Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human cell surface protein CD4 is not only an important accessory molecule in the activation of MHC class-II-restricted T cells, but has also been implicated to be a receptor for the human immunodeficiency virus HIV-I on lymphoid and monocytic cells. We have found that a 24-h treatment of the promonocytic leukemia cell line U937 with rIFN-gamma decreases the expression of the CD4 Ag by 50% as measured by cytofluorographic analysis. The decrease in CD4 expression was dependent on the concentration of rIFN-gamma, with maximal effects occurring at 20 to 200 U/ml. The decrease appeared to be due to actual loss of the CD4 molecule from the cell surface rather than masking of a particular epitope, inasmuch as similar results were obtained with the OKT4 and OKT4A antibodies. The effect of rIFN-gamma to decrease CD4 expression was not due to a general loss of cell surface Ag, because the binding of OKM1 and anti-HLe-1 increased after rIFN-gamma treatment. Treatment of rIFN-gamma also decreased cell surface CD4 expression on the promyelocytic leukemia cell line HL-60, and on the monocytic cell line THP-1, although the extent of the decrease was less than on U937 cells. Freshly isolated normal peripheral blood monocytes treated for 48 h with rIFN-gamma bound much less OKT4 or OKT4A antibody than cells incubated in the absence of rIFN-gamma. Moreover, treatment with rIFN-gamma reduced the percentage of peripheral blood monocytes that were positive for the CD4 Ag. In contrast with the decrease in CD4 levels on rIFN-gamma-treated monocytes, treatment with rIFN-gamma had no effect on CD4 levels on peripheral blood T lymphocytes or T cell lines.
 ...
PMID:Treatment with recombinant IFN-gamma decreases cell surface CD4 levels on peripheral blood monocytes and on myelomonocyte cell lines. 249 48

The CD4 molecule functions as a receptor for the binding and infectivity of the human immunodeficiency virus (HIV). It is of interest, therefore, to develop procedures for its down-regulation. In the present study, the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression of cell surface antigens of the HL-60 promyelocytic leukemia cell line was analyzed. Exposure of HL-60 cells to 1,25(OH)2D3 resulted in down-regulation of CD4 as assessed by their staining with the Leu-3a monoclonal antibody (MoAb). This treatment increased the staining of HL-60 cells with the monocyte-specific 63D3 MoAb. In contrast to the rapid elimination of cell surface CD4 by exposure of HL-60 to phorbol myristate acetate (PMA), the maximal reduction of CD4 by 1,25(OH)2D3 was attained within 48 h after the beginning of the exposure.
 ...
PMID:Modulation of the expression of CD4 on HL-60 cells by exposure to 1,25-dihydroxyvitamin D3. 269 87

The human promyelocytic leukemia cell line HL-60 overexpresses the c-myc protooncogene. A calculated secondary structure for c-myc mRNA placed the initiation codon in a bulge of a weakly base-paired region. Treatment of HL-60 cells with 5' d(AACGTTGAGGGGCAT) 3', complementary to the initiation codon and the next four codons of c-myc mRNA, inhibited c-myc protein expression in a dose-dependent manner. However, treatment of HL-60 cells with 5' d(TTGGGATAACACTTA) 3', complementary to nucleotides 17-31 of vesicular stomatitis virus matrix protein mRNA, displayed no such effects. These results agree with analogous studies of normal human T lymphocytes [Heikkila, R., Schwab, G., Wickstrom, E., Loke, S. L., Pluznik, D. H., Watt, R. & Neckers, L. M. (1987) Nature (London) 328, 445-449], except that only one-third as much oligomer was needed for a comparable effect. Proliferation of HL-60 cells in culture was inhibited in a sequence-specific, dose-dependent manner by the c-myc-complementary oligomer, but neither the oligomer complementary to vesicular stomatitis virus matrix protein mRNA nor 5' d(CATTTCTTGCTCTCC) 3', complementary to nucleotides 5399-5413 of human immunodeficiency virus tat gene mRNA, inhibited proliferation. It thus appears that antisense oligodeoxynucleotides added to myc-transformed cells via culture medium are capable of eliciting sequence-specific, dose-dependent inhibition of c-myc protein expression and cell proliferation.
 ...
PMID:Human promyelocytic leukemia HL-60 cell proliferation and c-myc protein expression are inhibited by an antisense pentadecadeoxynucleotide targeted against c-myc mRNA. 327 86

