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:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The constitutive transport element (CTE) of type D retroviruses mediates the nuclear export of unspliced viral transcripts. We previously showed that RNA helicase A functionally interacts with CTE and contains a bidirectional nuclear transport domain at the carboxyl terminus. Here we report the identification of a novel human protein, helicase A-binding protein 95 (HAP95), which specifically binds to the carboxyl terminus of RNA helicase A. HAP95 is partially homologous to AKAP95, a member of the A kinase-anchoring protein family, but lacks the protein kinase A binding domain characteristic of this family. HAP95 is a nuclear protein at steady state but shuttles between the nucleus and cytoplasm. Overexpression of HAP95 significantly increases CTE-dependent gene expression but has no effect on general gene expression or that mediated by the Rev/Rev response element of human immunodeficiency virus type 1.
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PMID:A novel shuttle protein binds to RNA helicase A and activates the retroviral constitutive transport element. 1074 71

The human genetic disorder ataxia-telangiectasia is characterized by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell cycle checkpoint defects, and cancer predisposition. The gene product [ataxia-telangiectasia mutation (ATM)] mutated in this syndrome is a component of the DNA damage detection pathway. Loss of ATM function in human and mouse cells causes defects in DNA repair and cell cycle checkpoint control and, not surprisingly, humans and mice with compromised ATM function are prone to cancers. An excess of breast cancer in the relatives of ataxia-telangiectasia patients has also been reported by epidemiological studies. Predisposition to breast and ovarian cancers is also observed in women with germline mutations in BRCA1, a tumor suppressor gene. BRCA1 is a nuclear protein with a cell cycle-regulated expression pattern and is hyperphosphorylated in response to DNA-damaging agents. Here we show that rapid ionizing radiation-induced in vivo phosphorylation of BRCA1 requires the presence of functional ATM protein. Furthermore, we show that ATM interacts with BRCA1, and this association is enhanced by radiation. We also demonstrate that BRCA1 is a substrate of ATM kinase in vitro and in vivo. Using phospho-specific antibodies against serines 1387, 1423, and 1457 of BRCA1, we demonstrate radiation-induced, ATM-dependent phosphorylation of BRCA1 at these sites. These findings show that BRCA1 is regulated by an ATM-dependent mechanism as a part of the cellular response to DNA damage. This interaction between ATM and BRCA1 argues in favor of the involvement of particular aspects of ATM function in breast cancer predisposition.
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PMID:Role for ATM in DNA damage-induced phosphorylation of BRCA1. 1086 24

DiGeorge syndrome (DGS) is a developmental field defect of the third and fourth pharyngeal pouches that are associated with congenital heart defects, hypoparathyroidism, cell-mediated immunodeficiency, velopharyngeal insufficiency, and craniofacial anomalities. Approximately 90% of patients exhibit monosomy in the 22q11 region. In order to isolate the critical gene responsible for DGS, the cDNA libraries were screened with a probe containing the ADU balanced translocation break point, that is a locus reported in one patient (ADU) caused by a balanced translocation between chromosomes 22 and 2. Out of 10(6) clones, three independent overlapping clones were isolated, which were assumed to have originated from a single transcript, DGCR7. This transcript contained a 175-aa long open reading frame (ORF), encoding an acidic (pI = 5.81) and a proline-rich peptide, which are often found in the activation domain of several transcription factors. Also, it was predicted to be a nuclear protein. Northern hybridization detected an approx 1.9 kb transcript in all fetal and adult tissues tested, with strong expression in the fetal liver and kidney. In the case of adult tissues, strong expression was also detected in areas such as the heart, skeletal muscle, liver, and kidney.
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PMID:Isolation of novel cDNA encompassing the ADU balanced translocation break point in the DiGeorge critical region. 1143 9

