Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 three 21-bp repeats (Tax-responsive elements) of the long terminal repeat (LTR) of the human T-cell leukemia virus (HTLV-I) mediates the response of the Tax protein. All three Tax-responsive elements (TREs) contain a TGACG motif, reminiscent of the CREB/ATF-binding site TGACGTCA. DNA-affinity chromatography with the 5'-TRE resulted in a previous study in proteins of about 32, 36 to 42, 50 and 110 kDa. Here we demonstrate that the 42 kDa protein is the cAMP-response element-binding (CREB) protein. This is shown by phosphorylation of the proteins eluted from the DNA-affinity column with protein kinase A (PKA) in vitro and subsequent indirect immunoprecipitation with a CREB-specific antiserum raised against an internal CREB-specific peptide. This method allows detection of phosphorylated proteins by autoradiography with high sensitivity and is superior to metabolic labeling. One of the phosphorylated proteins co-migrates with immuno-affinity-purified CREB protein--also phosphorylated in vitro--and competes with the peptide antigen, which proves the specificity of the reaction. The purified CREB protein leads to specific DNA-protein complexes in DNA mobility-shift analyses with all three TREs. Comparison of these TRE-CREB complexes with those formed by nuclear extracts from the HTLV-I-transformed T-cell line C81-66-45 indicates that additional cellular factors contribute to the complexes, especially to the middle TRE. This is also shown by using CREB-depleted instead of complete nuclear extracts for DNA mobility-shift assays. Antibodies against CREB but not Tax affect the mobility of the DNA-protein complex.
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PMID:Direct interaction of CREB protein with 21 bp Tax-response elements of HTLV-ILTR. 153 42

The human T-cell leukemia virus type I (HTLV-I) promoter contains three copies of imperfect repeats of a 21-base pair sequence designated here as TRE (Tax-response element) that is responsive to the virally encoded transactivator protein Tax. We have identified and separated four nuclear proteins from C81-66-45 cells, an HTLV-I immortalized Tax-expressing human T-lymphocyte line (Salahuddin et al., 1983), that interact with the TRE-DNA, none of which are identical with the Tax-protein. The proteins identified have molecular weights of about 32, 36 to 42, 50 and 110 kD. Four different methods were used to identify the proteins. First, from different cell lines three or all four of the nuclear proteins were specifically cross-linked by UV irradiation to the radioactively labeled TRE-DNA fragment. Second, TRE-DNA binding proteins sedimented through a glycerol density gradient at rates corresponding to proteins of native molecular weights of 35 to 50 kD and 110 kD. Third, only the 50 kD protein was retained on a biotinylated DNA-streptavidin matrix when the DNA fragment contained the TRE-DNA. Fourth, extensive purification by several cycles of TRE-DNA affinity chromatography resulted in the 32, 36 to 42 and 110 kD proteins and to less extent the 50 kD factor. Two abundant proteins of 75 and 80 kD were competed out by poly[d(I-C)] in all reactions. The cAMP-response element CRE, TGACGTCA, present in the 21 base-pair sequence, appears to be essential for specific protein-TRE-DNA interactions because mutation of the two G's destroys this complex. This result suggests that the cAMP response element binding protein, CREB, is involved in the protein-TRE-DNA complex and in mediating the Tax response.
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PMID:Tax-independent binding of multiple cellular factors to Tax-response element DNA of HTLV-I. 231 99

Two cis-acting promoter elements (-108 to -100 and -49 to -33) of the mouse alpha A-crystallin gene, which is highly expressed in the ocular lens, were studied. Here we show that DE1 (-108 to -100; 5'TGACGGTG3'), which resembles the consensus cyclic AMP (cAMP)-responsive element sequence (CRE; 5'TGACGT[A/C][A/G]3'), behaves like a functional CRE site. Transfection experiments and electrophoretic mobility shift assays (EMSAs) using site-specific mutations correlated a loss of function with deviations from the CRE consensus sequence. Results of EMSAs in the presence of antisera against CREB, delta CREB, and CREM were consistent with the binding of CREB-like proteins to the DE1 sequence. Stimulation of alpha A-crystallin promoter activity via 8-bromo-cAMP, forskolin, or human T-cell leukemia virus type I Tax1 in transfections and reduction of activity of this site in cell-free transcription tests by competition with the somatostatin CRE supported the idea that DE1 is a functional CRE. Finally, Pax-6, a member of the paired-box family of transcription factors, activated the mouse alpha A-crystallin promoter in cotransfected COP-8 fibroblasts and bound to the -59 to -29 promoter sequence in EMSAs. These data provide evidence for a synergistic role of Pax-6 and CREB-like proteins for high expression of the mouse alpha A-crystallin gene in the lens.
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PMID:Transcriptional regulation of the mouse alpha A-crystallin gene: activation dependent on a cyclic AMP-responsive element (DE1/CRE) and a Pax-6-binding site. 782 34

