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)

We have utilized antisense oligodeoxynucleotides (ODNs) to modulate transcriptional activation by the human T-cell leukemia virus type I (HTLV-I) tax gene, the major transcriptional regulator of this virus. 3'-Terminal phosphorothioate-modified antisense ODNs were shown to efficiently inhibit Tax protein expression both in vitro and in vivo. Terminal substitution did not affect the affinity of ODNs for their target sequence but conferred a 9-fold increase in tax inhibition in vitro. When delivered into mice by intraperitoneal injection, ODNs inhibited tax expression in established tumors by 90%. Unmanipulated tax-transformed mouse fibroblasts, or HTLV-I-transformed human lymphocytes, showed at least 5-fold higher ODN binding and uptake over control cells. Balb/3T3 cell binding was induced to similar levels by cellular activators. This suggests that constitutive activation by tax transformation may increase susceptibility of HTLV-I-transformed cells to antisense therapy, providing a rationale for the use of antisense ODN therapeutics in HTLV-I-associated diseases.
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PMID:Human T-cell leukemia virus type I tax transformation is associated with increased uptake of oligodeoxynucleotides in vitro and in vivo. 128 76

Rex, the post-transcriptional regulator of human T-cell leukemia virus type I (HTLV-I), is known to induce accumulation of the unspliced viral gag-pol mRNA. Rex is a phosphoprotein found in the cell nucleolus, whose function may be regulated by its localization and phosphorylation. We have examined the role of phosphorylation on Rex function by using a protein kinase inhibitor, H-7 [1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine]. Treatment of an HTLV-I infected human T-cell line with H-7 blocked specifically accumulation of the unspliced gag-pol mRNA, resulting in the decreased Gag protein synthesis that corresponds with the decreased in vivo phosphorylation of Rex. In contrast, other viral and cellular products have not been influenced by the level of H-7 used. Therefore, the phosphorylation of Rex is required for the viral RNA partition of HTLV-I.
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PMID:Protein kinase inhibitor H-7 blocks accumulation of unspliced mRNA of human T-cell leukemia virus type I (HTLV-I). 235 16

Gene expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by two trans-acting factors encoded by the pX region, p40tax and p27tax.p40tax is a transcriptional activator and p27rex is a post-transcriptional regulator. Using full-length viral DNA, we studied the regulatory effects of rex on HTLV-1 gene expression. p27rex is required for expression of both gag and env proteins, increasing the level of their mRNAs. The effect was dependent on the dose of p27rex expression plasmid. In parallel, increased doses of p27rex suppressed the expression of fully spliced pX mRNA, which encodes the regulatory proteins. These two effects of p27rex operated at the post-transcriptional level and were independent of transcriptional regulation. Lowering the level of pX mRNA down-regulates transcription of the proviral genome. These observations demonstrate that rex is a positive post-transcriptional regulator for gag, pol and env protein expression, and acts at the same time as an indirect negative regulator of viral transcription.
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PMID:Post-transcriptional regulator (rex) of HTLV-1 initiates expression of viral structural proteins but suppresses expression of regulatory proteins. 283 30

Rhombotin-2 (RBTN-2) is a LIM domain protein that, with the exception of thymocytes, is widely expressed during fetal development. Although RBTN-2 is crucial for normal erythropoiesis, the ectopic expression of RBTN-2 in T lymphocytes results in T-cell proliferation and leukemogenesis. Thus, while a proliferative function for RBTN-2 has been established in T-cells, neither its role in erythropoiesis nor its function(s) in other tissues are known. We have examined the expression and location of RBTN-2 in normal and malignant cells. Similar to fetal development, RBTN-2 RNA was detected in all normal adult tissues tested with the exception of colon and thymocytes. RBTN-2 RNA was not detected in all primary tumors and tumor cell lines, indicating RBTN-2 expression is not ubiquitous in proliferating cells. Using polyclonal antisera, RBTN-2 was detected predominantly in the nucleus of human hematopoietic cells. Significantly, human leukemic T cells with disruption of the RBTN-2 locus and thymocytes from transgenic mice with enforced expression of RBTN-2 showed similar nuclear location of RBTN-2 protein, consistent with the notion that RBTN-2 acts as a transcriptional regulator in T-cell proliferation. Surprisingly, in normal tissues, RBTN-2 showed a strikingly similar distribution to that of metallothionein-1, having both nuclear and cytoplasmic localization that suggested that RBTN-2 may be involved in the acute phase response. Indeed, similar to metallothionein-1, RBTN-2 mRNA was induced in thymocytes of mice exposed to zinc and in human thymocytes treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Since the LIM domain permits binding of multiple protein partners, the specific function of RBTN-2 may depend upon subcellular sequestration through interaction with different cofactors. Thus, in addition to its roles in erythropoiesis and T-cell leukemia, RBTN-2 may also be involved in the acute phase response.
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PMID:Expression of the proto-oncogene rhombotin-2 is identical to the acute phase response protein metallothionein, suggesting multiple functions. 754 55

