Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NK cells migrate in response to C-C chemokines, including monocyte chemotactic protein-1 (MCP-1) and MCP-3. Increased migration was observed in IL-2-activated NK cells. It was therefore of interest to define the expression in resting and activated NK cells of the MCP-1 receptor (CCR2) for which two cDNAs (A and B) have been described. Specific oligonucleotides and reverse-transcriptase PCR revealed the presence in activated NK cells and mononuclear phagocytes of the fragments expected on the basis of the reported cDNAs. In addition, amplification with a common A/B- and an A-specific oligonucleotide yielded an unexpected, abundant, 1649-bp fragment. Sequence analysis as well as Northern blotting and RNase protection with different probes revealed that the CCR2 gene is expressed in activated NK cells and mononuclear phagocytes as a predominant long transcript (3.4 kb) consisting of CCR2B, followed by a novel sequence (X), corresponding to an intron in the genome, and by a CCR2A-specific portion. The predominant long transcript is polyadenylated and present in the cytoplasm. The augmented migratory capacity of IL-2 activated vs resting NK cells was associated with increased CCR2 transcript levels.
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PMID:IL-2-regulated expression of the monocyte chemotactic protein-1 receptor (CCR2) in human NK cells: characterization of a predominant 3.4-kilobase transcript containing CCR2B and CCR2A sequences. 905 2

A human monocyte-activating CC chemokine has been identified based on sequences in an expressed sequence tag (EST) cDNA database. The protein shows highest sequence identity to the macrophage inflammatory protein (MIP) group of chemokines, particularly MIP-3 (76.7%) and MIP-1alpha (75.4%), and has been named MIP-5. Model building confirms that the protein has a similar three dimensional structure to other chemokines, but has an additional third disulphide bond. Northern blot analysis and reverse-transcriptase PCR show that the mRNA for MIP-5 is expressed at a high levels in liver, intestine and in lung leukocytes. MIP-5 induces chemotaxis of human monocytes, T-lymphocytes and, to a lesser degree, eosinophils at nanomolar concentrations; it has no effect on neutrophil migration. In receptor-binding assays, MIP-5 shows IC50 values of 12 nM for competition with 125I-MIP-1alpha for binding to CC-chemokine receptor (CCR)1, and 2.5 nM for competition with 125I-MCP-3 for binding to CCR3. It shows no ability to compete with ligand for binding to the two interleukin (IL)-8 receptors (CXC-chemokine receptors 1 and 2) or to CCR2, CCR4 or CCR5. Consistent with this binding data, MIP-5 was only able to induce calcium fluxes in CHO cells stably transfected with CCR1 or CCR3.
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PMID:Characterisation of macrophage inflammatory protein-5/human CC cytokine-2, a member of the macrophage-inflammatory-protein family of chemokines. 934 9

Eosinophilic tissue infiltration of nasal mucosa typical for allergic rhinitis and chronic polypous sinusitis may be due to chemotactic activity of chemokines specific for eosinophils. The CC-chemokines eotaxin, RANTES and MCP-3 have been postulated to be involved in the recruitment of eosinophils to certain inflamed tissues. To explore their possible role in chronic polypous sinusitis we examined eotaxin-, RANTES- and MCP-3-gene expression in human nasal polyps and normal human nasal mucosa of patients undergoing endonasal surgery for treatment of chronic polypous sinusitis. Using gene-specific primers in semi-quantitative reverse-transcriptase polymerase-chain-reaction experiments we found elevated expression of eotaxin- and RANTES-mRNA but no MCP-3-mRNA in non-atopic and atopic nasal polyps when compared to normal nasal mucosa.
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PMID:Increased eotaxin-mRNA expression in non-atopic and atopic nasal polyps: comparison to RANTES and MCP-3 expression. 953 37