The human T-cell leukemia virus type I (HTLV-I) Tax protein increases the DNA binding activity of a number of different host cell transcription factors, including the cyclic AMP response element binding protein (CREB). We have performed quantitative studies of CREB binding in the presence and absence of Tax in an attempt to gain insight into the mechanism of the Tax effect. Enhancement of binding occurred over a wide range of CREB concentrations, but sharply increased at the lowest concentrations tested. The data are best explained by a two-step binding model where Tax changes the apparent equilibrium constants for both a CREB-CREB dimerization step and a (CREB)2-DNA binding step. We used the model to perform a quantitative analysis of the binding of CREB to DNA that had been mutated at positions flanking the core CREB recognition site. Results suggest that there are altered or more extensive DNA-protein contacts at these positions in the presence of Tax. We also used the model to analyze differences in the interaction of Tax with nonphosphorylated and protein kinase A-phosphorylated CREB protein. There was no significant change in the behavior of CREB upon phosphorylation.
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PMID:Quantitative studies of the effect of HTLV-I Tax protein on CREB protein--DNA binding. 806 35

The Tax protein, encoded by the human T-cell leukemia virus type I, is a potent activator of viral and cellular gene transcription. Tax does not bind DNA directly but appears to trans-activate through an interaction with host-cell transcription factors that recognize sequences within the promoters of Tax-responsive genes. Cellular transcriptional activators implicated in mediating Tax trans-activation include members of the activating transcription factor/cAMP response element binding protein (ATF/CREB) family of proteins, serum response factor, Fos-Jun, and NF-kappa B. Recent evidence suggests that Tax may stimulate human T-cell leukemia virus type I transcription, at least in part, through enhanced binding of ATF/CREB proteins to their recognition elements within the Tax-responsive 21-bp repeats of the viral promoter. In this report, we demonstrate that Tax also enhances the site-specific DNA binding activity of serum response factor and Fos-Jun and modestly enhances the binding of the NF-kappa B subunits, p50 and p65. We also show that Tax increases the DNA binding activity of the eukaryotic transcription factors ATF-1, Sp1, and GAL4. These results are consistent with the finding that Tax is highly pleiotropic and suggest that Tax trans-activation may involve enhancement in the DNA binding activity of target transcriptional regulatory proteins. In addition, we show that the mechanism of Tax-enhanced DNA binding activity does not involve an alteration in the redox state of the target protein.
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PMID:Pleiotropic effect of the human T-cell leukemia virus Tax protein on the DNA binding activity of eukaryotic transcription factors. 834 48

The regulation of human T-cell leukemia virus type 1 (HTLV-1) gene expression is dependent on three cis-acting elements, known as the 21-bp repeats, in the long terminal repeat. Each of the 21-bp repeats contains a nonpalindromic cyclic AMP response element (CRE) sequence which is capable of binding members of the ATF/CREB family of transcription factors. The HTLV-1 transactivator protein Tax is able to markedly stimulate the in vitro binding of CREB to the CRE sites present in each of the 21-bp repeats but not to CRE sites present in cellular promoters. The ability to Tax to stimulate CREB binding to different CRE sites correlates with the ability of Tax to activate gene expression from these sites. We wished to determine how sequence differences between the somatostatin CRE and the 21-bp repeat were involved in this different response to Tax. Scatchard analysis indicated that CREB bound to the somatostatin CRE with a single class of high-affinity binding while CREB bound to the 21-bp repeats with a biphasic binding pattern, indicating the presence of both low- and high-affinity binding. Tax increased the affinity of CREB binding but not that of another ATF/CREB protein, CREB2, to the 21-bp repeat. However, Tax did not increase affinity of binding of CREB to the somatostatin CRE. To determine the mechanism by which Tax increased dCREB binding affinity, immobilized oligonucleotides corresponding to either the 21-bp repeat or the somatostatin CRE were used to demonstrate that Tax formed a highly specific complex with CREB on the 21-bp repeat but not on the somatostatin CRE. These results indicate that formation of a complex between Tax and CREB results in specific high-affinity binding of this ternary complex to the HTLV-1 21 bp repeats.
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PMID:Complex formation between CREB and Tax enhances the binding affinity of CREB for the human T-cell leukemia virus type 1 21-base-pair repeats. 864 26

Resistance to radiation leukemia virus (RadLV)-induced leukemia is correlated with an increase in H-2Dd expression on the thymocyte surface. It has been shown that elevated H-2Dd expression on infected thymocytes is a result of elevated mRNA transcription and that the transcriptional increase is correlated with elevated levels of a DNA binding activity, H-2 binding factor 1 (H-2 BF1), which recognizes the 5'-flanking sequence (5'-TGACGCG-3') of the H-2Dd gene. Recently, it has been shown that the activation transcription factor 1 (ATF-1) homodimer is one form of the H-2 BF1 complex. Here we demonstrate that the cAMP response element binding protein (CREB) homodimer and the heterodimer of CREB/ATF-1 also recognize the cis regulatory motif and are two additional forms of the H-2 BF1 complex. The levels of mRNA encoding ATF-1 and CREB were both increased in RadLV-infected thymocytes that showed increased levels of H-2 mRNA. Also, all three H-2 BF1 binding activities, ATF-1 homodimer, CREB homodimer, and ATF-1/CREB heterodimer, were increased in RadLV-infected thymocytes that expressed high levels of H-2Dd Ag on the cell surface. Transfection experiments demonstrated that ATF-1 and CREB activated a reporter plasmid containing the H-2 BF1 motif. These observations strongly suggest that both ATF-1 and CREB are involved in the regulation of H-2 gene expression following RadLV infection of mouse thymocytes.
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PMID:The regulation of murine H-2Dd expression by activation transcription factor 1 and cAMP response element binding protein. 963 3

