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PubMed2000

Interferon-alpha and the pathogenesis of myeloproliferative disorders.

Interferon-alpha (IFN-alpha), a molecule with multiple biological actions, is widely used in the treatment of chronic myelogenous leukemia (CML) and the other myeloproliferative disorders. This glycoprotein belonging to the type I subfamily of interferons has been recombinantly manufactured and has been approved for the biotherapy of CML, now becoming the first line of treatment for CML patients in chronic phase who are not candidates for allogeneic hematopoietic stem cell or bone marrowtransplantation. Interferon-alpha action involves binding to its cell membrane receptor and initiation of an intracellular signal transduction cascade. Two major pathways mediate the biologic actions of IFN-alpha. The JAK-STAT pathway leads to phosphorylation and activation of STAT 1 and STAT 2 molecules and transcription of genes like p21 and caspase-1 resulting in cycle arrest and apoptosis. The PKR (protein kinase dsRNA-induced) kinase phosphorylates and inhibits the eukaryotic initiator of translation eIF-2alpha leading again to apoptosis. The PKR kinase cascade also leads to activation of the transcription factor NF-kappaB. The relevance of this activation is unclearand it is possiblethat NF-kappaB has not had the opportunity to transcribe its target genes as it is a substrate of effector caspases and is maybe cleaved by them before exerting any transcription activity. Through the JAK-STAT and the PKR kinase pathways IFN-alpha is able to modify the proliferative and antiapoptotic actions of the constitutively activated kinase bcr-abl, the product of the t(9;22) translocation present in CML, and has therapeutic effects in this disease.

Antineoplastic Agents↗
PubMed1995

Differentiation between minus- and plus-strand synthesis: polymerase activity of dsRNA bacteriophage phi 6 in an in vitro packaging and replication system.

Empty procapsids of the segmented dsRNA virus phi 6, produced in Escherichia coli from a cloned L genome segment, package plus-strand phi 6 ssRNA genomic segments, synthesize minus strands, and transcribe the newly formed dsRNA templates. Procapsids can be restricted to minus-strand synthesis by high concentrations of CaCl2 or low concentrations of nucleotides, enabling us to separate the viral minus-strand (replication) and plus-strand (transcription) RNA-dependent RNA polymerase activities in vitro. Reaction conditions for minus-strand synthesis were optimized. Plus-strand synthesis by procapsids could be activated by binding of purine nucleoside triphosphates to a low-affinity NTP-binding site. The second 5'-terminal nucleotide of the phi 6 plus-sense ssRNA L genomic segment is important for determining the level of transcription of that segment and the generation of infectious procapsids.

Bacteriophage phi 6↗
PubMed2002

ARGONAUTE1 is required for efficient RNA interference in Drosophila embryos.

Double-stranded RNA (dsRNA) triggers homology-dependent posttranscriptional gene interference (RNAi) in a diverse range of eukaryotic organisms, in a process mechanistically related to viral and transgene-mediated cosuppression. RNAi is characterized by the conversion of long dsRNA into approximately 21-25-nt small interfering RNAs (siRNA) that guide the degradation of homologous mRNA. Many of the genes required for siRNA production and target mRNA degradation are widely conserved. Notably, members of the Argonaute-like gene family from Arabidopsis, Caenorhabditis elegans, Drosophila, and Neurospora have been genetically and/or biochemically identified as components of the RNAi/cosuppression pathway. We show here that mutations in the Drosophila Argonaute1 (AGO1) gene suppress RNAi in embryos. This defect corresponds to a reduced ability to degrade mRNA in response to dsRNA in vitro. Furthermore, AGO1 is not required for siRNA production in vitro nor can the introduction of siRNA bypass AGO1 mutants in vivo. These data suggest that AGO1 functions downstream of siRNA production.

ATP-Binding Cassette Transporters↗
PubMed2000

Modulation of double-stranded RNA-mediated gene induction by interferon in human umbilical vein endothelial cells.

