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)

A family of nuclear proteins, designated SL3-3 enhancer factors 2 (SEF2), were found to interact with an Ephrussi box-like motif within the glucocorticoid response element in the enhancer of the murine leukemia virus SL3-3. Mutation of the DNA sequence decreased the basal enhancer activity in various cell lines. The important nucleotides for binding of SEF2 are conserved in most type C retroviruses. Various cell types displayed differences both in the sets of SEF2-DNA complexes formed and in their amounts. A cDNA which encoded a protein that interacted specifically with the SEF2-binding sequence was isolated from human thymocytes. The nucleotide sequence specificity of the recombinant protein, expressed in Escherichia coli, corresponded to that of at least one of the nuclear SEF2 proteins. Sequence analysis of the cDNA revealed that it belongs to the basic helix-loop-helix class of DNA-binding proteins. Several mRNA transcripts of different sizes were identified. Molecular analysis of cDNA clones revealed multiple related mRNA species containing alternative coding regions, which are most probably a result of differential splicing.
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PMID:Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers. 168 Nov 16

The human T-cell leukemia virus type I oncoprotein Tax transcriptionally deregulates a wide variety of viral and cellular genes. Tax deregulation of gene expression is mediated through interaction with a variety of structurally unrelated cellular transcription factors, as Tax does not bind DNA in a sequence-specific manner. Although most of these cellular transcription factors have been shown to mediate activation by Tax, we have recently demonstrated that members of the basic helix-loop-helix (bHLH) family of transcription factors, which play a critical role in progression through the cell cycle, mediate repression by Tax. In this report, we examined whether Tax might repress transcription of the tumor suppressor p53, as the p53 gene has recently been demonstrated to be regulated by the bHLH protein c-Myc. Furthermore, loss or inactivation of the p53 gene has been shown to be causally associated with oncogenic transformation. We show that Tax represses transcription of the p53 gene and that this repression is dependent upon the bHLH recognition element in the p53 promoter. Together, these results suggest that Tax may promote malignant transformation through repression of p53 transcription.
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PMID:Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein. 749 59

The RBTN2 LIM-domain protein, originally identified as an oncogenic protein in human T-cell leukemia, is essential for erythropoiesis. A possible role for RBTN2 in transcription during erythropoiesis has been investigated. Direct interaction of the RBTN2 protein was observed in vivo and in vitro with the GATA1 or -2 zinc-finger transcription factors, as well as with the basic helix-loop-helix protein TAL1. By using mammalian two-hybrid analysis, complexes involving RBTN2, TAL1, and GATA1, together with E47, the basic helix-loop-helix heterodimerization partner of TAL1, could be demonstrated. Thus, a molecular link exists between three proteins crucial for erythropoiesis, and the data suggest that variations in amounts of complexes involving RBTN2, TAL1, and GATA1 could be important for erythroid differentiation.
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PMID:Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. 756 77

A basic helix-loop-helix phosphoprotein gene, G0S8, was recently isolated by differential screening of cDNA from human blood mononuclear cells stimulated with a T cell mitogen and cycloheximide. In this study, G0S8 expression was examined in normal and malignant hematopoietic cells by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). G0S8 expression was observed in most fresh samples of acute myelogenous leukemia (AML) (28/30) and most cases of adult acute lymphoblastic leukemia (ALL) (9/11) regardless of clinical classification. G0S8 mRNA was also detected in all cases tested of chronic myelogenous leukemia (CML) in blast crisis. However, G0S8 expression was not detected in CML patients in chronic phase, nor in normal bone marrow or other hematopoietic cells. G0S8 has been mapped using fluorescence in situ hybridization (FISH) to human chromosome 1q31, the same site reported for the B cell homolog BL34/1R20 and within a region implicated in the development of hematological malignancies. The consistent observation of G0S8 mRNA in patient samples of acute leukemia suggests that G0S8 expression may either play a role in leukemogenesis or represent a common consequence of dysregulated growth.
Leukemia 1995 Aug
PMID:Differential expression of a basic helix-loop-helix phosphoprotein gene, G0S8, in acute leukemia and localization to human chromosome 1q31. 764 15