Chemokines are a large family of low-molecular-weight proinflammatory cytokines that stimulate recruitment of leukocytes. We previously reported that among six chemokines, the expression of mRNAs for MCP-1, MCP-3, TCA3, and MIP-1alpha, but not for MIP-1beta and RANTES, was markedly elevated in the renal cortex of rats with puromycin aminonucleoside induced nephrosis. In this study we have determined the glomerular expression of the chemokine mRNAs in this model using quantitative competitive reverse-transcriptase polymerase chain reaction. After an injection of puromycin aminonucleoside, the number of monocytes/macrophages and CD4+ and CD8+ cells markedly increased by day 5 and increased thereafter until day 10. The levels of mRNAs for MCP-1, MCP-3, and lymphotactin increased on day 5 and returned to their normal levels by day 7. The level of TCA3 mRNA increased on day 3, and that of MIP-1alpha mRNA increased on day 7, but both returned to their normal levels within 2 days. No increase in the mRNAs of MIP-1beta or RANTES was observed until day 10. These results indicate that the expression pattern of the chemokine mRNAs in glomeruli resembles that in renal cortex, but is more transient and sequential.
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PMID:Transient and sequential expression of chemokine mRNA in glomeruli in puromycin aminonucleoside nephrosis. 1086 41

The anti-HIV activity of niglizin (penta-O-nicotinate of glycyrrhizic acid) and of its combinations was studied in the culture of infected MT-4 cells and in respect to the recombinant reverse HIV-1 transcriptase. Niglizin was shown to suppress effectively the HIV replication and to be a noncompetitive inhibitor of reverse transcriptase. Research of a combined anti-HIV action of niglizin and of azidothimidine (AZT) demonstrated that the preparations, when used at ratios of 1:20, 1:50, 1:200 and 1:2000, suppressed the synergetic effect both in the cell culture and in the recombinant reverse HIV transcriptase. A study of the antiviral activity of niglizin and of its joint use with AZT in respect to the AZT-resistant HIV-1 mutant showed niglizin to be more effective (ID50 = 0.134 microM) versus the "wild" strain. (ID50 = 9.64 micriM); whereas, its combined use AZT:niglizin = 1:100 displayed synergism (FIC = 0.553). The efficiency of the combined AZT/niglizin anti-HIV effect both in respect to the "wild" strain and to the AZT-resistant mutant confirms that such combinations are promising for the treatment of HIV infection.
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PMID:[The anti-HIV activity of glycyrrhizic acid penta-O-nicotinate]. 1565 64

Monocyte chemotactic protein 3 (MCP-3/CCL7), a CC chemokine able to attract and activate a large panel of leukocytes including natural killer cells and T lymphocytes, could be beneficial in antitumor therapy. Vectors were constructed based on the autonomous parvovirus minute virus of mice (MVMp), carrying the human (MCP-3) cDNA. These vectors were subsequently evaluated in the poorly immunogenic mouse melanoma model B78/H1. The infection of the tumor cells with MCP3-transducing vector at low virus input multiplicities, but not with wild-type virus, strongly inhibited tumor growth after implantation in euthymic mice. In a therapeutic B78/H1 model, repeated intratumoral injections of MCP3-tranducing virus prevented further tumor expansion as long as the treatment was pursued. The antitumor effects of the MCP-3-transducing vector were not restricted to this tumor model since they could also be observed in the K1735 melanoma. The depletion of CD4, CD8, NK cells and of interferon gamma (IFNgamma) in mice implanted with MVMp/MCP3-infected B78/H1 cells abolished the antitumor activity of the vector. The latter data, together with tumor growth in nude mice and reverse-transcriptase (RT)-PCR analyses of MVMp/MCP3-treated tumors, clearly showed that activated CD4, CD8 and NK cells were indispensable for the antineoplastic effect in the B78/H1 tumor. Altogether, our results show that MCP3-transducing parvovirus vectors may be quite potent against poorly or nonimmunogenic tumors, even in conditions where only a fraction of the tumor cell population is efficiently infected with recombinant parvoviruses.
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PMID:MCP-3 (CCL7) delivered by parvovirus MVMp reduces tumorigenicity of mouse melanoma cells through activation of T lymphocytes and NK cells. 1715 74