Endothelial cells respond to double-stranded RNA (dsRNA) with expression of a number of important immunomodulatory and inflammatory response genes, including adhesion molecules, cytokines, and antiviral genes. Considerable differences are seen when genes are induced by dsRNA compared with cytokines. Much higher levels of mRNA for interleukin-6 (IL-6), 2',5'-oligoadenylate synthetase (2',5'-OAS), protein kinase (PKR), and interferon (IFN) regulatory factor-1 (IRF-1) result from incubation with dsRNA than with IL-1beta, tumor necrosis factor-alpha (TNF-alpha), or IFN-alpha, whereas the differences in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA expression in response to dsRNA, IL-1beta, and TNF-alpha are relatively minor. IFN-alpha priming enhances responsiveness of some, but not all, genes to dsRNA but not to IL-1beta, but the optimal time for pretreatment varies considerably among different dsRNA-responsive genes. Protein translation is reduced in human umbilical vein endothelial cells (HUVEC) in response to incubation with dsRNA, and this decrease is accentuated if cells are primed with IFN-alpha. Despite this decrease, IFN-alpha priming causes very high levels of IL-6 protein expression in response to dsRNA but not in response to IL-1beta or TNF-alpha. These studies demonstrate that priming with class I IFN can enhance the response to dsRNA through the heightened expression of genes that contribute to both the cellular response to viral infection and the host immunologic response.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

Binding of Epstein-Barr virus small RNA EBER-1 to the double-stranded RNA-activated protein kinase DAI.

Epstein-Barr virus encodes two small RNAs, EBER-1 and -2, that are abundantly expressed in latently infected cells. Recent evidence suggests a role for EBER-1 in regulation of translation since this RNA is able to prevent the inhibition of protein synthesis by double-stranded RNA in rabbit reticulocyte lysates. We show here that EBER-1 that has been synthesized in vitro forms a complex with the dsRNA-activated inhibitor of protein synthesis DAI, a protein kinase that specifically phosphorylates polypeptide chain initiation factor eIF-2. Gel retardation assays and UV crosslinking experiments indicate that complex formation is specific for EBER-1 and requires the presence of some secondary structure in the molecule. RNA competition studies show that EBER-1-DAI complex formation is not inhibited in the presence of other small RNA species, heparin or the synthetic double-stranded RNA, poly(I).poly(C). SDS gel analysis reveals the existence of two forms of the crosslinked complex, of 64-68kDa and 46-53kDa, both of which are recognized by anti-DAI antibodies in immunoprecipitation experiments. These data suggest that EBER-1 regulates protein synthesis through its ability to interact with DAI.

Blotting, Western↗
PubMed2007

Coupling of rotavirus genome replication and capsid assembly.

The Reoviridae family represents a diverse collection of viruses with segmented double-stranded (ds)RNA genomes, including some that are significant causes of disease in humans, livestock, and plants. The genome segments of these viruses are never detected free in the infected cell but are transcribed and replicated within viral cores by RNA-dependent RNA polymerase (RdRP). Insight into the replication mechanism has been provided from studies on Rotavirus, a member of the Reoviridae whose RdRP can specifically recognize viral plus (+) strand RNAs and catalyze their replication to dsRNAs in vitro. These analyses have revealed that although the rotavirus RdRP can interact with recognition signals in (+) strand RNAs in the absence of other proteins, the conversion of this complex to one that can support initiation of dsRNA synthesis requires the presence and partial assembly of the core capsid protein. By this mechanism, the viral polymerase can carry out dsRNA synthesis only when capsid protein is available to package its newly made product. By preventing the accumulation of naked dsRNA within the cell, the virus avoids triggering dsRNA-dependent interferon signaling pathways that can induce expression and activation of antiviral host proteins.

Amino Acid Sequence↗
PubMed1998

Localization of the active site of HIV-1 reverse transcriptase-associated RNase H domain on a DNA template using site-specific generated hydroxyl radicals.

Reverse transcriptase (RT)-associated ribonuclease H (RNase H) can cleave both the RNA template of DNA/RNA hybrids as well as double-stranded (ds) RNA. This report shows that human immunodeficiency virus (HIV)-RT can also cleave the template strand of dsDNA when Mg2+ is replaced by Fe2+ in the RNase H active site of HIV-RT. The cleavage mechanisms as well as the positions of the cut vary depending on whether RNA or DNA is used. While DNA is cleaved 17 base positions upstream of the primer 3'-end, RNA is cleaved 18 base positions upstream. Competition experiments show that Fe2+ replaces the catalytically active Mg2+ of RT-associated RNase H. The bound Fe2+ is the source of locally generated OH-radicals that cleave the most proximate base in the DNA. Electrophoretic mobility studies of the cleaved fragments suggest that DNA is cleaved by an oxidative mechanism, while RNA is cleaved by an enzymatic mechanism which is indistinguishable from the Mg2+-dependent cleavage. The Fe2+-dependent cuts can be used to trace the active site of RT-associated RNase H on dsDNA as well as on dsRNA and DNA/RNA hybrids. The observed 1 base difference in the cleavage positions on DNA and RNA templates can be attributed to conformational differences of the bound nucleic acids. We suggest that the lower pitch of dsRNA and DNA/RNA hybrids compared with dsDNA permits accommodation of an additional base pair in the region between the primer 3'-end and the Fe2+-dependent cleavage position at the RNase H active site.