The genomes of most recombinant murine leukemia viruses (MuLVs) inherit pathogenic U3 region sequences from the endogenous xenotropic provirus Bxv-1. However, the U3 regions of about one-third of recombinant MuLVs from CWD mice, such as CWM-T15, have nonecotropic substitutions that are probably derived from an endogenous polytropic provirus. The CWM-T15 U3 region sequences contain five nucleotide substitutions compared with the less pathogenic sequences of the endogenous ecotropic virus parent, Emv-1. Three of these substitutions are located immediately 3' of the enhancer core, and two form part of an E-box motif that is also found in the Bxv-1 sequence. A series of electromobility shift assays revealed that nuclear extracts from S194 cells and the basic helix-loop-helix transcription factor E47 could distinguish between oligonucleotides that contained the core region sequences of CWM-T15 or Emv-1. The E47 homodimers appeared to bind to the CWM-T15 E-box motif and when expressed at high levels in cells transactivated the CWM-T15 but not the Emv-1 enhancer. Taken together, these results suggest that E47 or related basic helix-loop-helix proteins that are expressed in lymphoid cells bind to and transactivate the CWM-T15 enhancer in vivo. This transactivation may explain why the CWM-T15 and Bxv-1 U3 regions accelerate the onset of lymphoid neoplasms and why related enhancer core region sequences are preferentially incorporated into the genomes of recombinant MuLVs and are found in other leukemogenic mammalian retroviruses.
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PMID:The E47 transcription factor binds to the enhancer sequences of recombinant murine leukemia viruses and influences enhancer function. 776 73

The protein products of proto-oncogenes implicated in T cell acute lymphoblastic leukemia include two distinct families of presumptive transcription factors. RBTN1 and RBTN2 encode highly related proteins that possess cysteine-rich LIM motifs. TAL1, TAL2 and LYL1 encode a unique subgroup of basic helix-loop-helix (bHLH) proteins that share exceptional homology in their bHLH sequences. We have found that RBTN1 and RBTN2 have the ability to interact with each of the leukemogenic bHLH proteins (TAL1, TAL2 and LYL1). These interactions occur in vivo and appear to be mediated by sequences within the LIM and bHLH domains. The LIM-bHLH interactions are highly specific in that RBTN1 and RBTN2 will associate with TAL1, TAL2 and LYL1, but not with other bHLH proteins, including E12, E47, Id1, NHLH1, AP4, MAX, MYC and MyoD1. Moreover, RBTN1 and RBTN2 can interact with TAL1 polypeptides that exist in assembled bHLH heterodimers (e.g. TAL1-E47), suggesting that the RBTN proteins can influence the functional properties of TAL1. Finally, we have identified a subset of leukemia patients that harbor tumor-specific rearrangements of both their RBTN2 and TAL1 genes. Thus, the activated alleles of these genes may promote leukemia cooperatively, perhaps as a result of bHLH-LIM interactions between their protein products.
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PMID:Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. 795 52

Recombinant murine leukemia viruses (MuLVs) from high-leukemia-incidence mouse strains typically acquire pathogenic U3 region sequences from the genome of the endogenous xenotropic virus, Bxv-1. However, a recombinant virus isolated from a leukemic HRS/J mouse and another from a CWD mouse contained U3 regions that lacked genetic markers of Bxv-1. The U3 regions of both recombinants were derived from the endogenous ecotropic virus Env-1 and had retained a single enhancer element. However, compared with that of Emv-1, the U3 region of each of the recombinant viruses contained five nucleotide substitutions, one of which was shared. To determine the biological significance of these substitutions, chimeric ecotropic viruses that contained the U3 region from one of the two recombinant viruses or from Emv-1 were injected into NIH Swiss mice. All three of the chimeric ecotropic viruses were leukemogenic following a long latency. Despite the presence of an enhancer core motif that is known to contribute to the leukemogenicity of the AKR MuLV SL3-3, the HRS/J virus U3 region induced lymphomas only slightly more rapidly than the allelic Emv-1 sequences. The chimeric virus with the U3 region of the CWD recombinant caused lymphomas more frequently and more rapidly than either of the other two viruses. The results support the hypothesis that one or more of the five nucleotide substitutions in the U3 regions of the recombinants contribute to viral pathogenicity. Comparison of DNA sequences suggests that the pathogenicity of the CWD virus U3 region was related to a sequence motif that is shared with Bxv-1 and is recognized by the basic helix-loop-helix class of transcription factors.
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PMID:Pathogenic determinants in the U3 region of recombinant murine leukemia viruses isolated from CWD and HRS/J mice. 803 16

