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)

Fli-1, an ets related gene, was found to be rearranged in 75% of erythroleukemias induced by Friend murine leukemia virus. We have shown previously that the Fli-1 gene codes for a sequence specific transcriptional activator which contains two autonomous transcriptional activation domains, one at the amino terminal region and the other at the carboxy terminal region. Recently human Fli-1 gene was shown to be involved in Ewing's sarcoma and related subtypes of primitive neuroectodermal tumors which share t(11;22) (q24;q12) chromosome translocation. In these tumors the carboxyl terminal region of Fli-1 was found to be fused with the amino terminal region of a putative RNA binding protein, EWS. Because part of the amino terminal transcriptional activation domain of Fli-1 was replaced with the amino terminal domain of the EWS (NTD-EWS) which shares homology with RNA polymerase II, it was speculated that NTD-EWS may interfere with RNA pol II function. Alternatively, NTD-EWS could also contribute to the transcriptional activation function of EWS/Fli-1 chimeric protein by providing either a modulatory/regulatory domain or a novel transcriptional activation domain. Here we show that EWS/Fli-1 chimeric protein functions as a transcriptional activator. Deletion analysis reveals that the EWS domain functions as a modulatory/regulatory domain for the transcriptional activation properties of the carboxy terminal transcriptional activation domain of EWS/Fli-1. We therefore propose that replacement of the amino terminal transcriptional activation domain of the Fli-1 protein with the regulatory domain of NTD-EWS results in the activation of the carboxy terminal transcriptional activation domain of Fli-1 which may be the molecular mechanism involved in these human tumors.
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PMID:EWS/Fli-1 chimeric protein is a transcriptional activator. 750 13

Liver-directed gene therapy will be applicable to many inherited diseases. Although various protocols have been devised for in vivo delivery of retrovirus, comparison of hepatocyte transduction frequencies has been difficult due to variations in retroviral titer and a paucity of DNA data. We have previously reported an in vivo rat hepatocyte transduction technique which involves 70% hepatectomy followed 24 hr later by portal vein injection of retrovirus during hepatic in-flow occlusion. In this study, we employed this method and concentrated retroviral preparations to achieve transduction of up to 15% of hepatocytes as determined by a quantitative PCR assay. As an initial step toward identifying promoters which lead to high-level long-term expression of retroviral transduced genes, we used our in vivo delivery system to compare the Moloney murine leukemia virus long terminal repeat (LTR) promoter with the promoter for the large subunit of murine RNA polymerase II (Pol-II). Human alpha 1-antitrypsin (hAAT) was used as the reporter gene to facilitate long-term analysis of expression. Serum hAAT levels were higher for the Pol-II promoter (143 ng/ml) than for the LTR promoter (50 ng/ml). This difference was consistent with the higher transduction frequency observed for the Pol-II-hAAT vector. Although serum hAAT expression was sustained for up to 1 year in six of eight Pol-II-hAAT-transduced rats and three of five LTR-hAAT-transduced rats and was proportional to hAAT mRNA level and proviral DNA frequency, in vivo expression was significantly lower than in transduced tissue culture cells. We conclude that a high frequency of in vivo transduction can be achieved by using retroviral vectors and our rapid transduction protocol, but transduced gene expression remains a serious problem. The quantitative assays described herein will facilitate in vivo comparisons of gene regulatory elements.
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PMID:Liver-directed gene therapy: quantitative evaluation of promoter elements by using in vivo retroviral transduction. 810 31

Regulation of gene expression in response to steroids, thyroid hormone, and retinoids is mediated by an impressive array of intracellular receptors. Sequence analysis showed that the hormone receptors comprise a large superfamily of ligand-responsive transcription factors. Upon binding to hormones, the receptors interact with specific hormone response elements located in the promoters of numerous genes. Promoter-bound receptors communicate with distinct receptors and/or additional members of the transcriptional machinery, frequently evoking protein-protein interactions. Ultimately, this results in the induction of complex gene systems that control hormone-induced processes such as differentiation, cell growth, and homeostasis. In addition to the genes transcribed by RNA polymerase II, the lipophilic hormones, particularly glucocorticoids, can also modulate RNA polymerase I-directed transcription of the ribosomal gene. For both transcription systems, activation and repression of genes in response to hormones have been reported. Finally, the involvement of hormone receptors in tumorigenesis has been discussed. It is likely that receptor studies will have major implications in the diagnosis and therapy of diseases such as leukemia.
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PMID:Control of gene expression by lipophilic hormones. 838 39

