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 ATF/CRE binding site can mediate transcriptional activation by cAMP, the adenovirus E1A protein and the human T-cell leukaemia virus 1 (HTLV1) tax protein. A large number of different proteins bind specifically to this element either as homodimers or as heterodimers. Using GAL4-ATF/CREB fusions, we have investigated the regulatory functions of three members of this family. CREB1 (CREB) is strongly activated by cAMP and weakly activated by the E1A protein. In contrast, CREB2 (CRE-BP1, ATF2) is strongly activated by E1A but is insensitive to cAMP stimulation. ATF1 is weakly activated by cAMP but is not activated by E1A. All three proteins are insensitive to activation by the HTLV1 tax protein. The N-terminal region of CREB2, from amino acid residues 19 to 112, is both necessary and sufficient for E1A activation. This region contains a putative C2H2 metal-binding finger, and single amino acid substitutions of the cysteine residues severely decreased CREB2 activity. In contrast, mutations affecting a potential protein kinase A and casein kinase II phosphorylation site within this region had little effect.
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PMID:Differential regulation of three members of the ATF/CREB family of DNA-binding proteins. 165 8

The adenovirus E1A protein and tax protein (Tax) of human T-cell leukemia virus-1 (HTLV-1) are transcriptional regulators that do not bind to DNA directly. The ATF sites/CRE (cyclic AMP response element) of the adenovirus E4 promoter and the long terminal repeat of HTLV-1 have been shown to be required for E1A and Tax inducibility, respectively. Using the c-Myb-CRE-BP1 fusion protein, it was shown that CRE-BP1, which could bind to the ATF sites/CRE, mediated the E1A-induced trans-activation. For this activation, the N-terminal portion of CRE-BP1, which contained the putative metal finger structure, was essential but not sufficient. In contrast, the trans-activation induced by HTLV-1 Tax was not mediated by CRE-BP1. These results strongly suggested that E1A activates transcription through interaction with CRE-BP1, but another CRE-binding protein participates in the Tax-induced trans-activation.
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PMID:Cyclic AMP response element-binding protein, CRE-BP1, mediates the E1A-induced but not the Tax-induced trans-activation. 182 68

The trans-activator protein, tax, from the human T leukemia virus type 1 (HTLV-1) trans-activates both viral and cellular genes. It has previously been shown that granulocyte macrophage-colony stimulating factor (GM-CSF) is constitutively expressed in HTLV-1 infected cells and in cells artificially expressing tax. We show here that the GM-CSF promoter is tax responsive in fibroblasts and T cells, whereas the granulocyte (G)-CSF promoter is tax responsive only in fibroblasts. The tax protein can activate cellular genes through a least two families of transcription factors; the NF-kB/rel and CREB/ATF families. We have used mutant tax proteins to show that the activation of NF-kB proteins is essential for tax trans-activation of both the GM-CSF and G-CSF promoters. The ability of tax to activate CREB/ATF proteins is also essential for GM-CSF transactivation. We have identified a 44 bp region of the GM-CSF promoter that contains tax responsive elements. This region contains a classical NF-kB site, a CK-1 element that can bind the NF-kB p65 protein, as well as a putative ATF binding site. The tax response of the G-CSF promoter requires not only the conserved CK-1 sequence but also an adjacent NF-IL6 binding site that may explain the cell restricted function of the G-CSF promoter.
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PMID:HTLV-1 tax activation of the GM-CSF and G-CSF promoters requires the interaction of NF-kB with other transcription factor families. 750 30

TREB5 (hXBP-1) protein is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and activates their transcription. TREB5 is a member of the CREB/ATF family, containing a basic amino acid region and leucine zipper structure (b-Zip structure). To characterize the key domain of TREB5 for transcriptional activation, mutational analysis was carried out. The C-terminal region of 148-221 amino acids was identified as an activation domain and was also active when fused to Gal4 DNA binding domain. This domain contains three unique regions rich in glutamic acid, glutamine, or serine/threonine and is active in both osteosarcoma (HOS) and T (Jurkat) cell lines. All of these three regions are essential; however, a part of the serine/threonine region was dispensable in Jurkat, but not in HOS cells. In addition to the activation domain, the N-terminal region showed activity in conjunction with the b-Zip structure, but not with the Gal4 DNA binding domain. Furthermore, this region showed activity in Jurkat cells, but not in HOS cells. These results suggest that TREB5 has two activational functions in transcription and may provide diversity in cell-type-specific transcriptional activation, possibly through dimerization with other b-Zip proteins and phosphorylation.
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PMID:Identification of transcriptional activation domain of TREB5, a CREB/ATF family protein that binds to HTLV-1 enhancer. 760 16

