive temperature exhibit elevated levels of erythroid cells and eosinophils, whereas at the nonpermissive temperature they are induced to differentiate along the erythroid and myelomonocytic lineages and, to a lesser extent, along the eosinophil lineage. Induction of the former two lineages cannot be separated by pulse shift experiments and is essentially completed 2.5 days after temperature shift. Our results indicate that the Ets portion of the Myb-Ets fusion protein inhibits the lineage commitment of multipotent hematopoietic progenitors, probably via binding to regulatory DNA sequences of specific target genes.
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PMID:A functional Ets DNA-binding domain is required to maintain multipotency of hematopoietic progenitors transformed by Myb-Ets. 828 26

Tax1 of human T-cell leukemia virus type 1 (HTLV-1) is an enigmatic viral transactivator that regulates expression of the viral gene and also several cellular genes normally controlled by various mitogenic signals. However, previous studies have failed to define the functional domains of Tax1 for enhancer specificities and for transcriptional activation (95% of the protein portion was indispensable for the activation function). This complexity has hampered understanding of the molecular basis of Tax1 action. In this study, we analysed the activation function of a Tax1 fused to the heterologous DNA-binding domain of the yeast transcription factor GAL4 and dissected the domain required for the activation function by using derivatives of a Tax1 mutant with an insertion between amino acids (a.a.) 170 and 171. Analysis of the derivatives of the mutant fusion protein having various partial overlaps encompassing the interrupted site suggested that two contiguous stretches, AD-I (2-255 a.a.) and AD-II (227-337 a.a.), should be both intact for the activation function of Tax1 and that they form a functional activation domain.
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PMID:Two distinct regions form a functional activation domain of the HTLV-1 trans-activator Tax1. 830 1

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M(r) 116,000 pADPRp polypeptide to an M(r) approximately 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M(r) approximately 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M(r) approximately 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum(II), colcemid, 1-beta-D-arabinofuranosylcytosine, and methotrexate; to gamma-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in gamma-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.
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PMID:Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. 835 26

The human ets-2 proto-oncogene is one of the homologs of the v-ets gene, found in avian acutely transforming retrovirus E26 (D. Leprince, A. Gegonne, J. Call, C. de Taisne, A. Schneeberger, C. Lagrou, and D. Stehelin, Nature [London] 306:395-397, 1983; M. F. Nunn, P. H. Seeburg, C. Moscovici, and P. H. Duesberg, Nature [London] 306:391-395, 1983), which causes leukemia in chickens. We used the DNA-binding domain of yeast transcriptional activator GAL4 to locate the transactivation region of human ets-2. The transactivation domain of ets-2 was found in the N-terminal part of the protein, which is homologous to ets-1, and can be disrupted by deletion of a stretch of acidic amino acid residues. A transactivation-deficient mutant of ets-2 failed to transform Rat-1 cells and suppressed the transforming activity of coexpressed wild-type ets-2. A mutation in the putative DNA-binding region of ets-2 abolished transforming activity. We show that the motif crucial for ets-2 transactivation capability is necessary for transforming activity in Rat-1 cells. Mutant ets-2 protein that lacks the transactivation domain has a dominant negative effect on transformation by wild-type ets-2. We were unable to detect ets-2-dependent transcriptional regulation of several enhancers containing ets-binding motifs.
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PMID:Localization of the c-ets-2 transactivation domain. 844 38

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.
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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

We describe the isolation of human LH-2, a putative transcription factor containing two cysteine-rich regions (LIM domains) and a homeobox (Hox) DNA-binding domain. High levels of hLH-2 expression were observed in all cases of chronic myelogenous leukaemia (CML) tested, regardless of disease status. hLH-2 was mapped to chromosome 9Q33-34.1, in the same region as the reciprocal translocation that creates the BCR-ABL chimera of the Philadelphia chromosome (Ph'), the hallmark of CML; hLH-2 was retained on the derivative 9 chromosome and is therefore centromeric of c-ABL. The proximity of hLH-2 to the breakpoint on chromosome 9 raises the possibility of cis-activation by the t(9;22)(q34;q11) translocation. In addition to finding hLH-2 expression in all cases of CML, expression was observed in lymphoid malignancies and myeloid cell lines, but not in primary cases of acute myelogenous leukaemia. The role of hLH-2 in the development or progression of leukaemia is not known. However, hLH-2 may prove useful as a marker of CML for monitoring residual disease.
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PMID:Identification of a human LIM-Hox gene, hLH-2, aberrantly expressed in chronic myelogenous leukaemia and located on 9q33-34.1. 864 22

