Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on the generation and functional characterization of a humanized immunoenzyme comprising a stable humanized single chain Fv (scFv) with grafted specificity of the anti-CD22 murine monoclonal antibody RFB4 and the human ribonuclease angiogenin (ANG). The fusion protein produced from transiently transfected mammalian Chinese hamster ovary cells could easily be purified to homogeneity, retained full ribonucleolytic activity, and efficiently killed CD22(+) tumour cells with an IC(50) of 56 nmol/l. In contrast, incubation of tumour cells with either ANG or scFv alone did not result in any cytotoxicity. Potent receptor-mediated killing of target cells, expected lack of extracellular toxicity, predictable low immunogenic potential, and ease of production, suggest that this novel immunoenzyme has potential for the immunotherapy of CD22(+) malignancies.
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PMID:Targeting malignant B-cell lymphoma with a humanized anti-CD22 scFv-angiogenin immunoenzyme. 1572 80

Human ribonuclease inhibitor (RI) is a cytoplasmic acidic protein. The experiment demonstrated that it might effectively inhibit tumor-induced angiogenesis and inhibit tumor growth. Ribonuclease inhibitor is constructed almost entirely of leucine-rich repeats, which might be involved in unknown biological effects besides inhibiting RNase A and angiogenin activities. The exact molecular mechanism of antitumor on ribonuclease inhibitor remains unclear so far. In order to further understand the function of ribonuclease inhibitor and investigate the relationship with tumor growth, our study established a transfection of human ribonuclease inhibitor cDNA into the murine B16 cells by the retroviral packaging cell line PA317. The cell line transfected with a stably high expression of ribonuclease inhibitor was identified. We found that the transfected ribonuclease inhibitor could obviously inhibit cell proliferation, regulate cell cycle and induce cell apoptosis in vitro. Mice that were injected with the B16 cells transfected RI cDNA showed a significant inhibition of the tumor growth with lighter tumor weight, lower density of microvessels, longer latent periods, and survival time than those in the other two control groups. In conclusion, the results reveal the novel mechanism that antitumor effect of ribonuclease inhibitor is also associated with inducing apoptosis, regulating cell cycle and inhibiting proliferation besides antiangiogenesis. These results suggest that ribonuclease inhibitor might be a candidate of tumor suppressor gene in some tissues. RI could become a target gene for gene therapy. Our study may be of biological and clinical importance.
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PMID:Antitumor effects of human ribonuclease inhibitor gene transfected on B16 melanoma cells. 1577 86

To improve selective cytotoxicity and pharmacokinetics of an anti-CD22 antibody single chain Fv (scFv)-ribonuclease fusion protein, a dimeric derivative was generated. Human angiogenin was fused via a (G4S)3 spacer peptide to the carboxy-terminal end of the stable dimeric anti-CD22 VL-VH zero-linker scFv MLT-7. The dimeric fusion protein and a monovalent counterpart were produced as soluble proteins in the periplasm of Escherichia coli. Comparative studies with homogeneously purified fusion proteins revealed that both constructs specifically bound to the target antigen and retained ribonucleolytic activity. However, they exhibited a markedly different capability for killing CD22+ tumor cells. The monomeric construct inhibited protein synthesis of target cells in a dose-dependent manner, but 50% inhibition (IC50) could be achieved only at the highest tested concentration (>350 nM). In contrast, the dimeric fusion protein efficiently killed CD22+ Raji and Daudi tumor cell lines with IC50 values of 74 nM and 118 nM, respectively. These results show that the therapeutic potential of scFv-ANG fusion proteins can be markedly enhanced by engineering dimeric derivatives.
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PMID:A dimeric angiogenin immunofusion protein mediates selective toxicity toward CD22+ tumor cells. 1583 81

Human ribonuclease inhibitor (hRI) can inhibit angiogenesis by reversibly binding angiogenin, a member of the RNaseA superfamily, and by suppressing the expression of basic fibroblast growth factor (bFGF). Angiogenesis is necessary for the growth and metastasis of tumors. To study the links between hRI, angiogenesis, and melanoma growth, the hRI gene was intravenously administered to mice in a recombinant retroviral vector, and expression of the hRI gene was induced to block melanoma angiogenesis. Expression, distribution, and contribution of the target gene in mice were assayed. The results showed that the tumors of mice in the hRI treatment group grew slower with less vascularity than those of mice in control groups. The introduced hRI gene inhibited tumor growth without causing significant side effects in the animals. More hRI expression in vimentin-positive cells of the tumor than in melanoma cells suggested that mesenchymal cells in the fibrous envelope of the tumor play important roles in this gene therapy.
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PMID:Inhibition of B16 melanoma growth in vivo by retroviral vector-mediated human ribonuclease inhibitor. 1613 20

In this study, we report the inhibition of ribonuclease A (RNase A) by certain aminonucleosides. This is the first such instance of the use of this group of compounds to investigate the inhibitory activity of this protein. The compounds synthesized have been tested for their ability to inhibit the ribonucleolytic activity of RNase A by an agarose gel-based assay. A tRNA precipitation assay and inhibition kinetic studies with cytidine 2',3'-cyclic monophosphate as the substrate have also been conducted for two of the compounds. Results indicate substantial inhibitory activity with inhibition association constants in the micromolar range. The experimental studies have been substantiated by docking of the aminonucleoside ligands to RNase A using AutoDock. We find that the ligands preferentially bind to the active site of the protein molecule with a favorable free energy of binding. The study has been extended to a member of the ribonuclease superfamily, angiogenin, which is a potent inducer of blood vessel formation. We show that the aminonucleosides act as potent inhibitors of angiogenin induced angiogenesis.
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PMID:3'-N-Alkylamino-3'-deoxy-ara-uridines: a new class of potential inhibitors of ribonuclease A and angiogenin. 1621 13