The long terminal repeat (LTR) of human T-cell leukemia virus type 1 (HTLV-1) has two distinct DNA elements, one copy of TRE2S and three copies of a 21-bp sequence that respond to the viral trans-activator protein, Tax. Either multiple copies of the 21-bp sequence or a combination of one copy each of TRE2S and 21-bp sequence is required for efficient trans activation by Tax. In the trans activation of multiple copies of 21-bp sequence, CREB/ATF protein plays an essential role in forming a complex with Tax. To understand the role of TRE2S in trans activation of one copy of 21-bp sequence, we examined protein binding to the DNA elements by DNA affinity precipitation assay including Gli2 protein binding to TRE2S and CREB protein binding to 21-bp sequence. Binding of CREB to a DNA probe containing both elements, TRE2S-21bp probe, was dependent on Gli2 protein under restricted conditions and was enhanced in a dose-dependent fashion by the binding of Gli2 protein to the same probe. Mutation in either element abolished the efficient binding of CREB. A glutathione S-transferase fusion protein of a fragment of Gli2 was able to bind to CREB. Therefore, Gli2-CREB interaction on the DNA probe is proposed to stabilize CREB binding to DNA. Tax can bind to CREB protein on the DNA; therefore, stabilization of DNA binding of CREB results in more recruitment of Tax onto DNA. Conversely, Tax increased the DNA binding of CREB, although it had almost no effect on the binding of Gli2. These results suggest that Gli2 binds to the DNA element and interacts with CREB, resulting in more recruitment of Tax, which in turn stabilizes DNA binding of CREB. Similar cooperation of the protein binding to TRE2S-21bp probe was also observed in nuclear extract of an HTLV-1-infected T-cell line. Consistent with the Gli2-CREB interaction on the DNA elements, Tax-mediated trans activation was dependent on the size of the spacer between TRE2S and 21-bp sequence. The effective sizes of the spacer suggest that TRE2S in the LTR would cooperate with the second and third copies of the 21-bp sequence and contribute to trans activation of the viral gene transcription.
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PMID:Interaction of Gli2 with CREB protein on DNA elements in the long terminal repeat of human T-cell leukemia virus type 1 is responsible for transcriptional activation by tax protein. 1007 79

The human T-cell leukemia virus Tax protein directs binding of a host factor, cAMP response element binding protein, to an extended recognition sequence in the proviral promoter. Prior cross-linking experiments have revealed that Tax makes restricted contact with this DNA at two symmetric positions, 14 nucleotides apart on opposite strands of the DNA. Tax lacks a conventional DNA binding domain, and the sequences in Tax that are in contact with DNA have not been previously identified. Analysis of cross-linked peptides now shows that the contact occurs between Tax residues 89 and 110, corresponding to a protease-sensitive linker joining two protein structural domains. The linker assumes a protease-resistant conformation in the cross-linked complex. Point mutations within the linker prevent cross-linking and interfere with Tax function. These data suggest that entry of Tax into the ternary complex may be coupled to folding of an unstructured protein domain, which then makes base-specific contacts with DNA.
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PMID:Identification of a human T-cell leukemia virus type I tax peptide in contact with DNA. 1056 95

We report that antisense phosphorothioate oligodeoxyribonucleotides (PS-ODNs) against cyclic AMP response element-binding protein (CREB) induce the death of human leukemia cell lines including HL-60, Kasumi-1 and K562, OCI-AML1a and also primary leukemia cells isolated from patients with acute myelocytic leukemia and chronic myelocytic leukemia in blastic crisis. In contrast, normal human bone marrow CD34+ cells and normal peripheral blood lymphocytes were resistant to the antisense-mediated cell death. We found that antisense-treated HL-60 cells had prominent nuclear fragmentations but lacked apoptotic features including internucleosomal DNA cleavage and TUNEL positivity. Cell cycle analysis demonstrated a remarkable reduction in G1 phase population along with a mild accumulation of S phase and good preservation of G2/M phase, indicating cells died at G2/M without cycling into G1 phase. None of the sense-sequenced PS-ODNs induced cell death. Further, neither the expression nor the message of CREB protein was reduced by antisense treatment, indicating that cell death was mediated by a non-antisense mechanism. On the other hand, no consensus oligonucleotide sequence for cell death induction was detected. Rather, we found a good correlation between the melting temperatures and the anti-proliferative activities of the oligonucleotides. Thus, CREB antisense PS-ODNs selectively induce a non-apoptotic cell death in leukemic cells by an unknown hybridization-dependent mechanism.
Leukemia 2001 Feb
PMID:CREB antisense oligonucleotides induce non-apoptotic cell death in proliferating leukemia cells, but not normal hematopoietic cells, by a bizarre non-antisense mechanism. 1123 39


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