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)

Tumor necrosis factor (TNF) is a multifunctional cytokine, which induces proliferation or death in a cell type-dependent manner. We previously showed that murine embryonic fibroblasts (MEFs) from TNF receptor-associated factor 2 (Traf2) and Traf5 double-deficient (double knockout (DKO)) mice were highly susceptible to TNF-induced cell death. By functional cloning to rescue DKO MEFs from TNF-induced cell death, we have identified a novel gene, Bsac. BSAC is composed of N-terminal basic, SAP (SAF-A/B, Acinus, PIAS), and coiled-coil domains. BSAC is a nuclear protein, and overexpression of BSAC potently activates promoters containing A + T-rich sequences named CArG boxes. Domain mapping analysis revealed that both N-terminal basic and C-terminal proline-rich sequence are required for the transcriptional activity. Overexpression of BSAC in DKO MEFs partially inhibited TNF-induced cell death by suppressing activation of caspases. Interestingly, inhibition of TNF-induced cell death was not observed in DKO MEFs transfected with either N-terminal or C-terminal deletion mutant of BSAC, revealing an intimate correlation between transcriptional activity and antiapoptotic function. Recently, a human homologue of BSAC named MAL/MKL1 (megakaryocytic acute leukemia/megakaryoblastic leukemia-1) was identified as a fusion transcript generated by t(1,22) translocation in acute megakaryoblastic leukemia. Collectively, BSAC is a novel transcriptional activator with antiapoptotic function, which may be involved in the leukemogenesis.
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PMID:Identification of a novel transcriptional activator, BSAC, by a functional cloning to inhibit tumor necrosis factor-induced cell death. 1201 65

Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the viral transcriptional activator Tax. Tax activates viral transcription through interaction with the cellular transcription factor CREB and the coactivators CBP/p300. One key property of the coactivators is the presence of histone acetyltransferase (HAT) activity, which enables p300/CBP to modify nucleosome structure. The data presented in this manuscript demonstrate that full-length p300 and CBP facilitate transcription of a reconstituted chromatin template in the presence of Tax and CREB. The ability of p300 and CBP to activate transcription from the chromatin template is dependent upon the HAT activity. Moreover, the coactivator HAT activity must be tethered to the template by Tax and CREB, since a p300 mutant that fails to interact with Tax did not facilitate transcription or acetylate histones. p300 acetylates histones H3 and H4 within nucleosomes located in the promoter and 5' proximal regions of the template. Nucleosome acetylation is accompanied by an increase in the level of binding of RNA polymerase II transcription factor TFIID and RNA polymerase II to the promoter. Interestingly, we found distinct transcriptional activities between CBP and p300. CBP, but not p300, possesses an N-terminal activation domain which directly activates Tax-mediated HTLV-1 transcription from a naked DNA template. Finally, using the chromatin immunoprecipitation assay, we provide the first direct experimental evidence that p300 and CBP are associated with the HTLV-1 long terminal repeat in vivo.
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PMID:Acetylation of nucleosomal histones by p300 facilitates transcription from tax-responsive human T-cell leukemia virus type 1 chromatin template. 1205 56

Constitutive expression of the IL-2 receptor (IL-2R) on adult T-cell leukemia (ATL) cells and the presence of permanent IL-2-dependent ATL cell lines indicate that the signal transduction system via IL-2R is a key element for the development of this disease. IL-2R is a member of the common gamma-chain (gammac)-receptor family and shares gamma with IL-4R, IL-7R, IL-9R, and IL-15R. In addition to IL-2R, ATL cells express IL-15R and respond to IL-15. In the present study, we examined other members of this receptor family. ATL cells showed various levels of IL-4Ralpha (CD124) and IL-7Ralpha (CD127) expression, and responded to these cytokines. In contrast, ATL cells hardly responded to IL-9. As primary samples were a mixed population and the results may have been modified by contaminating normal cells, we used ATL cell lines as pure ATL cell populations. Here, we report that IL-2-dependent ATL cell lines also express IL-4Ralpha and respond to IL-4, which was verified by the activation of cytoplasmic transcriptional activator Stat6 protein. Moreover, a novel ATL cell line that grows stably in an IL-7-dependent manner was established from one of the cell lines, and IL-7 induced Stat5 activation in this cell line. These results indicated that ATL cells have the potential to express all gammac-receptors except IL-9R. Overlapping and switching of cytokine receptors supported the idea that ATL cells can rapidly select the appropriate gammac-receptor according to conditions.
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PMID:Multiple gammac-receptor expression in adult T-cell leukemia. 1222 94

