Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of a gene encoding the diphtheria toxin A (DT-A) chain, under the control of human immunodeficiency virus-1 (HIV-1) proteins Tat and Rev, has previously been shown to confer on cells an impaired ability to produce HIV. That work was done in HeLa cell lines that had stably integrated the regulated DT-A gene in a plasmid context. To increase the efficiency with which the HIV-regulated DT-A gene could be introduced into cells, we studied a recombinant, amphotropic murine leukemia virus containing the HIV-regulated DT-A transcription unit. Here we demonstrate that such recombinant retroviruses can be packaged, for both wild-type DT-A and an attenuated version, tox 176. In transient transfection assays, the proviral constructs exhibited similar basal and trans-activated levels of DT-A expression to the parental plasmids. Transduced H9 cells expressed the integrated DT-A gene upon transfection with plasmids encoding Tat and Rev, as assayed by decreased expression of a cotransfected luciferase reporter gene. Furthermore, the transduced H9 cells were substantially impaired in their ability to produce HIV, as demonstrated by p24 assays of culture supernatants following either transfection with an HIV proviral clone or infection with HIV-IIIB. These data demonstrate that basal expression of the regulated DT-A gene has been reduced to a tolerable level, both in packaging cells and transduced H9 cells. The use of HIV-regulated retroviruses encoding the highly lethal DT-A product may eventually be applicable as a gene therapy approach for the acquired immunodeficiency syndrome (AIDS).
 ...
PMID:Inhibition of human immunodeficiency virus-1 production resulting from transduction with a retrovirus containing an HIV-regulated diphtheria toxin A chain gene. 132 91

Human T-cell leukemia virus type I (HTLV-I) is associated with a large spectrum of clinical manifestations in man. Viral and host factors are probably involved in determining the consequences of infection. Although most of the genome of HTLV-I appears remarkably stable, considerable variation is observed in the long terminal repeat (LTR) which harbors the promoter region. So far, no correlation between specific mutations and pathogenesis has been found, and the current opinion is that sequence variations reflect the geographical origin of the isolate more than the associated pathology. To assess whether the mutations observed between two HTLV-I LTRs were functionally significant, two LTRs, which differ by ten mutations, were coupled to the highly sensitive eukaryotic luciferase-encoding reporter gene, luc, and tested by transfection in a variety of cell lines. Marked differences in promoter activity were observed in some of the cells tested, whereas in other both LTRs were equally active. This result demonstrates that the minor differences observed between two HTLV-I LTRs can affect the activity level of the promoter in some cellular environments, a result which could point to the LTR as one determinant of HTLV-I cell tropism in vivo.
 ...
PMID:Functional analysis of two long terminal repeats from the HTLV-I retrovirus. 163 12

HepG2 human hepatoma cells were transfected with the luciferase reporter gene, linked with a liver-specific enhancer plus a minimal promoter, contained within either pBR/pUC or Moloney murine leukaemia virus (MMLV) proviral plasmid contexts. Reporter expression from the proviral plasmid was decreased 10- to 20-fold, regardless of whether or not the orientation within the proviral DNA was appropriate for the use of the poly(A) signal in the 3' long terminal repeat (LTR). Efficient reporter expression was restored when the proviral transcription unit was provided with a simian virus 40 poly(A) signal. These results imply that the MMLV LTR poly(A) signal is inefficient. Therefore, strategies to maximize expression of internal transcription units from retroviral vectors should include the provision of an efficient (unidirectional) poly(A) signal (its requiring insertion in the reverse orientation to that of viral transcription).
 ...
PMID:Inefficiency of expression of luciferase reporter from transfected murine leukaemia proviral DNA may be partially overcome by providing a strong polyadenylation signal. 164 5