Deregulated expression of v-abl and BCR/abl genes has been associated with myeloproliferative syndromes and myelodysplasia, both of which can progress to acute leukemia. These studies identify the localization of the oncogenic form of the abl gene product encoded by the Abelson murine leukemia virus in the nuclei of myeloid cells and the association of the v-Abl protein with the transcriptional regulator cyclic AMP response element-binding protein (CREB). We have mapped the specific domains within each of the proteins responsible for this interaction. We have shown that complex formation is a prerequisite for transcriptional potentiation of CREB. Transient overexpression of the homologous cellular protein c-Abl also results in the activation of promoters containing an intact CRE. These observations identify a novel function for v-Abl, that of a transcriptional activator that physically interacts with a transcription factor.
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PMID:Nuclear localization of v-Abl leads to complex formation with cyclic AMP response element (CRE)-binding protein and transactivation through CRE motifs. 756 61

Adult T-cell leukemia (ATL) associated with HTLV-1 infection is characterized by the development of hypercalcemia in over two thirds of patients. Dysregulation of cellular gene transcription by viral proteins is an emerging paradigm for molecular pathogenesis of disease. A recent example is the parathyroid hormone-related protein (PTHrP) gene, which has been implicated in the hypercalcemia of ATL, and is transactivated by the HTLV-1 tax and HTLV-11 tax proteins. PTHrP is expressed at high levels in leukemia cells derived from ATL patients, as well as in asymptomatic HTLV-1 positive carriers. This article reviews the interaction of the HTLV-1 transcriptional regulator tax with the PTHrP promoter. Tax mediates its effects on PTHrP via cellular transcription factors AP-2 and AP-1, and transactivation via an AP-2 motif represents a novel interaction of tax with a cellular transcription factor.
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PMID:Hypercalcemia, parathyroid hormone-related protein expression and human T-cell leukemia virus infection. 781 98

Primary RNA transcripts of the human T-cell leukemia virus type 1 (HTLV-1) are processed into mature mRNA by a complex series of splicing events. In this paper, we report the finding of a novel doubly spliced pX mRNA in two out of eight HTLV-1-infected cell lines and in one out of 13 peripheral blood mononuclear cells from HTLV-1-infected individuals. The second splicing for this novel pX mRNA is different from that for the known doubly spliced pX mRNA. A novel acceptor site in this splicing was generated by a single point mutation (G to A) at nucleotide 7,337 of the pX gene. This mRNA contained a complete open reading frame that encodes an amino-terminal truncated p27rex protein with 189 amino acids. A new 25-kD protein was detected in the cell lines expressing the novel pX mRNA by an antibody against the carboxy-terminal peptide of p27rex and was termed p25rex. Although the function of p25rex is not clear, we clarified that p25rex is a cytoplasmic phosphoprotein and its function is different from the transcriptional regulator function of p27rex. The possibility that the mutated virus is replicable only in cells coinfected with the wild type HTLV-1 may explain why the incidence of the mutants observed here is low.
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PMID:A spontaneous point mutation in the human T-cell leukemia virus type 1 pX gene leads to expression of a novel doubly spliced pX-mRNA that encodes a 25-kD, amino-terminal deleted rex protein. 801 Nov 62

