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)

HMG I(Y) proteins bind to double-stranded A + T oligonucleotides longer than three base pairs. Such motifs form part of numerous NF-AT-binding sites of lymphokine promoters, including the interleukin 4 (IL-4) promoter. NF-AT factors share short homologous peptide sequences in their DNA-binding domain with NF-kappa B factors and bind to certain NF-kappa B sites. It has been shown that HMG I(Y) proteins enhance NF-kappa B binding to the interferon beta promoter and virus-mediated interferon beta promoter induction. We show that HMG I(Y) proteins exert an opposite effect on the DNA binding of NF-AT factors and the induction of the IL-4 promoter in T lymphocytes. Introduction of mutations into a high-affinity HMG I(Y)-binding site of the IL-4 promoter, which decreased HMG I(Y)-binding to a NF-AT-binding sequence, the Pu-bB (or P) site, distinctly increased the induction of the IL-4 promoter in Jurkat T leukemia cells. High concentrations of HMG I(Y) proteins are able to displace NF-ATp from its binding to the Pu-bB site. High HMG I(Y) concentrations are typical for Jurkat cells and peripheral blood T lymphocytes, whereas E14 T lymphoma cells and certain T helper type 2 cell clones contain relatively low HMG I(Y) concentrations. Our results indicate that HMG I(Y) proteins do not cooperate, but instead compete with NF-AT factors for the binding to DNA even though NF-AT factors share some DNA-binding to DNA even though NF-AT factors share some DNA-binding properties with NF-kB factors. This competition between HMG I(Y) and NF-AT proteins for DNA binding might be due to common contacts with minor groove nucleotides of DNA and may be one mechanism contributing to the selective IL-4 expression in certain T lymphocyte populations, such as T helper type 2 cells.
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PMID:HMG I(Y) interferes with the DNA binding of NF-AT factors and the induction of the interleukin 4 promoter in T cells. 898 8

Rhombotin-2 (RBTN-2) is a proto-oncogene only in the context of T lymphocytes. We postulated that the oncogenic effect of RBTN-2 in T cells is likely mediated by binding protein(s) with T cell-specific expression. By screening a T cell cDNA library, we identified a novel ets transcription factor that binds RBTN-2. This protein was named elf-2 because its DNA-binding domain is virtually identical to that of ets family member elf-1. Northern analyses showed similar levels of two elf-2 transcripts (3.5 kb and 3.8 kb) in all tissues except thymus. Thymocytes expressed four- to 10-fold greater amounts of the 3.5 kb transcript than other tissues. Sequence analyses of cDNA clones indicated that these transcripts encode proteins differing only at their amino termini, and likely represent alternatively spliced isoforms. These isoforms (elf-2a and elf-2b) contain identical RBTN-2 binding regions and DNA-binding domains. Elf-2b lacks a putative transactivation domain. The expression patterns suggest that RBTN-2 normally interacts equally with elf-2a and elf-2b. In contrast, when RBTN-2 is inappropriately expressed in T cells, RBTN-2 would interact predominantly with elf-2b; this interaction may lead to T cell proliferation.
Leukemia 1997 Jan
PMID:Elf-2, a rhombotin-2 binding ets transcription factor: discovery and potential role in T cell leukemia. 900 22

EVI1, located at chromosome band 3q26, encodes a 1051 amino acid zinc finger protein inappropriately expressed in the leukemic cells of 2-5% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. The activation of EVI1 often follows a chromosomal rearrangement involving band 3q26, and the two most frequent rearrangements are the t(3;3)(q21;q26) and the inv(3)(q21q26). EVI1 exists also as a longer protein that includes 188 additional amino acids at the N-terminus, named MDS1/EVI1. Both genes are expressed at very low levels in the normal bone marrow. The genomic region between the first coding exon of MDS1/EVI1 and the first coding exon of EVI1 is 150-300 kb. The majority of the chromosomal breakpoints at the 5' end of EVI1 in the t(3;3) resulting in EVI1 activation have been mapped in this region. As a consequence of the t(3;3), the cell would be unable to express MDS1/EVI1, although it would express EVI1. We have compared the transcriptional activity of MDS1/EVI1 and EVI1, and we show that MDS1/EVI1 is a strong activator of promoters containing the AGATA motif, whereas EVI1 is a repressor. In addition, whereas EVI1 represses activation by the GATA-1 erythroid factor, MDS1/EVI1 does not, and is itself repressed by EVI1. By gene fusion to the DNA-binding domain of Gal4, we further show that the activation properties of MDS1/EVI1 are restricted to an acidic segment encoded by the second and third exons in the 5' untranslated region of EVI1. We have also examined the relative expression of the two genes in normal bone marrow and in the bone marrow of leukemia patients with 3q26 rearrangements. Our results indicate that the rearrangements at 3q26 affect expression of EVI1, but not of MDS1/EVI1. We propose that rearrangements at 3q26 involving EVI1 could result in leukemia by a two-step process involving first transcriptional disruption of MDS1/EVI1, and next by inappropriately activating expression of EVI1.
Leukemia 1997 Mar
PMID:The leukemia-associated gene MDS1/EVI1 is a new type of GATA-binding transactivator. 906 73

