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)

Children with primary combined immunodeficiency (CID) and human cytomegalovirus (HCMV) infection often deteriorate despite antiviral therapy. In this study, the emergence of ganciclovir-resistant strains was examined in 6 children with CID and HCMV infection, using sequence analysis of the HCMV UL97 gene and virus susceptibility assays. Mutations in the proposed ATP binding site associated with ganciclovir resistance were found in 4 of the 6 children. In 1 patient with B severe CID, an unusual multiplicity of mutations was found in the UL97 substrate binding domain between aa 590-606. All mutations were detected within 10 days to 3 weeks from initiation of therapy. The emergence of resistant strains in children with CID appears earlier than in other groups of HCMV-infected patients. These findings may have relevance to the cellular pathways involved in viral DNA repair and mutagenesis, and they indicate the need for early and frequent genotypic monitoring and prompt therapeutic modification in this patient population.
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PMID:Early emergence of ganciclovir-resistant human cytomegalovirus strains in children with primary combined immunodeficiency. 969 38

The human immunodeficiency virus type 1 (HIV-1) Tat protein strongly and specifically stimulates transcription elongation from the HIV-1 LTR and provides an important in vitro model system to study this process. Here we use protein-affinity chromatography to identify cellular factors involved in transcription elongation. A Tat-affinity column bound one transcription factor, Tat-SF1, efficiently and selectively. Tat-SF1 was identified originally as a Tat-specific coactivator, but we show it is a general transcription elongation factor. Our results also reveal the existence of an ATP-inactivatable general elongation factor (AIEF) required for Tat-SF1 activity and for which Tat can substitute functionally.
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PMID:The HIV-1 Tat cellular coactivator Tat-SF1 is a general transcription elongation factor. 976 1

T cells are important effector cells in natural antiviral and anticancer immunity. It is important to reveal the cellular and molecular requirements for T cell differentiation and effector functions. We explored the idea that the final outcome of antigen receptor-driven immune processes is at least partially determined by physiologically abundant small signaling molecules in extracellular environment of lymphocytes in different tissues. Extracellular purines (ATP and adenosine) and their (purinergic) receptors were studied as an example of such molecules. Studies of functional effects of extracellular ATP and adenosine in immunoregulation have evolved in studies of individual molecules of purinergic receptors and of phosphorylation of extracellular domains of functionally important proteins. ATP-gated membrane pore, p2x 7(formerly p2z receptor) and A2a adenosine receptors are found to be predominantly expressed in T cells. The Gs-protein coupled A2a receptors activate cAMP-dependent protein kinase which was shown to have dual role in regulation of T cells functions. The results of our recent studies of adenosine receptors indicate that A2a receptors on T cell surface may play immunosuppressive role in conditions which lead to accumulation of extracellular adenosine. These conditions include pharmacological intervention with widely used anti-inflammatory drugs (methotrexate and sulfasalazine) and extracellular environment near large solid tumors. Hypoxic conditions in such tumors are known to cause accumulation of extracellular adenosine, which, in turn, as we have shown, could inhibit incoming antitumor cytotoxic T-lymphocytes from destroying the tumor. Normal development and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. We propose that T cell depletion, immunodeficiency, and autoimmunity could also be due to extracellular adenosine-induced signaling, which inhibits the antigen receptor (TCR) signaling and therefore affects the TCR-driven positive and negative selection of thymocytes. This, in turn, may lead to changes in antigen receptor repertoires and to immunodeficiency, Such properties of adenosine receptors suggest an expanded understanding of pathogenesis of ADA SCID as being due to two independent (intracellular and extracellular) mechanisms of adenosine action. It was conclusively demonstrated that functionally important T cell surface proteins including T cell receptor- are constitutively Ser/Thr phosphorylated on their ectodomains. We identified the major ecto-protein kinase activity in T-lymphocytes as casein kinase II-like (CKII-like) protein kinase. Consensus phosphorylation sites for serine and threonine protein kinases were found to be strongly evolutionary conserved in both alfa and beta TCR chains constant region. We have shown that ecto- or releasable by T-cells protein phosphatase has properties of PP1 and PP2a class protein phosphatase. Such covalent modifications of ectodomains may change T cells cognate interactions by e.g. affecting TCR-multimolecular complex formation and antigen binding affinity. It is suggested that TCR ectodomain phosphorylation could serve as a potential mechanism for regulation of TCR-mediated T-lymphocytes response.
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PMID:Extracellular purines and their receptors in immunoregulation. Review of recent advances. 980 87