The human T-cell leukemia virus-encoded tax protein is a potent activator of many viral and cellular genes transcribed by RNA polymerase II. We find that both chromatin and cell extracts derived from human T-cell leukemia virus type 1-infected human T lymphocytes support higher levels of 5S rRNA and tRNA gene transcription than chromatin or extracts from uninfected T lymphocytes. The viral protein Tax was likely responsible for this higher level of class II gene transcription, as purified Tax was found to stimulate both genes when added to the uninfected cell extract or in reconstituted systems. Both limiting-component transcription assays and DNA binding assays identified the class III gene transcription factor TFIIIB as the principle target of Tax activity. Surprisingly, we find that Tax increases the effective concentration of active TFIIIB molecules. These data suggest that Tax stimulates RNA polymerase III-dependent gene expression by accelerating the rate and/or extent of transcription initiation complex assembly.
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PMID:Transcriptional activation of RNA polymerase III-dependent genes by the human T-cell leukemia virus type 1 tax protein. 865 53

TLS (FUS) and the related gene EWS encode the N-terminal portion of many fusion oncoproteins involved in human sarcomas and leukemia. TLS is an RNA-binding nuclear protein that is identical to hnRNP P2 and may be implicated in mRNA metabolism. When RNA polymerase II is inhibited, TLS immunostaining in the nucleus is dramatically altered, from its normal diffuse nucleoplasmic pattern to accumulation in dense nuclease-resistant aggregates. Co-immunostaining with antibodies to fibrillarin or p80 coilin and immunoelectron microscopy revealed that the TLS aggregates are associated with the nucleolus and are distinct from other known structures such as the coiled body or the interchromatin granule. Injection of cells with an oligodeoxynucleotide that disrupts splicing does not result in redistribution of TLS, indicating that the event is specific to inhibition of transcription. Oncoproteins that contain the N-terminal domain from either TLS, EWS or their Drosophila homologue, SARFH (CAZ), are also targeted to the same structure. These findings suggest a correlation between the topogenic and transforming activities of TLS and EWS N-termini and imply the existence of cellular targets that are shared by the germ-line encoded proteins and their oncogenic derivatives.
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PMID:A topogenic role for the oncogenic N-terminus of TLS: nucleolar localization when transcription is inhibited. 905 42

The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is a potent activator of viral transcription. Tax also activates the expression of specific cellular genes involved in the control of T-lymphocyte growth via effects on cellular transcription factors, including members of the NF-kappaB/cRel family. Immunocytochemistry and electron microscopy were used to characterize the intracellular localization of Tax and identify cellular factors which are the potential targets for its transcriptional activity. These studies indicated that Tax localizes in discrete nuclear foci in T lymphocytes transformed by HTLV-1 and in cells transduced with Tax expression vectors. The Tax-containing foci are complex nuclear structures comprising a central core in which Tax colocalizes with splicing factor Sm. In addition to splicing factors Sm and SC-35, the Tax-containing nuclear structures also contain transcriptional components, including the largest subunit of RNA polymerase II and cyclin-dependent kinase CDK8. The inclusion of the two subunits of NF-kappaB, p50 and RelA, and the presence of the mRNA from a gene specifically activated by Tax through NF-kappaB binding sites suggest that these unique nuclear structures participate in Tax-mediated activation of gene expression via the NF-kappaB pathway.
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PMID:The human T-cell leukemia virus type 1 transactivator protein Tax colocalizes in unique nuclear structures with NF-kappaB proteins. 909 20