The ACTGCTGA sequence (CTG motif) is located immediately upstream of the NF-kappaB enhancer in the human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR). We previously reported on the frequent duplication of this motif in HIV-1-infected individuals. In this study we further characterized the role of the CTG element in transcription and its interaction with cellular proteins. We analyzed the biological activity of LTR promoters with dimeric, monomeric or deleted CTG motifs. Our results indicate that LTRs containing the monomeric CTG motif are the most active transcriptional promoters. Furthermore, mutant viruses with dimeric or deleted CTG motif were consistently out-competed by the wild-type virus in co-culture experiments. Gel mobility shift assays were used to identify a nuclear protein of approximately 68 kD that specifically interacts with this DNA sequence. Copyright 1994 S. Karger AG, Basel
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PMID:Functional Analysis of the ACTGCTGA Sequence Motif in the Human Immunodeficiency Virus Type-1 Long Terminal Repeat Promoter. 1172 10

To overcome poor immunogenicity of prothymosin alpha, a small and highly acidic nuclear protein involved in cell proliferation, production of anti-prothymosin alpha antibodies in mice immunized with free human prothymosin alpha, with prothymosin alpha coupled to different carriers and with prothymosin alpha fused to green fluorescent protein was assessed. Fusing prothymosin alpha to green fluorescent protein turned out to be the superior approach resulting in production of high titer anti-prothymosin alpha antibodies. From these studies, two highly specific anti-prothymosin alpha monoclonal antibodies recognizing epitopes within the amino terminal (2F11) and middle (4F4) portions of the human prothymosin alpha molecule were obtained and characterized. As expected, the 2F11 antibody displayed broad species specificity, whereas the 4F4 antibody appeared to be species-specific permitting discrimination of human versus rat protein. Furthermore, a combination of point mutations in prothymosin alpha that alter the properties of the protein precluded recognition by the 4F4 antibody. Intramolecular masking of the 4F4 epitope in prothymosin alpha fused to the Tat transduction peptide of human immunodeficiency virus type 1 was observed. The anti-prothymosin alpha antibodies obtained were suitable for precipitation of human prothymosin alpha from HeLa cell lysates and for immunolocalization of the endogenous prothymosin alpha within the cells. Fusion with green fluorescent protein may thus be helpful in raising antibodies against 'problematic' proteins.
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PMID:Sensing prothymosin alpha origin, mutations and conformation with monoclonal antibodies. 1213 36

Kappa-opioid receptor (KOR) ligands have been reported to alter many cell functions and to exert an immunomodulatory role in the CNS. Astrocytes, the predominant brain cell type, have been implicated in the neuropathogenesis of human immunodeficiency virus type 1 (HIV-1). HIV-1 nuclear protein Tat has been reported to induce production of the chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2) and to activate nuclear factor kappaB (NF-kappaB) in human astrocytes. In the present study, we investigated whether the synthetic KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate (U50,488) would down-regulate MCP-1 production in primary human astrocytes stimulated by Tat. Treatment of astrocytes with U50,488 inhibited Tat-induced MCP-1 production in a concentration-dependent manner. The KOR-selective antagonist nor-binaltrophimine (nor-BNI) completely blocked the inhibitory effect of U50,488, indicating involvement of KOR. While U50,488 alone had a partial inhibitory effect on constituent NF-kappaB activation, it potently suppressed Tat-induced NF-kappaB activation. These findings suggest that KOR ligands could have an anti-inflammatory effect in the CNS and thereby be beneficial in the treatment of HIV-1-associated brain disease.
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PMID:U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes. 1247 73

The Rev protein of human immunodeficiency virus type 1 (HIV-1) is essential for the nucleocytoplasmic transport of unspliced and partially spliced HIV mRNAs containing the Rev response element (RRE). In a yeast two-hybrid screen of a HeLa cell-derived cDNA expression library for human factors interacting with the Rev leucine-rich nuclear export sequence (NES), we identified a kinesin-like protein, REBP (Rev/Rex effector binding protein), highly homologous to Kid, the carboxy-terminal 75-residue region of which interacts specifically with the NESs of HIV-1 Rev, human T-cell leukemia virus type 1 Rex, and equine infectious anemia virus Rev but not with functionally inactive mutants thereof. REBP is a nuclear protein that colocalizes with Rev in the nucleoplasm and nuclear periphery of transfected cells. Specific, albeit weak, interaction between REBP and Rev could be demonstrated in coimmunoprecipitation assays in BSC-40 cells. REBP can modestly enhance Rev-dependent RRE-linked reporter gene expression both independently and in cooperation with the nucleoporin cofactor Rab/hRIP. Thus, REBP displays the characteristics expected of an authentic mediator of Rev NES function and may play a role in RRE RNA transport during HIV infection.
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PMID:A nuclear kinesin-like protein interacts with and stimulates the activity of the leucine-rich nuclear export signal of the human immunodeficiency virus type 1 rev protein. 1280 22