Binding Sites↗
PubMed1991

Characterization of the VPg-dsRNA linkage of infectious pancreatic necrosis virus.

By the use of strong denaturing agents, a genome-linked protein (VPg)-RNA complex was purified from infectious pancreatic necrosis virus. Ribonuclease treatment of 125I-labelled VPg-RNA released a 90K polypeptide identical to the minor structural polypeptide VP1 (the putative RNA polymerase), as determined by peptide mapping. The polypeptide is linked to the RNA by a serine-5' GMP phosphodiester bond. The results identify birnaviruses as the only dsRNA viruses with a VPg, the size of which is the largest of the VPgs of RNA viruses.

Electrophoresis, Agar Gel↗
PubMed1999

Failure of measles virus to activate nuclear factor-kappa B in neuronal cells: implications on the immune response to viral infections in the central nervous system.

Neurons are postmitotic cells that foster virus persistence. These cells lack the HLA class I molecules required for clearance of infected cells. Previously, we showed that HLA class I is induced by measles virus (MV) on glial cells, which is primarily mediated by IFN-beta. In contrast, MV was unable to induce HLA class I or IFN-beta in neuronal cells. This failure was associated with lack of NF-kappa B binding to the positive regulatory domain II element of the IFN-beta promoter, which is essential for virus-induced IFN-beta gene activity. In this study, we demonstrate that the failure to activate NF-kappa B in neuronal cells is due to the inability of MV to induce phosphorylation and degradation of I kappa B, the inhibitor of NF-kappa B. In contrast, TNF-alpha induced degradation of I kappa B alpha in the neuronal cells, suggesting that failure to induce I kappa B alpha degradation is likely due to a defect in virus-mediated signaling rather than to a defect involving neuronal I kappa B alpha. Like MV, mumps virus and dsRNA failed to induce I kappa B alpha degradation in the neuronal cells, suggesting that this defect may be specific to viruses. Autophosphorylation of the dsRNA-dependent protein kinase, a kinase possibly involved in virus-mediated I kappa B alpha phosphorylation, was intact in both cell types. The failure of virus to induce I kappa B alpha phosphorylation and consequently to activate NF-kappa B in neuronal cells could explain the repression of IFN-beta and class I gene expression in virus-infected cells. These findings provide a potential mechanism for the ability of virus to persist in neurons and to escape immune surveillance.

DNA-Binding Proteins↗
PubMed2004

HRP-2, a heterogeneous nuclear ribonucleoprotein, is essential for embryogenesis and oogenesis in Caenorhabditis elegans.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) have fundamental roles in the posttranscriptional control of gene expression. Here, we describe an hnRNP from Caenorhabditis elegans(HRP-2), which shares significant homology with mammalian hnRNP R, hnRNP Q and ACF, the essential complementation factor in ApoB mRNA editing. All four proteins possess a similar molecular architecture, with three closely linked RNA-binding domains and a C-terminus that contains RG/RGG repeat motifs. An HRP-2::GFP fusion protein was ubiquitously expressed in C. elegans during embryogenesis and subsequent larval development. Expression was also detected in the hermaphrodite gonad using a specific antibody, suggesting that HRP-2 is provided maternally. HRP-2 was predominantly localised to nuclei and analysis of transgenic lines expressing C-terminal deletions of HRP-2 defined a functional nuclear localisation signal. Analysis by RNAi demonstrated that HRP-2 was essential for embryogenesis and fertility. Cell divisions were slower in hrp-2(RNAi) embryos and the majority showed an early embryonic arrest phenotype. Shorter exposure to dsRNA allowed development to the twofold stage and the few embryos that hatched were abnormal. Adult worms that developed from embryos exposed to RNAi were completely sterile due to a failure in oocyte formation. These results demonstrate that HRP-2 or its RNA targets are essential for normal embryonic development and oogenesis in C. elegans.

Animals↗
PubMed2000

HIV-I TAT inhibits PKR activity by both RNA-dependent and RNA-independent mechanisms.