E boxes, recognition sequences for basic helix-loop-helix (bHLH) transcription factors, are detected in the enhancer and promoter regions of several murine type C retroviruses. Here we show that ALF1, a member of bHLH protein family of transcription factors, in vitro binds with differing affinities to distinct E-box sequences found in the U3 regulatory regions of Friend, Moloney, SL3-3, and Akv murine leukemia viruses (MLVs) as well as Friend spleen focus-forming virus (SFFV). In NIH 3T3 fibroblasts, ALF1 overexpression elevated transcription from the U3 region of Moloney MLV and the complete long terminal repeat regions of Friend SFFV, Akv MLV, and SL3-3 MLV but neither from the U3 region nor from the complete long terminal repeat of Friend MLV. Introduction of mutations in the Akv MLV E boxes showed the E-box cis elements to be required for the function of ALF1 as a transcription factor. ALF1 and the glucocorticoid receptor, with overlapping DNA binding sequences, did not act synergistically with respect to transcriptional trans activation of expression from the Akv MLV promoter-enhancer region. We conclude that ALF1 in vivo may be an important transcription regulator for Akv, SL3-3, and Moloney MLVs as well as for Friend SFFV.
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PMID:Basic helix-loop-helix proteins in murine type C retrovirus transcriptional regulation. 805 44

The human T-cell leukemia virus type I (HTLV-I) oncoprotein Tax is a potent activator of viral and cellular gene transcription. Tax does not bind DNA directly but utilizes cellular transcription factors to mediate activation. In this report, we examine the role of the basic helix-loop-helix (bHLH) proteins in Tax deregulation of gene expression, as these proteins play a critical role in progression through the cell cycle and have been implicated in neoplastic disease. We show that the bHLH proteins do not mediate activation, but instead mediate repression of gene expression in the presence of Tax. We further show that a consensus bHLH binding site in the promoter of the beta-polymerase gene, which encodes an enzyme involved in DNA repair, mediates the previously reported repression of beta-polymerase gene expression by Tax. Together, these results suggest that Tax may induce malignant transformation, at least in part, through bHLH-mediated repression of key cellular regulatory genes.
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PMID:Human T-cell leukemia virus type I Tax protein represses gene expression through the basic helix-loop-helix family of transcription factors. 807 90

Activation of the SCL (or TAL-1) gene as a result of chromosomal translocation or deletion is a frequent molecular lesion in acute T-cell leukemia. By virtue of its membership in the basic helix-loop-helix family of transcription factors, the SCL gene is a candidate to regulate events in hematopoietic differentiation. We have used polyclonal antibody raised against a bacterial expressed malE-SCL fusion protein to characterize SCL protein expression in postimplantation embryos and in neonatal and adult mice. SCL protein was detected at day 7.5 post coitum at both embryonic and extraembryonic sites, approximately 24 hours before the formation of recognizable hematopoietic elements. Expression then localized to blood islands of the yolk sac followed by localization to fetal liver and spleen, paralleling the hematopoietic activity of these tissues during development. SCL protein was detected in erythroblasts in fetal and adult spleen, myeloid cells and megakaryocytes in spleen and bone marrow, mast cells in skin, and in rare cells in fetal and adult thymus. In addition, SCL protein was noted in endothelial progenitors in blood islands and in endothelial cells and angioblasts in a number of organs at times coincident with their vascularization. SCL expression was also observed in other nonhematopoietic cell types in the developing skeletal and nervous systems. These results show that SCL expression is one of the earliest markers of mammalian hematopoietic development and are compatible with a role for this transcription factor in terminal differentiation of the erythroid and megakaryocytic lineages. SCL expression by cells in the thymus suggests that the gene may be active at some stage of T-cell differentiation and may be relevant to its involvement by chromosomal rearrangements in T-lymphoid leukemias. Finally, expression of the gene in developing brain, cartilage, and vascular endothelium indicates SCL may have actions in neural development, osteogenesis, and vasculogenesis, as well as in hematopoietic differentiation.
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PMID:The SCL/TAL-1 gene is expressed in progenitors of both the hematopoietic and vascular systems during embryogenesis. 811 24


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