Gene expression from the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) is mediated by three cis-acting regulatory elements known as 21-bp repeats and the transactivator protein Tax. The 21-bp repeats can be subdivided into three motifs known as A, B, and C, each of which is important for maximal gene expression in response to Tax. The B motif contains nucleotide sequences known as a cyclic AMP response element (CRE) or tax-response element which binds members of the ATF/CREB family of transcription factors. Though mutations of this element in the HTLV-I LTR eliminate tax activation, Tax will not activate most other promoters containing these CRE sites. In this study, we investigated the mechanism by which Tax activates gene expression in conjunction with members of the ATF/CREB family. We found that Tax enhanced the binding of one member of the ATF/CREB family, CREB 1, to each of the three HTLV-I LTR 21-bp repeats but not another member designated CRE-BP1 or CREB2. Tax enhanced the binding of CREB1 to nonpalindromic CRE binding sites such as those found in the HTLV-I LTR, but Tax did not enhance the binding of CREB1 to palindromic CRE binding sites such as found in the somatostatin promoter. This finding may help explain the failure of Tax to activate promoters containing consensus CRE sites. These studies were extended by use of the mammalian two-hybrid system. Tax was demonstrated to interact directly with CREB1 but not with other bZIP proteins, including CREB2 and Jun. Site-directed mutagenesis of both Tax and CREB1 demonstrated that the amino terminus of Tax and both the basic and the leucine zipper regions of CREB1 were required for direct interactions between these proteins both in vivo and in vitro. This interaction occurred in vivo and thus did not require the presence of the HTLV-I 21-bp repeats, as previously suggested. These results define the domains required for interaction between Tax and CREB that are likely critical for the activation of HTLV-I gene expression.
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PMID:Protein domains involved in both in vivo and in vitro interactions between human T-cell leukemia virus type I tax and CREB. 774 88

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67SRF. An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-1 latency observed in adult T-cell leukemia.
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PMID:Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency. 828 13

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

Interleukin-6 (IL-6) activation of the immediate-early gene junB has been shown to require both a tyrosine kinase and an unknown 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7)-sensitive pathway. Here we report the identification and characterization of an IL-6 immediate-early response element in the junB promoter (designated JRE-IL6) in HepG2 cells. The JRE-IL6 element, located at -149 to -124, contains two DNA motifs, an Ets-binding site (EBS) (CAGGAAGC) and a CRE-like site (TGACGCGA). Functional studies using variously mutated JRE-IL6 elements showed that both motifs were necessary and sufficient for IL-6 response of the promoter. The EBS of the JRE-IL6 element (JEBS) appears to bind a protein in the Ets family or a related protein which could also form a major complex with the EBSs of the murine sarcoma virus long terminal repeat or human T-cell leukemia virus type 1 long terminal repeat. The CRE-like site appears to weakly bind multiple CREB-ATF family proteins. Despite the similarity in the structure between the JRE-IL6 element and the polyomavirus enhancer PyPEA3, composed of an EBS and an AP1-binding site and known to be activated by a variety of oncogene signals, JRE-IL6 could not be activated by activated Ha-Ras, Raf-1, or 12-O-tetradecanoylphorbol-13-acetate. We show that IL-6 activates JRE-IL6 through an H7-sensitive pathway that does not involve protein kinase C, cyclic AMP-dependent kinase, Ca(2+)- or calmodulin-dependent kinases, Ras, Raf-1, or NF-IL6 (C/EBP beta). The combination of JEBS and the CRE-like site appears to form the basis for the selective and efficient response of JRE-IL6 to IL-6 signals, but not to signals generated by activated Ha-Ras, Raf-1, or protein kinase C.
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PMID:Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. 838 18

The trans activator protein of Bovine Leukaemia Virus (tax) increases the rate of transcription from the virus promoter through 21 bp sequences located in three tandem copies in the virus LTR. Based on data obtained by three different experimental approaches we concluded that the central CRE-like motif found in each of the BLV 21 bp repeats plays an important and indispensable role in tax mediated trans activation. These include (i) in vivo analysis of the function of mutant 21 bp sequences in transient transfection, (ii) gel mobility shift assay to show that CREB binds to BLV 21 bp repeats in vitro and (iii) the demonstration that the production of antisense CREB mRNA inhibits tax trans activation. Further studies with different deletion mutant CREB proteins suggest that although CREB alpha can interact with factors involved in BLV trans activation, it does not promote transcription initiation; consequently some other member/s of the CREB/ATF family must be involved.
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PMID:Member of the CREB/ATF protein family, but not CREB alpha plays an active role in BLV tax trans activation in vivo. 839 35


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