Potent drugs such as cyclosporine have provided effective probes of signal transduction pathways and, as well, of human immunodeficiency virus type 1 (HIV-1) replication mechanisms. Recently, it was reported that As(2)O(3), a drug used to treat acute promyelocytic leukemia (PML), stimulates HIV-1 replication. We found that As(2)O(3) accelerates the kinetics of a spreading HIV-1 infection in human T cells and increases the number of cells bearing HIV-1 provirus after a single round of infection. The stimulatory effect occurred after membrane fusion and resulted in increased steady-state levels of newly synthesized viral cDNA. Stimulation was independent of HIV-1 env and most viral accessory genes, and As(2)O(3) had no detectable effects on viral expression postintegration or virion assembly. Murine leukemia virus (MLV) transduction was enhanced by As(2)O(3) to the same extent as HIV-1 transduction, but As(2)O(3) had no additional effect on Fv1 restriction. In contrast, As(2)O(3) largely overcame the specific block to N-tropic MLV reverse transcription posed by human Ref1. As(2)O(3) disrupts PML bodies, nuclear structures named for a major component, the PML protein. We observed no changes in PML bodies in response to HIV-1 infection. Experiments with PML-null target cells indicated that PML has no effect on HIV-1 infectivity and is dispensable for the stimulatory effect of As(2)O(3). As(2)O(3) caused cell death in uninfected cells at the same concentrations which stimulate HIV-1 replication. Among four additional apoptosis-inducing agents, a boost in HIV-1 infectivity was observed only with carbonyl cyanide m-chlorophenylhydrazone, a compound which, like As(2)O(3), disrupts the mitochondrial transmembrane potential. In summary, As(2)O(3) stimulates retroviral reverse transcription, perhaps via effects on mitochondria, and provides a useful tool for characterizing Ref1.
 ...
PMID:As(2)O(3) enhances retroviral reverse transcription and counteracts Ref1 antiviral activity. 1258 41

Herpes simplex virus type 1 (HSV-1) ICP0 directs the degradation of cellular proteins associated with nuclear structures called ND10, a function thought to be closely associated with its broad transactivating activity. Roscovitine (Rosco), an inhibitor of cyclin-dependent kinases (cdks), inhibits the replication of HSV-1, HSV-2, human cytomegalovirus, varicella-zoster virus, and human immunodeficiency virus type 1 by inhibiting specific steps or activities of viral regulatory proteins, indicating the broad and pleiotropic effects that cdks have on the replication of these viruses. We previously demonstrated that Rosco inhibits the transactivating activity of ICP0. In the present study, we asked whether Rosco also affects the ability of ICP0 to direct the degradation of ND10-associated proteins. For this purpose, WI-38 cells treated with cycloheximide (CHX) were mock infected or infected with wild-type HSV-1 or an ICP0(-) mutant (7134). After release from the CHX block, the infections were allowed to proceed for 2 h in the presence or absence of Rosco at a concentration known to inhibit ICP0's transactivating activity. The cells were then examined for the presence of ICP0 and selected ND10-associated antigens (promyelocytic leukemia antigen [PML], sp100, hDaxx, and NDP55) by immunofluorescence. Staining for the ND10-associated antigens was detected in </=20% of KOS-infected cells in the presence or absence of Rosco, demonstrating that Rosco-sensitive kinases are not required for ICP0's ability to direct the dispersal or degradation of these antigens. In contrast, >90% of 7134- and mock-infected cells stained positive for all ND10-associated antigens in the presence or absence of Rosco. Similar results were obtained with a non-ND10-associated antigen, DNA-PK(cs), a known target of ICP0-directed degradation. The results of the PML and DNA-PK(cs) immunofluorescence studies correlated with a decrease in the levels of these proteins as determined by Western blotting. Thus, the differential requirement for Rosco-sensitive cdk activities distinguishes ICP0's ability to direct the dispersal or degradation of cellular proteins from its transactivating activity.
 ...
PMID:The differential requirement for cyclin-dependent kinase activities distinguishes two functions of herpes simplex virus type 1 ICP0. 1461 Jan 83