Chronic myeloid leukaemia (CML) is a malignant clonal disorder of the haematopoietic stem cell. Treatment of CML patients with interferon alpha (IFN-alpha) has induced haematological and cytogenetic remission. Interferons transcriptionally activate target genes through the JAK-STAT and interferon regulated factors (IRFs) family pathways. Interferon regulated factor-1 (IRF-1) is a transcriptional activator of genes critical for cell growth, differentiation and apoptosis. The skipping of exons 2 or 2 and 3 of IRF-1 in patients with myelodysplastic syndromes and acute myelogenous leukaemia suggests that this factor may have a critical role in leukaemogenesis. The role of IRF-1 in CML is currently unknown. Therefore, mutational analysis of IRF-1 was performed and its expression pattern was also studied in CML patients. We studied IRF-1 in peripheral blood mononuclear cells of 21 patients in chronic phase CML. No point mutations were identified at the cDNA level. Surprisingly, fourfold reduction of full-length IRF-1 mRNA expression was established in 17/21 patients compared with normal individuals. Low expression of full-length IRF-1 was observed in conjunction with high levels of aberrantly spliced mRNAs, reported for the first time. In three patients who were also analysed during blastic transformation, further reduction of full-length IRF-1 mRNA was observed. These findings demonstrate that, in CML patients, IRF-1 can produce high levels of aberrant spliced mRNAs with subsequent reduction in the levels of full-length IRF-1 mRNA. This observation is consistent with the notion that exon skipping may constitute another mechanism of tumour suppressor gene inactivation in this disease.
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PMID:Low expression of interferon regulatory factor-1 and identification of novel exons skipping in patients with chronic myeloid leukaemia. 1235 2

The human T-cell leukemia virus (HTLV-I)-encoded Tax protein is a potent transcriptional activator that stimulates expression of the integrated provirus. Biochemical studies indicate that Tax, together with cellular transcription factors, interacts with viral cAMP-response element enhancer elements to recruit the pleiotropic coactivators CREB-binding protein and p300. Histone acetylation by these coactivators has been shown to play a major role in activating HTLV-I transcription from chromatin templates in vitro. However, the extent of histone modification and the precise identity of the cellular regulatory proteins bound at the HTLV-I promoter in vivo is not known. Chromatin immunoprecipitation analysis was used to investigate factor binding and histone modification at the integrated HTLV-I provirus in infected T-cells (SLB-1). These studies reveal the presence of Tax, a variety of ATF/CREB and AP-1 family members (CREB, CREB-2, ATF-1, ATF-2, c-Fos, and c-Jun), and both p300 and CREB-binding protein at the HTLV-I promoter. Consistent with the binding of these coactivators, we observed histone H3 and H4 acetylation at three regions within the proviral genome. Histone deacetylases were also present at the viral promoter and, following their inhibition, we observe an increase in histone H4 acetylation on the HTLV-I promoter and a concomitant increase in viral RNA. Together, these results suggest that a variety of transcriptional activators, coactivators, and histone deacetylases participate in the regulation of HTLV-I transcription in infected T-cells.
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PMID:Transcription factor binding and histone modifications on the integrated proviral promoter in human T-cell leukemia virus-I-infected T-cells. 1238 57

To achieve efficient and sustained gene expression, we developed a new lentivirus/adenovirus hybrid vector (LA vector) that encodes sequences required for production of a human immunodeficiency virus-based lentiviral vector (i.e., a lentiviral vector, a gag/pol/rev expression cassette, a tetracycline-inducible envelope cassette, and the tetracycline-inducible transcriptional activator cassette) in a single helper-dependent adenovirus vector backbone. Via either transfection or infection, human cell lines transduced with the LA vector produced a lentiviral vector in a doxycycline-dependent manner at titers up to 10(5) to 10(6) green fluorescent protein transducing units per ml, which are comparable to the titers obtained by conventional multiple plasmid transfection methods. Efficient spread and persistent expression of the transgene were observed in cells maintained in long-term culture that had been infected with the LA vector. Furthermore, when cocultured with adherent cells infected with the LA vector, the human T-cell leukemia cell line was successfully transduced with a marker gene. This LA vector possesses the advantages of efficient gene transfer from an adenoviral vector and stable integration from a lentiviral vector; therefore, it might have potential for a variety of gene therapy applications.
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PMID:A new hybrid system capable of efficient lentiviral vector production and stable gene transfer mediated by a single helper-dependent adenoviral vector. 1258 21

The mixed lineage leukemia (MLL) gene at chromosome band 11q23 is commonly involved in reciprocal translocations that are detected in acute leukemias. Evidence suggests that the resulting MLL fusion genes contribute to leukemogenesis. AF9 is a common MLL fusion partner in acute myeloid leukemia. The AF9 protein functions as a transcriptional activator in artificial reporter gene assays and a structurally related protein in yeast, ANC1/TFG3, is a component of the SWI/SNF complex. Apart from these observations, little is known about the biologic function of AF9 in mammals. We have found that a recently described transcriptional repressor, BCL-6 corepressor (BCoR), interacts with the carboxy-terminus of AF9. The interaction of AF9 with BCoR has been confirmed by independent in vitro and in vivo protein-binding studies. The BCoR gene is expressed as several alternatively spliced transcripts. AF9 only binds BCoR isoforms that contain a unique 34 aa sequence located in the mid-portion of the protein. In artificial reporter gene assays, a BCoR isoform that binds AF9 efficiently suppresses AF9 transcriptional activity, while a nonbinding isoform does not. These results indicate that different isoforms of BCoR have unique biologic properties and that cell function may be partly determined by the different isoforms that are present within the cell.
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PMID:The mixed lineage leukemia fusion partner AF9 binds specific isoforms of the BCL-6 corepressor. 1277 90