Truncated AML1 proteins are predicted to be expressed from out-of-frame AML1 transcripts present in myeloid leukemia cells harboring t(8;21) and t(3;21). To test whether these proteins, consisting of almost exclusively an N-terminal AML1 DNA-binding domain, interfere with myeloid differentiation we expressed a similar truncated AML1 protein in 32D cl3 myeloid cells. In all clones examined, the ectopically expressed truncated AML1 protein prevented binding of endogenous PEBP2/CBFs to DNA, possibly by interacting with all available CBF beta subunits. However, compared to control clones, the 32D cl3 clones expressing truncated AML1 remained IL-3 dependent for survival, proliferated similarly in low and high concentrations of IL-3, and differentiated similarly upon transfer to G-CSF. Thus, truncated AML1 proteins may contribute to myeloid leukemogeneis by inhibiting PEBP2/CBF activities, although contributions from other oncoproteins are likely required as well.
Leukemia 1996 Jun
PMID:DNA-binding domain of AML1, expressed in t(8;21) and t(3;21) myeloid leukemias, inhibits PEBP2/CBF DNA-binding but is not sufficient to transform 32D cl3 myeloid cells. 866 56

We have constructed a detailed map of the genomic region containing the ETS-variant gene 6 (ETV6), involved in translocations and deletions associated with hematologic malignancies. Thirty-eight cosmids were characterized belonging to two contigs spanning 340 kb, and an EcoRl restriction map was developed. The gap between the two contigs, 2 kb in size, was closed by PCR. The contigs contain the complete coding sequence and the 5' and 3' UTRs of ETV6. Eight exons accounting for the ETV6 cDNA sequence were identified. The helix-loop-helix (HLH) motif is coded by exons 3 and 4, whereas exons 6-8 code for the ETS DNA-binding domain. All introns show consensus 5' donor and 3' acceptor splice sites. Introns 1 and 2 span 100 and 82 kb, respectively, and introns 3-7 range from 15 to 1.3 kb. An alternative exon 1 (exon 1B) is localized in intron 2. The 5' end of the ETV6 gene is associated with a CpG island characterized by the presence of four Notl, four Sacll, and three BssHll recognition sites and several SP1- and AP2-binding motifs. Alternative polyadenylation at the 3' end of the ETV6 gene generates the three transcripts of 6200, 4300, and 2400 nucleotides, respectively. The ETV6 gene spans 240 kb and is flanked at its 5' and 3' end by D12S1697 and D12S98, respectively. The markers D12S1095 and D12S89 are located in the first intron. Two new DNA polymorphisms were identified in the ETV6 gene, which will be useful for the analysis of loss of heterozygosity reported for the ETV6 gene in leukemia.
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PMID:Genomic organization of TEL: the human ETS-variant gene 6. 874 90

Previously we have shown that glucocorticoid sensitivity could be restored to a clone of glucocorticoid-resistant leukemic T cells by transfecting them with an expression vector for the glucocorticoid receptor. Furthermore, transfection with plasmids expressing fragments of the receptor containing the DNA-binding domain resulted in constitutive loss of cells. In this paper, we report the results of transfecting both types of constructs into lines of glucocorticoid-resistant human leukemic cells of T cell, B cell, and myeloid origin. In all the lymphoid lines tested, transfection of the holoreceptor gene resulted in appearance of steroid-dependent cell death. In the same lines, transfection of glucocorticoid receptor fragments expressing amino acids 1-465* (465 residues of the normal sequence plus a novel 21 amino acid C-terminus) or expressing only 398-465* caused cell death without the addition of steroids. The amount of cell loss following transfection of these constitutively lethal fragments was in the same range as that following transfection of the holo glucocorticoid receptor plus administration of glucocorticoid. However, the cell loss due to the constitutively active fragments occurred more rapidly. Neither of the myeloid lines tested were sensitive to any of the transfected constructs, with or without added steroid.
Leukemia 1996 Nov
PMID:Transfected glucocorticoid receptor and certain GR fragments evoke cell death in malignant lymphoid, not myeloid cell lines. 889 83


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