Heat shock is a known transcriptional activator of human immunodeficiency virus type 1 (HIV1) long terminal repeat (LTR). However, HIV1 LTR suppression can occur under hyperthermic conditions. To investigate this phenomenon, a series of HIV1 LTR deletion luciferase constructs were generated and tested in cell culture in combination with a mutant heat shock factor 1 (HSF1+), which is transcriptionally active in the absence of heat stress. HSF1+ suppressed the activity of a minimal HIV1 LTR promoter, which contained NF-kappaB, Sp1, and tat consensus sequences. Electromobility shift assays showed nuclear protein-DNA complex formation with a Sp1 consensus sequence. Immunoprecipitation of nuclear extracts with Sp1 antibody did not affect nuclear protein-Sp1 oligonucleotide complex formation. In contrast, no complexes were formed with the Sp1 consensus sequence when the HSF protein was immunoprecipitated. These experiments indicate that modified heat shock factor can suppress HIV1 promoter activity by a mechanism involving interaction with Sp1 elements in the HIV1 promoter. The ability of HSF1+ to suppress HIV1 promoter activity suggests that HSF1+ could serve as a tool for the treatment of AIDS.
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PMID:Regulation of the HIV1 long terminal repeat by mutant heat shock factor. 1287 54

Human immunodeficiency virus-1 (HIV-1) infection of the nervous system can result in neuroinflammatory events leading first to neuronal dysfunction then to cognitive and behavioral impairments in infected people. The multifaceted nature of the disease process, commonly called HIV-1-associated dementia (HAD), provides a number of adjunctive therapeutic opportunities. One proposed adjunctive therapy is sodium valproate (VPA), an anticonvulsant known to promote neurite outgrowth and increase beta-catenin through inhibiting glycogen synthase kinase 3beta activity and tau phosphorylation. We now show that VPA treatment of rat cortical neurons exposed to HIV-1 gp120 prevents resultant neurotoxic activities. This includes the induction of significant neurite outgrowth and microtubule-associated protein 2 (MAP-2) and neuron-specific nuclear protein (NeuN) antigens in affected neuronal cell bodies and processes. Similarly, VPA protects severe combined immunodeficient (SCID) mice against the neurodegeneration of HIV-1ADA infected monocyte-derived macrophages (MDMs). In SCID mice with HIV-1 MDM-induced encephalitis, VPA treatment significantly reduced neuronal phosphorylatedbeta-catenin and tau without affecting HIV-1 replication or glial activation. We conclude that VPA protects neurons against HIV-1 infected MDM neurotoxicity, possibly through its effects on the phosphorylation of tau and beta-catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.
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PMID:Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. 1453 50

Feline immunodeficiency virus (FIV) gene orf-A, also designated orf-2, encodes a 77 amino acid accessory protein reported to be critical for efficient viral replication in vitro and in vivo and previously implicated to encode a Tat protein for FIV. However, recent studies have shown Orf-A to be important in the late steps of the FIV life cycle involved in virion formation and in early steps involved in virus infectivity. The present study reports that expression of a GFP-Orf-A fusion protein in both primate and feline cell lines results in nuclear localization of this FIV accessory protein. Moreover, a nuclear localization signal (NLS) critical for nuclear import was mapped to amino acid residues 43 through 53 of Orf-A. Lastly, transient expression of GFP-Orf-A in cells induced an arrest at the second gap (G(2)) of the cell cycle. Our findings reveal that Orf-A is a nuclear protein that expresses properties similar to those reported for human immunodeficiency virus-1 (HIV-1)-encoded Vpr.
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PMID:Feline immunodeficiency virus Orf-A localizes to the nucleus and induces cell cycle arrest. 1524 56


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