A human protein (RUVBL1), consisting of 456 amino acids (50 kDa) and highly homologous to RuvB, was identified by using the 14-kDa subunit of replication protein A (hsRPA3) as bait in a yeast two-hybrid system. RuvB is a bacterial protein involved in genetic recombination that bears structural similarity to subunits of the RF-C clamp loader family of proteins. Fluorescence in situ hybridization analysis demonstrated that the RUVBL1 gene is located at 3q21, a region with frequent rearrangements in different types of leukemia and solid tumors. RUVBL1 co-immunoprecipitated with at least three other unidentified cellular proteins and was detected in the RNA polymerase II holoenzyme complex purified over multiple chromatographic steps. In addition, two yeast homologs, scRUVBL1 and scRUVBL2 with 70 and 42% identity to RUVBL1, respectively, were revealed by screening the complete Saccharomyces cerevisiae genome sequence. Yeast with a null mutation in scRUVBL1 was nonviable. Thus RUVBL1 is an eukaryotic member of the RuvB/clamp loader family of structurally related proteins from bacteria and eukaryotes that is essential for viability of yeast.
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PMID:An eukaryotic RuvB-like protein (RUVBL1) essential for growth. 977 87

The Tax transactivator protein of human T-cell leukemia virus type 1 (HTLV-1) plays a central role in the activation of viral gene expression. In addition, Tax is capable of activating the expression of specific cellular genes and is involved in the transformation of T-lymphocytes resulting in the development of adult T-cell leukemia. Tax is a phosphoprotein that colocalizes in nuclear bodies with RNA polymerase II, splicing complexes, and specific transcription factors including members of the ATF/CREB and NF-kappaB families. In this study, we identified adjacent serine residues at positions 300 and 301 in the carboxy terminus of Tax as the major sites for phosphorylation. Phosphorylation of at least one of these serine residues is required for Tax localization in nuclear bodies and for Tax-mediated activation of gene expression via both the ATF/CREB and NF-kappaB pathways. Introduction of amino acid substitutions which are phosphoserine mimetics at positions 300 and 301 restored the ability of a phosphorylation-defective Tax mutant to form nuclear bodies and to activate gene expression. These studies define sites for regulatory phosphorylation events in Tax which are critical for its ability to activate gene transcription.
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PMID:Phosphorylation of the human T-cell leukemia virus type 1 transactivator tax on adjacent serine residues is critical for tax activation. 984 80

The product of the human oncogene ELL encodes an RNA polymerase II transcription factor that undergoes frequent translocation in acute myeloid leukemia (AML). In addition to its elongation activity, ELL contains a novel type of RNA polymerase II interaction domain that is capable of repressing polymerase activity in promoter-specific transcription. Remarkably, the ELL translocation that is found in patients with AML results in the deletion of exactly this functional domain. Here we report that the EAP30 subunit of the ELL complex has sequence homology to the Saccharomyces cerevisiae SNF8, whose genetic analysis suggests its involvement in the derepression of gene expression. Remarkably, EAP30 can interact with ELL and derepress ELL's inhibitory activity in vitro. This finding may reveal a key role for EAP30 in the pathogenesis of human leukemia.
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PMID:Cloning and characterization of the EAP30 subunit of the ELL complex that confers derepression of transcription by RNA polymerase II. 1041 21

Human T-cell leukemia virus type 1 (HTLV-1) encodes a transcriptional activator, Tax, whose activity is believed to contribute significantly to cellular transformation. Tax stimulates transcription from the proviral promoter as well as from promoters for a variety of cellular genes. The mechanism through which Tax communicates to the general transcription factors and RNA polymerase II has not been completely determined. We investigated whether Tax could function directly through the general transcription factors and RNA polymerase II or if other intermediary factors or coactivators were required. Our results show that a system consisting of purified recombinant TFIIA, TFIIB, TFIIE, TFIIF, CREB, and Tax, along with highly purified RNA polymerase II, affinity-purified epitope-tagged TFIID, and semipurified TFIIH, supports basal transcription of the HTLV-1 promoter but is not responsive to Tax. Two additional activities were required for Tax to stimulate transcription. We demonstrate that one of these activities is poly(ADP-ribose) polymerase (PARP), a molecule that has been previously identified to be the transcriptional coactivator PC1. PARP functions as a coactivator in our assays at molar concentrations approximately equal to those of the DNA and equal to or less than those of the transcription factors in the assay. We further demonstrate that PARP stimulates Tax-activated transcription in vivo, demonstrating that this biochemical approach has functionally identified a novel target for the retroviral transcriptional activator Tax.
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PMID:Identification of poly(ADP-ribose) polymerase as a transcriptional coactivator of the human T-cell leukemia virus type 1 Tax protein. 1066 46


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