The Immunodeficiency, Centromeric instability, and Facial (ICF) syndrome is a rare autosomal recessive disorder that results from mutations in the DNMT3B gene, encoding a DNA-methyltransferase that acts on GC-rich satellite DNAs. This syndrome is characterized by immunodeficiency, facial dysmorphy, mental retardation of variable severity and chromosomal abnormalities that essentially involve juxtacentromeric heterochromatin of chromosomes 1 and 16. These abnormalities demonstrate that hypomethylation of satellite DNA can induce alterations in the structure of heterochromatin. In order to investigate the effect of DNA hypomethylation on heterochromatin organization, we analyzed the in vivo distribution of HP1 proteins, essential components of heterochromatin, in three ICF patients. We observed that, in a large proportion of ICF G2 nuclei, all HP1 isoforms show an aberrant signal concentrated into a prominent bright focus that co-localizes with the undercondensed 1qh or 16qh heterochromatin. We found that SP100, SUMO-1 and other proteins from the promyelocytic leukemia nuclear bodies (NBs) form a large body that co-localizes with the HP1 signal. This is the first description of altered nuclear distribution of HP1 proteins in the constitutional ICF syndrome. Our results show that satellite DNA hypomethylation does not prevent HP1 proteins from associating with heterochromatin. They suggest that, at G2 phase, HP1 proteins are involved in the heterochromatin condensation and may therefore remain concentrated at these sites until the condensation is complete. They also indicate that proteins from the NB could play a role in this process. Finally, satellite DNA length polymorphism could affect the efficiency of heterochromatin condensation and thus contribute to the variability of the ICF phenotype.
 ...
PMID:Subcellular distribution of HP1 proteins is altered in ICF syndrome. 1547 Mar 59

Retroviral infection triggers the cytoplasmic translocation of two Crm1-dependent shuttle factors, namely the Ini1 (integrase interactor 1, hSNF5) and the promyelocytic leukemia (PML) protein. Blocking nuclear export of shuttle factors by leptomycin B increases the efficiency of retroviral integration, suggesting that some may mediate antiviral activity. While PML was shown to counteract proviral establishment, it remained unclear whether Ini1, a protein implicated in various processes during human immunodeficiency virus replication, has the same potential. Employing RNA interference-mediated knock-down of Ini1, we show here that the simultaneous accumulation of both proteins in the cytoplasm likely reflects two non-interdependent phenomena. Furthermore, Ini1 does not interfere with retroviral integration, as cells lacking Ini1 show no increased infection susceptibility.
 ...
PMID:Ini1/hSNF5 is dispensable for retrovirus-induced cytoplasmic accumulation of PML and does not interfere with integration. 1558 35

