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 t(6;9) that characterizes a specific subtype of ANLL fuses the 3' part of a gene located on chromosome 9q34, CAN, to the 5' part of a gene located on chromosome 6p23, DEK. On the 6p- chromosome, the resulting DEK-CAN fusion gene is transcribed into a leukaemia-specific 5.5 kb chimaeric mRNA that encodes a putative DEK-CAN fusion protein. No transcription could be detected from the reciprocal CAN-DEK fusion on chromosome 9q+. Analysis of 17 t(6;9) ANLL cases showed that the translocation breakpoints occur in a single intron of 7.5 kb in the CAN gene (ICB9) and in a single intron of 9 kb in the DEK gene (ICB6). As a result, the presence of a t(6;9) in blood or bone marrow cells can be faithfully diagnosed by Southern blotting. Moreover, the result of the translocation is an invariable DEK-CAN transcript, which can be sensitively monitored by RNA-PCR. Surprisingly, a SET-CAN fusion gene was found in leukaemic cells from a patient with AUL. Like CAN, SET is located on chromosome 9q34, which explains the apparently normal karyotype of the leukaemic cells. The occurrence of a SET-CAN fusion gene indicates that CAN may be the relevant oncogene involved in leukaemogenesis, and that activation of CAN can be effectuated through fusion of its 3' part to either DEK or SET. As yet, the function of CAN, DEK or SET is unknown. None of the proteins shows consistent homology to any known protein sequences. However, preliminary localization data and analysis of sequence motifs suggested that DEK-CAN may have a role in transcription regulation. CAN contains several dimerization domains and a repeated motif that can function as an ancillary DNA-binding domain. DEK and SET are non-related proteins, but they share a stretch of acidic amino acids, which is also present in the fusion proteins.
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PMID:Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene. 130 67

The genome of the avian leukemia virus E26 is a unique example of association between two transcription factors which appear as a fused composite nuclear oncoprotein, P135gag-myb-ets. Previous studies with E26 have shown that v-myb and v-ets must cooperate to fully transform both erythrocytic and myelomonocytic precursor cells in vivo and in vitro. To analyse further the contribution of the individual domains involved in the transformation of various hematopoietic lineages, we have constructed several mutant viruses expressing a fusion protein with deletions in either v-myb or v-ets. We show here that integrity of the v-ets oncogene is necessary for transformation of the erythrocytic cells but that neither the DNA-binding domain nor the trans-activating domain of v-myb is required for this transformation. The DNA-binding domain of v-ets is necessary to transform myelomonocytic cells. Furthermore, we show that E26 onco-protein also transforms granulocytic cells. The v-ets DNA-binding domain is not necessary to transform them, whereas deleting the v-myb DNA-binding domain strongly reduces transformation of these cells. These data show that the v-myb and v-ets DNA-binding domains provide quite different contributions to the transformation of various hematopoietic lineages by E26.
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PMID:The various domains of v-myb and v-ets oncogenes of E26 retrovirus contribute differently, but cooperatively, in transformation of hematopoietic lineages. 133 35

Tax1 of human T-cell leukemia virus type 1 (HTLV-1) is a transcriptional activator for viral gene expression and is also a transforming protein through inducing the expression of several cellular genes under the control of mitogenic signals. We identified the CArG boxes as a Tax1-responsive cis-acting element for the cellular immediate early genes c-fos, egr-1, and egr-2. Using a chimeric protein consisting of the CArG-binding factor p67SRF and the heterologous DNA-binding domain of a yeast transcription factor GAL4, we demonstrated that Tax1 activates the transcriptional activity of p67SRF through the GAL4-binding site. The carboxy-terminal half of p67SRF, which lacks domains for DNA-binding, dimerization, and ternary complex formation with p62TCF, was sufficient for the activation by Tax1. Tax1 produced in Escherichia coli bound p67SRF in vitro. The complex formation in vivo was also indicated by the finding that the acidic activation domain of VP16, by fusion to p67SRF, can complement the transcriptional activation function of a mutant Tax1 in trans. Thus, Tax1 activates CArG-mediated transcription without mitogenic signals through interaction with a CArG-binding factor, p67SRF. This must be one of the primary steps by which Tax1 causes aberration in growth control of the infected cells.
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PMID:Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes. 142 72