The Nef proteins of Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) have been shown to associate with several cellular kinases. Further, the ability of SIVmac239 Nef to associate with a p21-activated kinase (PAK)-related kinase has been correlated with pathogenic progression to AIDS in rhesus macaques. Because the ability of Nef to associate with the PAK-related kinase is viral isolate dependent, we reasoned that viral isolates derived from distinct physiological locations may encode Nef proteins that exhibit distinct kinase association profiles. In this study, we compared kinase activities associated with Nef proteins derived from the prototypic lymphocyte-tropic SIVmac239 and a macrophage-tropic, neurovirulent clone, SIV/17E-Fr. Our findings not only support previous studies that have documented the association of SIVmac239 Nef with a PAK-related kinase and a Nef-associated kinase complex (NAKC) but describe a novel serine kinase activity detectable only in conjunction with the Nef protein derived from the neurovirulent clone, SIV/17E-Fr. The latter Nef protein does not associate with PAK, and unlike PAK or NAKC, this novel kinase activity is enhanced in association with nonmyristoylated forms of Nef and can utilize both ATP and GTP as phosphodonors. We also show that at least one substrate for the kinase is Nef itself and demonstrate that the SIV/17E-Fr Nef protein is phosphorylated in SIV-infected cells. These results suggest that the ability to associate with cellular kinases in general may be a conserved feature of Nef, but particular kinase/Nef associations may evolve with changes in the host environment concomitant with viral spread.
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PMID:A novel kinase activity associated with Nef derived from neurovirulent simian immunodeficiency virus. 981 12

The movement of a cell through the sequential phases of apoptosis is accompanied by a progressive decrease in cell size with loss in protein mass. In lymphocytes from Hiv-infected persons, protein loss during apoptosis is due to increased protein degradation rather than decreased synthesis. To identify and characterize the proteolytic enzymes or enzyme systems involved in this process, we studied several features of protein turnover in lymphocytes from peripheral blood and lymph nodes during the natural and experimental infection by feline immunodeficiency virus (Fiv). This animal model allowed us to integrate in vivo results with in vitro observations of protein damage. Here we report that protein breakdown in apoptotic cells is concomitant with the activation of the ATP and ubiquitin-dependent multicatalytic system (proteasome). We suggest that proteasome activation is part of the proteolytic cascade in the execution phases of apoptosis in AIDS.
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PMID:Protein degradation and apoptotic death in lymphocytes during Fiv infection: activation of the ubiquitin-proteasome proteolytic system. 1022 30

Cyclin-dependent kinases (CDKs) trigger and co-ordinate the cell division cycle phases. They also play a role in neuronal cells and in the control of transcription. Intensive screening has led in the past few years to the identification of a series of chemical inhibitors of CDKs. Some of these compounds display remarkable selectivity and efficiency (IC50 <25 nM). Many have been co-crystallised with CDK2, and their atomic interactions with the kinase have been analysed in detail: all are located in the ATP-binding pocket of the enzyme. These inhibitors are antimitotic, they arrest cells in G1 and, at higher doses, in G2/M. Furthermore, they facilitate or even trigger apoptosis in proliferating cells. In contrast, they protect neuronal cells from apoptosis. The potential use of these inhibitors is being extensively evaluated in cancer chemotherapy (clinical trials, Phase I and II). Possible clinical applications are being investigated in other fields: cardiovascular (restenosis, tumoural angiogenesis, atherosclerosis), nephrology (glomerulonephritis), dermatology (psoriasis), parasitology (unicellular parasites such as Plasmodium, Trypanosoma, Toxoplasma, etc.), neurology (Alzheimer's disease), viral infections (cytomegalovirus, human immunodeficiency virus, herpes). We anticipate the discovery of novel selective and powerful inhibitors in the near future, and hope for their efficient applications in various human diseases.
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PMID:Properties and potential-applications of chemical inhibitors of cyclin-dependent kinases. 1045 5