Coenzyme Q (CoQ) is an isoprenoid quinine that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. CoQ having shorter isoprenoid chains, especially CoQ1 and CoQ2, selectively inhibited the in vitro activity of eukaryotic DNA polymerase (pol) gamma, which is a mitochondrial pol. These compounds did not influence the activities of nuclear DNA replicative pols such as alpha, delta and epsilon, and nuclear DNA repair-related pols such as beta, eta, iota, kappa and lambda. CoQ also inhibited DNA topoisomerase II (topo II) activity, although the enzymatic characteristics, including modes of action, amino acid sequences and three-dimensional structures, were markedly different from those of pol gamma. These compounds did not inhibit the activities of procaryotic pols such as Escherichia coli pol I, and other DNA metabolic enzymes such as human immunodeficiency virus reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. CoQ1, which has the shortest isoprenoid chains, had the strongest inhibitory effect on pol gamma and topo II activities among CoQ1-CoQ10, with 50% inhibitory concentration (IC50) values of 12.2 and 15.5 microM, respectively. CoQ1 could prevent the growth of human promyelocytic leukemia cells, HL-60, and the 50% lethal dose (LD50) value was 14.0 microM. The cells were halted at S phase and G1 phase in the cell cycle, and suppressed mitochondrial proliferation. From these results, the relationship between the inhibition of pol gamma/topo II and cancer cell growth by CoQ is discussed.
 ...
PMID:Inhibitory effect of coenzyme Q on eukaryotic DNA polymerase gamma and DNA topoisomerase II activities on the growth of a human cancer cell line. 1686 5

Granulocyte dysfunction is a central component of immunodeficiency in septic patients. Granulocyte transfusions appear to be pathophysiologically useful; however, they cause unwanted side-effects in the lungs and other organs. This study evaluates the safety of an extracorporeal immune support system with granulocytic cells in a rat model of Gram-negative sepsis. Three groups of male CD rats received either saline (control group, I), a dose of Escherichia coli O7:K1 lethal to 90% of the animals (LD90) (septic group, II), or an LD90 dose of E. coli that was incubated with the human promyelocytic leukemia cell line (HL-60) (differentiated into the granulocytic direction) for 20 min prior to infusion (second septic group, III). The animals were observed for seven days. Pre-treatment with HL-60 cells resulted in no adverse effects in the group III animals. Significantly lower bacterial counts and endotoxin levels in the plasma were detected after 24 h as compared to group II (P < 0.05). Group III animals had better weight gain and more stable hemodynamics than group II animals (P < 0.01). Seven day survival was 0/8 in group II, 6/8 in group III, and 8/9 in group I (log-rank test: II-III: P < 0.001). The data suggest that extracorporeal use of granulocytes allows the therapeutic use of these cells while avoiding unwanted effects resulting from direct contact to internal organs.
 ...
PMID:Safety evaluation for a cell-based immune support system in an ex vivo rat model of gram-negative sepsis. 1978 63

This study describes for the first time the ability of the novel BRCA1-binding protein 2 (BRAP2) to inhibit the nuclear import of specific viral proteins dependent on phosphorylation. Ectopic expression of BRAP2 in transfected African green monkey kidney COS-7 cells was found to significantly reduce nuclear localization signal (NLS)-dependent nuclear accumulation of either simian virus SV40 large-tumor antigen (T-ag) or human cytomegalovirus DNA polymerase processivity factor ppUL44; this was also observed in HL-60 human promyelocytic leukemia cells on induction of BRAP2 expression by vitamin D3 treatment. BRAP2 inhibition of nuclear accumulation was dependent on phosphorylation sites flanking the respective NLSs, where substitution of the cyclin-dependent kinase site T124 of T-ag with Ala or Asp prevented or enhanced BRAP2 inhibition of nuclear import, respectively. Substitution of T427 within the NLS of ppUL44 gave similar results, whereas no effect of BRAP2 was observed on nuclear targeting of other viral proteins, such as herpes simplex virus-1 pUL30, which lacks a phosphorylation site near its NLS, and the human immunodeficiency virus-1 Tat protein. Pulldowns/AlphaScreen assays indicated direct, high-affinity binding of BRAP2(442-592) to T-ag(111-135), strictly dependent on negative charge at T124 and the NLS. All results are consistent with BRAP2 being a novel, phosphorylation-regulated negative regulator of nuclear import, with potential as an antiviral agent.
 ...
PMID:The BRCA-1 binding protein BRAP2 is a novel, negative regulator of nuclear import of viral proteins, dependent on phosphorylation flanking the nuclear localization signal. 2004 May 18


1 2 Next >>