To study the basis of cellular latency of human immunodeficiency virus (HIV), we have used a recombinant luciferase-encoding HIV (HXB-Luc) to superinfect nonproductively HIV-1-infected human leukemic cell lines. HXB-Luc contains the Photinus pyralis luciferase gene in place of the nef gene and provides a highly sensitive, simple assay for HIV infection and expression. To circumvent any superinfection block in latently infected cells, we also generated viruses pseudotyped with murine leukemia virus amphotropic envelope (HXB-Luc:ampho). The parental uninfected lines, U937 and A3.01, from which the latently infected cell lines U1 and ACH-2, respectively, were derived could be readily infected with pseudotyped or nonpseudotyped reporter viruses. However, superinfection of U1 cells with either HXB-Luc or HXB-Luc:ampho resulted in only low levels of luciferase activity. Like the endogenous provirus, HXB-Luc provirus could be efficiently activated by phorbol ester treatment of HXB-Luc:ampho-superinfected U1 cells. In contrast, superinfection of ACH-2 cells resulted in active expression of the secondarily introduced virus even in unstimulated cells and luciferase production higher than in the parental cell line A3.01. Thus, the proviral latency in U1 cells appears to result from a defect in the cellular environment (a trans effect), whereas the latency in ACH-2 is specific to the integrated provirus and is probably a cis effect due to the site of integration. These results demonstrate distinct modes of proviral latency in these two cell line models and may have implications in our understanding of the regulation and significance of cellular latency in HIV infection.
 ...
PMID:Distinct modes of human immunodeficiency virus type 1 proviral latency revealed by superinfection of nonproductively infected cell lines with recombinant luciferase-encoding viruses. 750 83

Inflammatory genes are regulated in cells of monocyte (Mo) lineage by a variety of cellular encounters, including adhesion mediated by integrins. The role of the beta 1 family of integrins in the direct induction of immediate early gene expression was analyzed by using the tissue factor (TF) gene. Engagement of alpha 4 or beta 1 on Mo, but not members of the beta 2 integrin family, with specific mAbs as surrogate ligands immediately and directly induced high level surface expression of TF, and accumulation of TF mRNA, as well as production of TNF-alpha and HIV-1 virus. The mechanism responsible for induction of TF gene transcription mediated by the engagement of alpha 4 or beta 1 was elucidated by using THP-1 monoblastic leukemia cells. Functional analysis of plasmids containing the TF promoter expressing the luciferase reporter gene identified a cis-acting integrin-responsive element (InRE), which contained two AP-1 sites as well as a single kappa B-like site. Mutation of either the AP-1 sites or kappa B-like site greatly diminished responsiveness to integrin engagement. This InRE also conferred responsiveness to a heterologous promoter in the same reporter plasmid. Binding of mAbs to either alpha 4 or beta 1 led to nuclear translocation of the c-Rel/p65 heterodimer that preferentially bound to the TF kappa B-like site. In contrast, constitutive binding of AP-1 proteins to the two AP-1 sites was not increased by alpha 4 or beta 1 integrin engagement. These studies expand knowledge of integrin regulation of immediate early gene expression in Mo and molecular encounters that are inferred to play an active role in Mo effector functions.
 ...
PMID:Integrin regulation of an inflammatory effector gene. Direct induction of the tissue factor promoter by engagement of beta 1 or alpha 4 integrin chains. 753 94