Members of the ribonuclease (RNase) A superfamily participate in a diverse array of biological processes, including digestion, angiogenesis, innate immunity, and possibly male reproduction. The superfamily is vertebrate-specific, with 13-20 highly divergent members in primates and rodents, but only a few members in chicken and fish. This has led to the proposal that the superfamily started off from a progenitor with structural similarities to angiogenin and that the superfamily underwent a dramatic expansion during mammalian evolution. To date this evolutionary expansion and understand the functional diversification of the superfamily, we here determine its entire repertoire in the sequenced genomes of dog, cow, and opossum. We identified 7, 20, and 21 putatively functional RNase genes from these three species, respectively. Many of the identified genes are highly divergent from all previously known RNase genes, thus representing new lineages within the superfamily. Phylogenetic analysis indicates that the superfamily expansion predated the separation of placental and marsupial mammals and that differential gene loss and duplication occurred in different species, generating a great variation in gene number and content among extant mammals.
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PMID:Ancient expansion of the ribonuclease A superfamily revealed by genomic analysis of placental and marsupial mammals. 1653 Mar 54

Several studies attribute the slower phases in protein folding to prolyl isomerizations, and several others do not. A correlation exists between the number of prolines in a protein and the complexity of the mechanism with which it folds. In this study, we have demonstrated a direct correlation between the number of cis-prolyl bonds in a native protein and the complexity with which it folds via slower phases by studying the folding of three structurally homologous proteins of the ribonuclease family, namely RNase A, onconase and angiogenin, which differ in the number and isomerization states of their proline residues.
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PMID:Correlation of folding kinetics with the number and isomerization states of prolines in three homologous proteins of the RNase family. 1694 85

Angiogenin is a member of the ribonuclease (RNase) superfamily: enzymes of innate substrate specificity, but divergent functional capacities. Angiogenin is a normal constituent of the circulation and contained in a vasculature that rarely undergoes proliferation, but in some physiological and pathological conditions its levels increase in blood, promoting neovascularization. Hence, angiogenesis is a common pathophysiological attribute of angiogenin. In malignant disease, the most studied pathological state in regard to angionenin, abnormally high levels are seen, which may be of prognostic significance. Angiogenin has also been studied in other non-malignant pathological states. The aim of this review article is to provide an overview of the biochemistry and physiology of angiogenin, specifically in relation to the human pathological states where angiogenin has been implicated and finally, its potential clinical applications.
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PMID:Angiogenin: a review of the pathophysiology and potential clinical applications. 1696 95

The Ribonuclease A superfamily includes an extensive network of distinct and divergent gene lineages. Although all ribonucleases of this superfamily share invariant structural and catalytic elements and some degree of enzymatic activity, the primary sequences have diverged significantly, ostensibly to promote novel function. We will review the literature on the evolution and biology of the RNase A ribonuclease lineages that have been characterized specifically as involved in host defense including: (1) RNases 2 and RNases 3, also known as the eosinophil ribonucleases, which are rapidly-evolving cationic proteins released from eosinophilic leukocytes, (2) RNase 7, an anti-pathogen ribonuclease identified in human skin, and (3) RNase 5, also known as angiogenin, another rapidly-evolving ribonuclease known to promote blood vessel growth with recently-discovered antibacterial activity. Interestingly, some of the characterized anti-pathogen activities do not depend on ribonuclease activity per se. We discuss the ways in which the anti-pathogen activities characterized in vitro might translate into experimental confirmation in vivo. We will also consider the possibility that other ribonucleases, such as the dimeric bovine seminal ribonuclease and the frog oocyte ribonucleases, may have host defense functions and therapeutic value that remain to be explored. (190 words).
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PMID:The RNase a superfamily: generation of diversity and innate host defense. 1696 22

Ribonucleases (RNases) have therapeutic potential against cancer and viral diseases and have been reported to inhibit replication of the human immunodeficiency virus type 1 (HIV-1) in chronically infected cell lines. The ribonuclease eosinophil-derived neurotoxin (EDN) is responsible for the anti-HIV-1 activity of a soluble factor produced in response to human alloantigens (ASF). Four recombinant RNases (EDN; a four amino acid extension of the N-terminus EDN, -4EDN; RNase A; and angiogenin) were tested for inhibition of HIV-1 replication in PHA blasts. All RNases showed anti-HIV-1 activity, irrespective of whether the RNases were added before, during, or 2 h after infection. Polyclonal antibodies against the four RNases blocked the antiviral activity. ASF inhibited HIV-1 replication in vitro if added up to 4 h after infection. We demonstrated that allostimulation induced EDN, RNase A, and angiogenin mRNA expression in peripheral blood mononuclear cells (PBMCs), although only EDN protein was detected. We identified monocytes and dendritic cells, but not macrophages or T cells, as EDN-producing cells. These findings raise the possibilities that multiple naturally occurring RNases may contribute to protection against HIV-1 infection and could be considered for utilization in HIV-1 therapy.
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PMID:Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression. 1698 16


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