Non-structural protein 9 (Nsp9), a RNA-dependent RNA polymerase (RdRp) of the porcine reproductive and respiratory syndrome virus (PRRSV), is necessary for PRRSV replication. However, the binding partners of Nsp9 have not been identified. In this study, seven host proteins were identified as Nsp9-binding proteins using yeast two-hybrid (Y2H). Among of them, we confirmed the interaction of Nsp9 with Annexin A2 (ANXA2) using Y2H, Co-immunoprecipitation (Co-IP), GST pulldown and immunofluorescence assay (IFA). We found that only full-length ANXA2 could bind with Nsp9 in vitro and Nsp9 interacted with endogenous ANXA2 in PRRSV-infected MARC-145 cells. In addition, we found that the Nsp9-ANXA2 interaction was partially reduced by RNase A treatment. Furthermore, PRRSV growth was significantly hindered in ANXA2-knockdown MARC-145 cells. Taken together, these results indicate that Nsp9 binding partner ANXA2 is beneficial for PRRSV replication.
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PMID:The interaction between host Annexin A2 and viral Nsp9 is beneficial for replication of porcine reproductive and respiratory syndrome virus. 2487 99

The nonstructural protein 9 (Nsp9) of porcine reproductive and respiratory syndrome virus (PRRSV) is a RNA-dependent RNA polymerase (RdRp) that plays a vital role in viral replication. This study first demonstrated that the Nsp9 of genotype 2 PRRSV interacted with cellular retinoblastoma protein (pRb), and Nsp9 co-localized with pRb in the cytoplasm of PRRSV-infected MARC-145 cells and pulmonary alveolar macrophages (PAMs). Next, the overexpression of truncated pRb was shown to inhibit the PRRSV replication and silencing the pRb gene could facilitate the PRRSV replication in MARC-145 cells. Finally, the pRb level was confirmed to be down-regulated in PRRSV-infected MARC-145 cells, and Nsp9 was shown to promote the pRb degradation by proteasome pathway. These findings indicate that the interaction of Nsp 9 with pRb benefits the replication of genotype 2 PRRSV in vitro, helping to understand the roles of Nsp9 in the replication and pathogenesis of PRRSV.
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PMID:The interaction of nonstructural protein 9 with retinoblastoma protein benefits the replication of genotype 2 porcine reproductive and respiratory syndrome virus in vitro. 2514 1

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV), is a widespread viral disease that has led to huge economic losses for the global swine industry. Non-structural protein 9 (Nsp9) of PRRSV possesses essential RNA-dependent RNA polymerase (RdRp) activity for viral RNA replication. Our previous report showed that Nsp9-specific nanobody, Nb6, was able to inhibit PRRSV replication. In this study, recombinant Nsp9 and Nsp9-Nb6 complex were prepared then characterized using bio-layer interferometry (BLI) and dynamic light scattering (DLS) analyses that demonstrated high-affinity binding of Nb6 to Nsp9 to form a homogeneous complex. Small-angle X-ray scattering (SAXS) characterization analyses revealed that spatial interactions differed between Nsp9 and Nsp9-Nb6 complex molecular envelopes. Enzyme-linked immunosorbent assays (ELISAs) revealed key involvement of Nsp9 residues Ile588, Asp590, and Leu643 and Nb6 residues Tyr62, Trp105, and Pro107 in the Nsp9-Nb6 interaction. After reverse genetics-based techniques were employed to generate recombinant Nsp9 mutant viruses, virus replication efficiencies were assessed in MARC-145 cells. The results revealed impaired viral replication of recombinant viruses bearing I588A and L643A mutations as compared with replication of wild type virus, as evidenced by reduced negative-strand genomic RNA [(-) gRNA] synthesis and attenuated viral infection. Moreover, the isoleucine at position 588 of Nsp9 was conserved across PRRSV genotypes. In conclusion, structural analysis of the Nsp9-Nb6 complex revealed novel amino acid interactions involved in viral RNA replication that will be useful for guiding development of structure-based anti-PRRSV agents.
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PMID:Structural Characterization of Non-structural Protein 9 Complexed With Specific Nanobody Pinpoints Two Important Residues Involved in Porcine Reproductive and Respiratory Syndrome Virus Replication. 3328 76