The SCL/TAL1 gene was originally identified by virtue of its rearrangement and transcriptional activation in patients with T cell acute lymphoblastic leukaemia. It encodes a helix-loop-helix transcription factor, is not normally expressed in T cells, but is expressed in erythroid, mast, megakaryocytic and progenitor cells. Over-expression of sense and antisense constructs have implicated SCL as a positive regulator of erythroid differentiation. In addition we have previously shown that SCL mRNA levels undergo biphasic modulation during induced erythroid differentiation of murine erythroleukaemia (MEL) cells with a transient early fall followed by a late rise. In this paper we have studied expression of the SCL protein during erythroid differentiation and also the molecular basis for the raised SCL mRNA levels that accompany erythroid differentiation. We have generated an anti-SCL antiserum and used it to demonstrate that an early transient fall in SCL protein does not occur during induced differentiation of MEL cells. Furthermore SCL protein levels underwent a late fall in three different models of erythroid differentiation and in two models of myeloid differentiation. The fall in SCL protein levels during induced erythroid differentiation contrasted with the concomitant marked rise in SCL mRNA levels. These observations have significant implications for the mechanism by which SCL may regulate erythropoiesis. In addition we have demonstrated that the stability of SCL mRNA was only marginally enhanced during erythroid differentiation of MEL cells, whereas the activity of a luciferase reporter construct driven by the SCL promoter was increased 11- to 17-fold. Up-regulation of transcription therefore accounted for most of the increase in SCL mRNA levels during erythroid differentiation.
 ...
PMID:Discordant regulation of SCL/TAL-1 mRNA and protein during erythroid differentiation. 762 20

In this paper we report the presence and function of the 5' untranslated region (5'UTR) from the mRNA encoding human gamma-glutamyltransferase (GGT) in three different hematopoietic cell lines (HL-60, U-937 and K-562) as well as in the RNA of the leukocyte fraction from six acute lymphoblastic leukemias (ALL). Results obtained by RNase protection analysis demonstrate the presence of a unique form of 5'UTR expressed in most human tissues. In order to investigate the possible role of this type of sequence on regulation of GGT in hematopoietic cells, plasmid constructs carrying human hepatoma GGT 5'UTR and a luciferase reporter gene were transfected into the three blood cell lines. Compared to control untransfected cells, transfected HL-60 and K-562 showed a decrease in reporter gene activity of 51 and 73%, respectively. In contrast, transfected U-937 showed a 139% increase of reporter gene activity. Results were compared to GGT activity in the relevant cells and we concluded that the 5'UTR appears to have a regulatory role in GGT expression as a tissue-specific modulator of translation.
Leukemia 1995 Aug
PMID:Characterization and regulatory effect of gamma-glutamyltransferase messenger RNA untranslated regions in human leukemia. 764 21

The third component of the interleukin (IL) 2 receptor, gamma chain, is essential not only for IL-2- but also for IL-4-, IL-7-, IL-9-, and IL-15-induced proliferation of lymphocytes. To elucidate the mechanisms by which the gamma chain is expressed, we have analyzed the promoter region of the gamma chain gene. The 633-base pair fragment upstream of the initiation codon showed the promoter activity in human hematopoietic cell lines, Jurkat and THP-1, when linked to the luciferase gene. With a series of 5'-deletion mutants, the basal promoter activity was found in a fragment from nucleotide 80 to 58 upstream from the RNA start site, including an Ets binding sequence. Treatment of cells with either 12-O-tetradecanoylphorbol-13-acetate or phytohemagglutinin but not forskolin induced transcription from the gamma chain gene promoter. A viral trans-acting transcriptional activator, Tax, of human T-cell leukemia virus type I elevated expression of the gamma chain gene. In contrast, IL-2 decreased transcription from the IL-2 receptor gamma chain promoter. These results suggest that expression of the gamma chain is regulated at the transcription level by extracellular stimuli and may be implicated in immune response.
 ...
PMID:Functional analysis of the human interleukin 2 receptor gamma chain gene promoter. 770 94

Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease, helps to protect the epithelial surface of the airways from the destructive capacity of neutrophil elastase. Based on the recognition that SLPI levels can increase in the presence of airway inflammation, we hypothesized that inflammatory stimuli should modulate the expression of the SLPI gene in airway epithelial cells. To evaluate this, the modulation of SLPI gene expression with various inflammatory stimuli was evaluated in the HS-24 human bronchial epithelial cell line. After preliminary studies showed that several inflammatory mediators enhanced SLPI messenger RNA (mRNA) levels, PMA was used as a model inflammatory stimulus. PMA significantly increased the level of 0.7-kb SLPI mRNA transcripts in HS-24 cells in a dose- and time-dependent fashion and increased the amount of SLPI protein in the culture supernatant. Nuclear run-on analyses showed that the SLPI gene transcription rate increased approximately twofold after PMA stimulation. Transfection studies using fusion genes composed of fragments of up to 1.2 kb of the 5' flanking sequence of the SLPI gene and a luciferase reporter gene demonstrated potent promoter activity in the 131-bp segment (-115 to +16 relative to the transcription start site), and all longer segments up to 1.2 kb, whereas smaller segments showed low promoter activity. An 18-bp element (-98 to -115), in a region with homology to PMA-responsive regions in the Moloney murine leukemia virus enhancer and the IL-8 gene, was shown to be of importance in the level of transcription of the SLPI gene. However, this element was not responsible for the upregulation of SLPI gene expression by PMA. Evaluation of HS-24 cells in the presence of actinomycin D demonstrated that SLPI mRNA transcripts were very stable and became more so in the presence of PMA. Thus, SLPI gene expression in airway epithelial cells can be upregulated by an inflammatory stimulus, and this modulation is regulated at both the transcriptional and posttranscriptional levels. These mechanisms of SLPI upregulation likely play a role in defending the epithelial surface in the local milieu of inflammatory lung diseases.
 ...
PMID:Modulation of secretory leukoprotease inhibitor gene expression in human bronchial epithelial cells by phorbol ester. 791 12

Tartrate-resistant acid phosphatase (TRAP) was first identified in cells from patients with hairy cell leukaemia. Subsequently, it has been found in other leukaemias, B-lymphoblastoid cell lines, osteoclasts and subsets of normal lymphocytes, macrophages, and granulocytes. Recent data indicate that TRAP and porcine uteroferrin, a placental iron-transport protein, represent a single gene product. However, the intracellular role of TRAP is unknown. We used a full-length human placental TRAP cDNA probe to examine TRAP expression in human peripheral mononuclear cells (PMCs). TRAP mRNA increased 50-75-fold after 24 h in unstimulated PMC cultures. Cell-fractionation experiments indicated that monocytes were the main cell population accounting for increased TRAP mRNA transcripts, and this was confirmed by histochemical staining for TRAP enzyme activity. Because expression of other iron-binding and -transport proteins is controlled by iron availability, we examined the role of iron in regulating TRAP expression. Increase of TRAP mRNA transcripts in PMCs was inhibited by 50 microM desferrioxamine, a potent iron chelator. The 5' flanking region of the TRAP gene was cloned from a mouse genomic library. In preliminary transient transfection experiments, it was determined that the 5'-flanking region of the TRAP gene contained iron-responsive elements. Therefore, a series of stably transfected HRE H9 cell lines was developed bearing genetic constructs containing various segments of the murine TRAP 5' promoter region driving a luciferase reporter gene. Treatment of transfectants with 100 micrograms/ml iron-saturated human transferrin (FeTF) was performed to assess iron responsiveness of the constructs. Constructs containing a full-length TRAP promoter (comprising base pairs -1846 to +2) responded to FeTF with a 4-5-fold increase of luciferase activity whereas constructs containing only base pairs -363 to +2 of the TRAP promoter did not respond. Constructs containing 1240 or 881 bp of the TRAP promoter gave only a 1.5- to 2-fold increase of luciferase activity with FeTF. In all cases, increase of luciferase activity was blocked by desferrioxamine. Cells transfected with another luciferase construct driven by a simian virus 40 promoter did not show any increase of luciferase activity with FeTF. These data indicate that expression of TRAP is regulated by iron and that this regulation is exerted at the level of gene transcription. The transfection experiments also suggest that the region of the TRAP 5'-flanking sequence between base pairs -1846 and -1240 contains an iron regulatory element.
 ...
PMID:Transcriptional regulation of the tartrate-resistant acid phosphatase (TRAP) gene by iron. 813 51


1 2 3 4 5 6 7 8 9 10 Next >>