Using the OM-10.1 promyelocytic model of inducible human immunodeficiency virus type 1 (HIV-1) infection, we tested a panel of known protein kinase inhibitors for an ability to block tumour necrosis factor-alpha-induced HIV-1 expression. Among the compounds tested, the broad-spectrum protein kinase inhibitor H-7 uniquely blocked HIV-1 expression at the level of viral transcription, but did not inhibit nuclear factor kappaB activation or function. In structure-activity analysis this inhibitory activity of H-7 on HIV-1 expression corresponded with the known structural requirements for the interaction of H-7 with the ATP-binding region of protein kinase C, suggesting that it was indeed related to the kinase inhibitory properties of H-7. The mechanism of H-7 transcriptional inhibition did not involve chromatin remodelling at the HIV-1 long terminal repeat promoter, as shown by nuc-1 disruption, and appeared to involve HIV-1 RNA elongation but not initiation. Therefore, H-7 and related isoquinolinesulphonamide analogues are most likely inhibiting a kinase target essential for HIV-1 transcriptional elongation whose identity may provide new therapeutic targets for intervention.
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PMID:Isoquinolinesulphonamide derivatives inhibit transcriptional elongation of human immunodeficiency virus type 1 RNA in a promyelocytic model of latency. 1057 82

The intracellular metabolism of the beta-L- enantiomer of 2', 3'-dideoxyadenosine (beta-L-ddA) was investigated in HepG2 cells, human peripheral blood mononuclear cells (PBMC), and primary cultured human hepatocytes in an effort to understand the metabolic basis of its limited activity on the replication of human immunodeficiency virus and hepatitis B virus. Incubation of cells with 10 microM [2',3',8-(3)H]-beta-L-ddA resulted in an increased intracellular concentration of beta-L-ddA with time, demonstrating that these cells were able to transport beta-L-ddA. However, it did not result in the phosphorylation of beta-L-ddA to its pharmacologically active 5'-triphosphate (beta-L-ddATP). Five other intracellular metabolites were detected and identified as beta-L-2', 3'-dideoxyribonolactone, hypoxanthine, inosine, ADP, and ATP, with the last being the predominant metabolite, reaching levels as high as 5.14 +/- 0.95, 8.15 +/- 2.64, and 15.60 +/- 1.74 pmol/10(6) cells at 8, 4, and 2 h in HepG2 cells, PBMC, and hepatocytes, respectively. In addition, a beta-glucuronic derivative of beta-L-ddA was detected in cultured hepatocytes, accounting for 12.5% of the total metabolite pool. Coincubation of hepatocytes in primary culture with beta-L-ddA in the presence of increasing concentrations of 5'-methylthioadenosine resulted in decreased phosphorolysis of beta-L-ddA and formation of associated metabolites. These results indicate that the limited antiviral activity of beta-L-ddA is the result of its inadequate phosphorylation to the nucleotide level due to phosphorolysis and catabolism of beta-L-ddA by methylthioadenosine phosphorylase (EC 2.4.2.28).
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PMID:Intracellular metabolism of beta-L-2',3'-dideoxyadenosine: relevance to its limited antiviral activity. 1072 81

Bloom's syndrome (BS) is an autosomal recessive disorder associated with dwarfism, immunodeficiency, reduced fertility, and elevated levels of many types of cancer. BS cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. This instability is thought to result from defective processing of DNA replication intermediates. The gene mutated in BS, BLM, encodes a member of the RecQ family of DExH box DNA helicases, which also includes the Werner's syndrome gene product. We have investigated the mechanism by which BLM suppresses hyperrecombination. Here, we show that BLM selectively binds Holliday junctions in vitro and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. We present a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. Our results have implications for the role of BLM as an anti-recombinase in the suppression of tumorigenesis.
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PMID:The Bloom's syndrome gene product promotes branch migration of holliday junctions. 1082 97

Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.
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PMID:Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. 1090 20


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