The rev protein (Rev) of the human immunodeficiency virus type 1 (HIV-1) is known as a post-transcriptional regulator of viral gene expression. It is located in the cell nucleolus. Transiently expressed Rev caused nucleolar ballooning and deformity with aberrant accumulation of rRNAs, and de novo synthesis of rRNAs decreased dramatically in these cells. However, similarly expressed rex protein (Rex) of the human T-cell leukemia virus type I, which is a functional homologue to Rev, did not affect nucleolar structure and function. Rev expression resulted in cell death with nucleolar destruction in an inducible cell line. Analysis of Rev mutants revealed that both the nucleolar targeting signal of Rev and the multimerization domain are prerequisites to the nucleolar disintegration by Rev. Human T-cells acutely infected with HIV-1 contained nucleoli which were deformed and filled with Rev, but chronically infected cells had intact nucleoli. Involvement of Rev in cytopathic effects in HIV-1 infection is discussed.
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PMID:Cytotoxic activity of rev protein of human immunodeficiency virus type 1 by nucleolar dysfunction. 822 12

Rex protein, the post-transcriptional regulator of human T-cell leukemia virus type I, is located predominantly in the cell nucleolus and is associated with the cytoplasmic accumulation of unspliced and singly spliced viral mRNAs. The N-terminal 19-amino acid segment of Rex has been identified as the nucleolar targeting signal (NOS) and shown to be important for Rex function. To study the molecular interaction between the NOS region of Rex and its binding host protein(s) in the nucleolus, we chemically synthesized a functional NOS peptide (wild type) and mutant NOS peptides. Fluorescein isothiocyanate-conjugated functional NOS peptide was rapidly taken up by human cells and was transported to the nucleolus. Using affinity chromatography, we identified nucleolar protein B-23 as the major protein that binds to NOS. We also identified two highly acidic regions of B-23 (amino acids 120-132 and 161-188) as acceptor regions for NOS. Previous experiments have suggested that B-23 functions as a shuttle protein for the nucleolar transport of ribosomal components. Our results suggest that B-23 may also serve as a shuttle for the import of Rex from the cytoplasm to the nucleolus coupled to the export of viral mRNAs containing the Rex-responsive element.
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PMID:Nucleolar targeting signal of Rex protein of human T-cell leukemia virus type I specifically binds to nucleolar shuttle protein B-23. 831 59

B-Myb is a transcriptional regulator of gene expression and is highly homologous to c-Myb in its N-terminal DNA binding domain. However, unlike c-myb, whose expression is restricted largely to immature hematopoietic cells, B-myb mRNA has been found to be expressed in all proliferating mammalian cell lines and is clearly regulated in a cell cycle dependent manner. That c-Myb and B-Myb proteins perform different roles in proliferation and/or differentiation is suggested by the redundancy of their expression. It was previously shown that degenerated c-Myb expression can inhibit IL-6 induced terminal differentiation of the leukemia cell line M1. We found that, unlike the downregulation of c-Myb protein which is an early response of progenitor M1 cells to IL-6 treatment, the downregulation of B-Myb occurs late, just prior to terminal differentiation and growth arrest. It was, therefore, of interest to examine the role of the murine B-Myb protein in the proliferation and differentiation of the M1 cells and to compare these effects to those of c-Myb in the same system. Clones ectopically producing B-Myb, like those ectopically expressing c-Myb, proliferated in the presence of the differentiation-inducing agent and did not undergo the programmed cell death which normally follows terminal macrophage differentiation. In addition, the cell-cycle distribution of M1/B-Myb cells was comparable to untreated cells. Although M1/B-Myb and M1/c-Myb clones treated with IL-6 appeared quite immature, differentiation markers were demonstrated to be maintained at near normal levels (e.g. MyD88, Mac-2), or be partially reduced in expression (C3, Fc and Mac-1 receptors) suggesting that the cells had undergone commitment to maturation, but were unable to terminally differentiate.
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PMID:B-Myb prevents growth arrest associated with terminal differentiation of monocytic cells. 857 Feb 12


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