Retinoid-induced proliferation causing hyperleukocytosis is a severe complication of retinoid therapy in t(15;17) acute promyelocytic leukaemia. The molecular basis of this phenomenon is unknown. It is possible that the transiently enhanced cell proliferation results from RA-induction of growth regulatory genes. Using Differential Display of cDNAs from NB4 cells we have identified Jem, a novel gene transcript which is upregulated by retinoids during the early proliferative response in maturating cells but not in resistant cells. A 2.7 kb cDNA was cloned and sequenced. The open reading frame contains a 400 amino acid sequence corresponding to a novel 45 kDa basic protein (pI 8.9). The JEM DNA sequence is detected by FISH on human chromosome 1 at q24. The Jem peptide sequence shows a 'leucine-zipper' dimerisation motif with limited homology to Fos/Jun and ATF/CREB proteins and several putative phosphorylation sites. An atypical basic region may correspond to an unknown DNA-binding domain. The C-terminal end of Jem spans a long stretch featuring a PEST motif. After transfection into COS cells, the Jem protein shows a ponctuated nuclear localisation. We hypothesise that this novel nuclear factor may act as a transcription factor, or a coregulator, involved in either cell growth control and/or maturation.
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PMID:JEM-1, a novel gene encoding a leucine-zipper nuclear factor upregulated during retinoid-induced maturation of NB4 promyelocytic leukaemia. 912 47

The yeast one-hybrid and two-hybrid systems for the detection of protein-DNA and protein-protein interactions were used as an in vivo approach to investigate the functional characteristics of HTLV-1 Tax expressed in yeast. Tax, when targeted to the upstream activating sequence (UAS) via the DNA-binding domain of Gal4 (Gal4BD), was found to activate a minimal promoter in yeast, indicating the presence of a functionally intact activation domain. Using the two-hybrid assay in which Tax was fused to either Gal4BD or Gal4 activation domain (Gal4AD), we demonstrate that Tax self-associates in the nucleus of yeast cells. Mutational analysis was performed to delineate the functional domain(s) necessary for Tax-mediated trans-activation and self-association. Based on our results, we propose a pleiotropic mechanism in which Tax facilitates protein-protein dimerization of various cellular partners.
Leukemia 1997 Apr
PMID:Transcriptional activation and self-association in yeast: protein-protein dimerization as a pleiotropic mechanism of HTLV-I Tax function. 920 79

The AML1 is the most commonly involved transcription factor gene in human leukemias and forms chimeric transcription factor genes, namely, AML1/MTG8 by the t(8;21), AML1/EVI-1 by the t(3;21), and TEL/AML1 by the t(12;21). The AML1a and AML1b, two isoforms of the AML1 protein, are translated from the AML1 gene by the alternative splicing. The shorter form and longer form are named as AML1a and AML1b, respectively. The AML1b contains the runt homology domain as a DNA-binding domain and the serine/proline/threonine-rich domain (PST domain) as a putative transactivation domain. The AML1a contains only the runt homology domain, but not the PST domain. The AML1b has a transactivation ability through the PEBP2 site and stimulates differentiation of myeloid cells. On the other hand, AML1a cna bind the PEBP2 site, but does not show a transactivation ability through the PEBP2 site. The AML1a dominantly suppresses transactivation induced by the AML1b and has the ability to block differentiation of myeloid cells. It is a reasonable hypothesis that the molecular ratio of AML1a to AML1b in myeloid cells could determine whether they proliferate or undergo a terminal differentiation.
Leukemia 1997 Apr
PMID:Leukemogenesis by the chromosomal translocations. 920 70