Tax1 of human T-cell leukemia virus type 1 (HTLV-1) activates viral transcription dependent upon three 21-bp enhancer elements in the long terminal repeat. Difficulties in detecting any association of Tax1 with the viral enhancer have hampered elucidation of the molecular mechanisms of Tax1-mediated transcriptional activation. By constructing a fusion protein with the heterologous DNA-binding domain of yeast GAL4, Tax1 was shown to be a potent transcriptional activator dependent on the presence of GAL4-binding sites. Deletions of the Tax1 portion of the fusion protein revealed that almost the entire region of Tax1 (amino acids 2-337) is required for activation, and the activity correlated well with that of the viral enhancer. The GAL/Tax1 mutant lacking 41 residues of the C-terminus of Tax1, GAL/Tax1(2-312), was inactive for the viral enhancer, but activity was recovered by adding the heterologous activation domain of herpes simplex virus VP16. These results indicate that Tax1 has two distinct but overlapping functional domains for transcriptional activation and for enhancer specificity. Thus, Tax1 is thought to be a transcription factor acting in the enhancer complex rather than as a catalytic or allosteric modifier of pre-existing cellular transcription factors.
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PMID:HTLV-1 Tax has distinct but overlapping domains for transcriptional activation and for enhancer specificity. 176 79

The v-myb oncogene of avian myeloblastosis virus causes acute myelomonocytic leukemia in chickens and transforms avian myeloid cells in vitro. Its protein product p48v-myb is a nuclear, sequence-specific, DNA-binding protein which activates gene expression in transient DNA transfection studies. To investigate the relationship between transformation and trans-activation by v-myb, we constructed 15 in-frame linker insertion mutants. The 12 mutants which transformed myeloid cells also trans-activated gene expression, whereas the 3 mutants which did not transform also did not trans-activate. This implies that trans-activation is required for transformation by v-myb. One of the transformation-defective mutants localized to the cell nucleus but failed to bind DNA. The other two transformation-defective mutants localized to the cell nucleus and bound DNA but nevertheless failed to trans-activate. These latter mutants define two distinct domains of p48v-myb which control trans-activation by DNA-bound protein, one within the amino-terminal DNA-binding domain itself and one in a carboxyl-terminal domain which is not required for DNA binding.
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PMID:Transformation by v-myb correlates with trans-activation of gene expression. 216 May 80

The v-myb oncogene causes acute myelomonocytic leukemia in chickens and transforms avian myeloid cells in vitro. Its product, p48v-myb, is a short-lived nuclear protein which binds DNA. We demonstrate that p48v-myb can function as a trans activator of gene expression in transient DNA transfection assays. trans activation requires the highly conserved amino-terminal DNA-binding domain and the less highly conserved carboxyl-terminal domain of p48v-myb, both of which are required for transformation. Multiple copies of a consensus sequence for DNA binding by p48v-myb inserted upstream of a herpes simplex virus thymidine kinase promoter are strongly stimulatory for transcriptional activation by a v-myb-VP16 fusion protein but not by p48v-myb itself, suggesting that the binding of p48v-myb to DNA may not be sufficient for trans activation.
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PMID:trans activation of gene expression by v-myb. 232 52

The nucleotide sequence of a feline v-myc gene and feline leukemia virus (FeLV) flanking regions was determined. Both the nucleotide and predicted amino acid sequences are very similar to the murine and human c-myc genes (ca. 90% identity). The entire c-myc coding sequence is represented in feline v-myc and replaces portions of the gag and env genes and the entire pol gene. The coding sequence is in phase with the gag gene reading frame; v-myc, therefore, appears to be expressed as a gag-myc fusion protein. Viral sequences at the 3' myc-FeLV junction begin with the hexanucleotide CTCCTC, which is also found at the 3' fes-FeLV junction of both Gardner-Arnstein and Snyder-Theilen feline sarcoma viruses. These similarities suggest that some sequence specificity may exist for the transduction of cellular genes by FeLV. Feline v-myc lacks a potential phosphorylation site at amino acid 343 in the putative DNA-binding domain, whereas both human and murine c-myc have such sites. Avian v-myc has lost a potential phosphorylation site which is present in avian c-myc five amino acids from the potential mammalian site. If these sites are actually phosphorylated in normal c-myc proteins, their loss may alter the DNA-binding affinity of v-myc proteins.
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PMID:Nucleotide sequence of a transduced myc gene from a defective feline leukemia provirus. 298 54