Human T-cell leukemia virus type 1 (HTLV-1) is associated with leukemia/lymphoma and neurologic disorders. Although the viral transcriptional activator Tax is the critical viral oncoprotein, Rex, which regulates the expression of the viral structural and enzymatic genes, is essential for efficient viral replication. Herein, we investigate the contribution of Rex in HTLV-1 immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. A Rex-deficient HTLV-1 (HTLVRex-) was constructed and characterized for viral gene expression, protein production, and immortalization capacity. Cells transiently transfected with the HTLVRex- proviral clone produced low detectable levels of p19 Gag. 729HTLVRex- stable transfectants produced functional Tax, but undetectable levels of Rex or p19 Gag. Coculture of irradiated 729HTLVRex- cells with peripheral blood mononuclear cells (PBMCs) resulted in sustained interleukin-2 (IL-2)-dependent growth of primary T lymphocytes. These cells carried the HTLVRex- genome and expressed tax/rex mRNA but produced no detectable Rex or p19 Gag. Rabbits inoculated with irradiated 729HTLVRex- cells or 729HTLVRex- cells transiently transfected with a Rex cDNA expression plasmid failed to become persistently infected or mount a detectable antibody response to the viral gene products. Together, our results provide the first direct evidence that Rex and its function to modulate viral gene expression and virion production is not required for in vitro immortalization by HTLV-1. However, Rex is critical for efficient infection of cells and persistence in vivo.
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PMID:HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro. 1290 36

The human T-cell leukemia virus type 2 (HTLV-2), an oncogenic retrovirus closely related to HTLV-1, produces a lifelong infection whose possible association to certain human diseases is still debated. Although some viral products can influence the expression and action of cellular genes, very little is known about the molecular mechanisms involved. Here we show that the AIR-1-encoded human major histocompatibility complex (MHC) class II transactivator (CIITA) strongly inhibits viral replication, but not virus entry, in human B- and T-cell susceptible targets. This effect results from CIITA inhibiting the Tax-mediated transactivation of the HTLV-2 long-term repeat. Further molecular analysis shows that the N-terminal region of CIITA encompassing the first 321 amino acids is responsible for the inhibitory effect on viral replication. This region is crucial for the transactivation of human MHC class II genes and includes the activation domain as well as domains interacting with coactivators that also are used by the viral transactivator Tax to modulate cellular functions. These results represent the first evidence that a cellular transcriptional activator, controlling the coordinate expression of the entire family of MHC class II antigen-presenting molecules, inhibits HTLV-2 viral replication by a distinct mechanism. In this new role CIITA may represent a new tool for therapeutic strategies aimed at counteracting HTLV-2 replication and spreading.
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PMID:The MHC class II transcriptional activator (CIITA) inhibits HTLV-2 viral replication by blocking the function of the viral transactivator Tax-2. 1452 69

The HTLV-1 transcriptional activator Tax is required for viral replication and pathogenesis. In concert with human CREB, Tax recruits the human transcriptional coactivator and histone acetyltransferase p300/CBP to the HTLV-1 promoter. Here we investigate the structural features of the interaction between Tax and the KIX domain of p300/CBP. Circular dichroism spectroscopy, nuclear magnetic resonance chemical shift perturbation mapping, and sedimentation equilibrium analysis show that KIX binds a Tax subdomain corresponding to residues 59-98 of Tax (called Tax(59-98)). Circular dichroism spectroscopy suggests that Tax(59-98) is intrinsically disordered (natively unfolded) in isolation and adopts an ordered conformation upon binding KIX. The interaction is disrupted by a single amino acid variation of Tax(59-98) in which leucine 68 is substituted with proline. Chemical shift perturbation mapping reveals that the Tax-binding surface of KIX is distinct from that utilized by CREB, and corresponds to the site of KIX that interacts with the human transcription factors c-Jun and mixed lineage leukemia protein (MLL). Sedimentation equilibrium analysis shows that Tax and the phosphorylated KID domain of CREB can simultaneously bind KIX to form a ternary 1:1:1 complex. The results provide a molecular description of the concerted recruitment of p300/CBP via the KIX domain by Tax and phosphorylated CREB during Tax-mediated gene expression.
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PMID:KIX-mediated assembly of the CBP-CREB-HTLV-1 tax coactivator-activator complex. 1458 Jan 93


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