The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) translocations associated with myelogenous leukemias and encodes a DNA-binding protein. From AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by an alternative splicing. Both forms have DNA-binding domain, but AML1a lacks a putative transcriptional activation domain which AML1b has. Here we demonstrate that AML1a, which solely has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and that AML1a exhibits the higher affinity for DNA-binding than AML1b. Furthermore a dominant negative form of AML1, AML1a, totally suppressed granulocytic differentiation otherwise induced by granulocyte colony-stimulating factor when AML1a was overexpressed in 32Dc13 murine myeloid cells. Such differentiation block by AML1a was canceled by the concomitant overexpression of AML1b. These data strongly suggest that a transcriptionally active form of AML1 is essential for the myeloid cell differentiation. In addition, we observed an altered expression level of AML1 along with the myeloid differentiation in several hemopoietic cell lines. In these cases, at least, the AML1 expression level is a potential regulator for myeloid cell differentiation.
Leukemia 1997 Apr
PMID:An acute myeloid leukemia gene, AML1, regulates transcriptional activation and hemopoietic myeloid cell differentiation antagonistically by two alternative spliced forms. 920 72

The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA.
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PMID:Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. 948 55

The chimeric receptor, RARalpha/VDR, contains the DNA-binding domain of the retinoic acid receptor (RARalpha) and the ligand-binding domain of the vitamin D receptor (VDR). The ligand-binding properties of RARalpha/VDR are equivalent to that of VDR, with an observed Kd for 1alpha,25 dihydroxy-vitamin D3 (D3) of 0.5 nM. In CV-1 cells, both RARalpha and RARalpha/VDR induce comparable levels of ligand-mediated transcriptional activity from the retinoic acid responsive reporter gene, beta(RARE)3-TK-luciferase, in the presence of the ligand predicted from the receptor ligand-binding domain. Two chimeric RAR receptors were constructed which contained the ligand-binding domain of the estrogen receptor (ER): RARalpha/ER and ER/RARalpha/ER. Both RARalpha/ER and ER/RARalpha/ER bind beta-estradiol with high affinity, and are transcriptionally active only from palindromic RAREs (TREpal and/or (TRE3)3). Only RARalpha/VDR matched in kind and degree the functional characteristics of RARalpha: (1) maximally active from the beta(RARE); (2) moderately active from the TREs; (3) inactive from the retinoic X receptor response elements (RXREs) ApoA1 and CRBP II; (4) forms heterodimers with RXRalpha; and (5) binds to the betaRARE. F9 embryonal carcinoma cell lines were generated which express RARalpha/VDR mRNA (F9RARalpha/VDR cells) and compared with F9 wild-type (F9-Wt) cells, which do not express VDR mRNA. Treatment with all-trans retinoic acid (tRA) inhibits cell growth and induces the differentiation morphology in both F9-Wt and F9-RARalpha/VDR cells; whereas, treatment with D3 is similarly effective only for F9-RARalpha/VDR cells. It is concluded RARalpha/VDR is an useful 'tool' to pinpoint, or to augment transcription from RAREs in gene pathways controlled by RAR without inhibiting the retinoid responsiveness of endogenous RARs.
Leukemia 1998 Apr
PMID:Characterization of the chimeric retinoic acid receptor RARalpha/VDR. 955 14

The expression of human T-cell leukemia virus type 1 (HTLV-1) is activated by interaction of a viral transactivator protein, Tax, and cellular transcription factor, CREB (cyclic AMP response element binding protein), which bind to a 21-bp enhancer in the long terminal repeats (LTR). THP (Tax-helping protein) was previously determined to enhance the transactivation by Tax protein. Here we report novel forms of the human homolog of a member of the Gli oncogene family, Gli2 (also termed Gli2/THP), an extended form of a zinc finger protein, THP, which was described previously. Four possible isoforms (hGli2 alpha, beta, gamma, and delta) are formed by combinations of two independent alternative splicings, and all the isoforms could bind to a DNA motif, TRE2S, in the LTR. The longer isoforms, alpha and beta, were abundantly expressed in various cell lines including HTLV-1-infected T-cell lines. Fusion proteins of the hGli2 isoforms with the DNA-binding domain of Gal4 activated transcription when the reporter contained a Gal4-binding site and one copy of the 21-bp sequence, to which CREB binds. This activation was observed only in the presence of Tax. The 21-bp sequence in the reporter was also essential for the activation. These results suggest that simultaneous binding of hGli2 and CREB to the respective sites in the reporter seems to be critical for Tax protein to activate transcription. Consequently, it is probable that the LTR can be regulated by two independent signals through hGli2 and CREB, since the LTR contains the 21-bp and TRE2S sequences in the vicinity.
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PMID:Cloning of novel isoforms of the human Gli2 oncogene and their activities to enhance tax-dependent transcription of the human T-cell leukemia virus type 1 genome. 955 82


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