We have identified and further characterized a Caenorhabditis elegans gene, CEZF, that encodes a protein with substantial homology to the zinc finger and leucine zipper motifs of the human gene products AF10, MLLT6, and BR140. The first part of the zinc finger region of CEZF has strong similarity to the corresponding regions of AF10 (66%) and MLLT6 (64%) at the cDNA level. As this region is structurally different from previously described zinc finger motifs, sequence homology searches were done. Twenty-five other proteins with a similar motif were identified. Because the functional domain of this motif is potentially disrupted in leukemia-associated chromosomal translocations, we propose the name of leukemia-associated protein (LAP) finger. On the basis of these comparisons, the LAP domain consensus sequence is Cys1-Xaa1-2-Cys2-Xaa9-21-Cys3-Xaa2-4 -Cys4-Xaa4-5-His5-Xaa2-Cys6-Xaa12-46 - Cys7-Xaa2-Cys8, where subscripted numbers represent the number of amino acid residues. We review the evidence that this motif binds zinc, is the important DNA-binding domain in this group of regulatory proteins, and may be involved in leukemogenesis.
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PMID:The leukemia-associated-protein (LAP) domain, a cysteine-rich motif, is present in a wide range of proteins, including MLL, AF10, and MLLT6 proteins. 756 8

The Ikaros gene is essential for lymphoid lineage specification. As previously reported, mice homozygous for a mutation in the Ikaros DNA-binding domain fail to generate mature lymphocytes as well as their earliest described progenitors. In addition, our studies with mice heterozygous for this mutation establish the Ikaros gene as an essential regulator of T cell proliferation. Thymocytes display augmented TCR-mediated proliferative responses, and peripheral T cells are autoproliferative. A general lymphoproliferation precedes the T cell leukemia and lymphoma that rapidly develop in all heterozygotes. The first step toward leukemic transformation occurs within the maturing thymocyte population and is demarcated by clonal expansions and loss of the single Ikaros wild-type allele. From these studies, we propose that within developing and mature T lymphocytes, distinct thresholds of Ikaros activity are required to regulate proliferation. A decrease in Ikaros activity below the first threshold causes the rapid accumulation of T lymphoblasts, whereas a further decrease leads to neoplastic transformation.
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PMID:A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. 758 46

The PU.1 transcription factor is a member of the ets gene family of regulatory proteins. These molecules play a role in normal development and also have been implicated in malignant processes such as the development of erythroid leukemia. The Ets proteins share a conserved DNA-binding domain (the ETS domain) that recognizes a purine-rich sequence with the core sequence: 5'-C/AGGAA/T-3'. This domain binds to DNA as a monomer, unlike many other DNA-binding proteins. The ETS domain of the PU.1 transcription factor has been crystallized in complex with a 16-base pair oligonucleotide that contains the recognition sequence. The crystals formed in the space group C2 with a = 89.1, b = 101.9, c = 55.6 A, and beta = 111.2 degrees and diffract to at least 2.3 A. There are two complexes in the asymmetric unit. Production of large usable crystals was dependent on the length of both protein and DNA components, the use of oligonucleotides with unpaired A and T bases at the termini, and the presence of polyethylene glycol and zinc acetate in the crystallization solutions. This is the first ETS domain to be crystallized, and the strategy used to crystallize this complex may be useful for other members of the ets family.
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PMID:Co-crystallization of an ETS domain (PU.1) in complex with DNA. Engineering the length of both protein and oligonucleotide. 759 33


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