Replication of the human immunodeficiency virus type 1 (HIV-1) is inhibited by interferons (IFNs), in part through activity of the IFN-inducible protein kinase PKR. To escape this antiviral effect, HIV-1 has developed strategies for blocking PKR function. We have previously shown that the HIV-1 Tat protein can associate with PKR in vitro and in vivo and inhibit PKR activity. Here we present evidence that Tat can inhibit PKR activity by both RNA-dependent and RNA-independent mechanisms. Tat inhibited PKR activation by the non-RNA activator heparin, and also suppressed PKR basal level autophosphorylation in the absence of RNA. However, when Tat and dsRNA were preincubated, the amount of Tat required to inhibit PKR activation by dsRNA depended on the dsRNA concentration. In addition to its function in vitro, Tat can also reverse translation inhibition mediated by PKR in COS cells. The Tat amino acid sequence required for interaction with PKR was mapped to residues 40-58, overlapping the hydrophobic core and basic region of HIV-1 Tat. Alignment of amino acid sequences of Tat and eIF-2alpha indicates similarity between the Tat-PKR binding region and the residues around the eIF-2alpha phosphorylation site, suggesting that Tat and eIF-2alpha may bind to the same site on PKR.

Amino Acid Sequence↗
PubMed2003

Crystal structure of the 2'-specific and double-stranded RNA-activated interferon-induced antiviral protein 2'-5'-oligoadenylate synthetase.

2'-5'-oligoadenylate synthetases are interferon-induced, double-stranded RNA-activated antiviral enzymes which are the only proteins known to catalyze 2'-specific nucleotidyl transfer. This crystal structure of a 2'-5'-oligoadenylate synthetase reveals a structural conservation with the 3'-specific poly(A) polymerase that, coupled with structure-guided mutagenesis, supports a conserved catalytic mechanism for the 2'- and 3'-specific nucleotidyl transferases. Comparison with structures of other superfamily members indicates that the donor substrates are bound by conserved active site features while the acceptor substrates are oriented by nonconserved regions. The 2'-5'-oligoadenylate synthetases are activated by viral double-stranded RNA in infected cells and initiate a cellular response by synthesizing 2'-5'-oligoadenylates, which in turn activate RNase L. This crystal structure suggests that activation involves a domain-domain shift and identifies a putative dsRNA activation site that is probed by mutagenesis, thus providing structural insight into cellular recognition of viral double-stranded RNA.

2',5'-Oligoadenylate Synthetase↗
PubMed1999

Targeted mRNA degradation by double-stranded RNA in vitro.

Double-stranded RNA (dsRNA) directs gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and has provided a new tool for studying gene function. The biochemical mechanisms underlying this dsRNA interference (RNAi) are unknown. Here we report the development of a cell-free system from syncytial blastoderm Drosophila embryos that recapitulates many of the features of RNAi. The interference observed in this reaction is sequence specific, is promoted by dsRNA but not single-stranded RNA, functions by specific mRNA degradation, and requires a minimum length of dsRNA. Furthermore, preincubation of dsRNA potentiates its activity. These results demonstrate that RNAi can be mediated by sequence-specific processes in soluble reactions.

3' Untranslated Regions↗
PubMed2005

Stable siRNA-mediated silencing of antizyme inhibitor: regulation of ornithine decarboxylase activity.

Ornithine decarboxylase (ODC) is the rate-limiting enzyme involved in the biosynthesis of polyamines essential for cell growth and differentiation. Aberrant upregulation of ODC, however, is widely believed to be a contributing factor in tumorigenesis. Antizyme is a major regulator of ODC, inhibiting ODC activity through the formation of complexes and facilitating degradation of ODC by the 26S proteasome. Moreover, the antizyme inhibitor (AZI) serves as another factor in regulating ODC, by binding to antizyme and releasing ODC from ODC-antizyme complexes. In our previous report, we observed elevated AZI expression in tumor specimens. Therefore, to evaluate the role of AZI in regulating ODC activity in tumors, we successfully down-regulated AZI expression using RNA interference technology in A549 lung cancer cells expressing high levels of AZI. Two AZI siRNAs, which were capable to generate a hairpin dsRNA loop targeting AZI, could successively decrease the expression of AZI. Using biological assays, antizyme activity increased in AZI-siRNA-transfected cells, and ODC levels and activity were reduced as well. Moreover, silencing AZI expression decreased intracellular polyamine levels, reduced cell proliferation, and prolonged population doubling time. Our results directly demonstrate that downregulation of AZI regulates ODC activity, intracellular polyamine levels, and cell growth through regulating antizyme activity. This study also suggests that highly expressed AZI may be partly responsible for increased ODC activity and cellular transformation.

Cell Line, Tumor↗
PubMed2005

Single-molecule measurements of the persistence length of double-stranded RNA.

Over the past few years, it has become increasingly apparent that double-stranded RNA (dsRNA) plays a far greater role in the life cycle of a cell than previously expected. Numerous proteins, including helicases, polymerases, and nucleases interact specifically with the double helix of dsRNA. To understand the detailed nature of these dsRNA-protein interactions, the (bio)chemical, electrostatic, and mechanical properties of dsRNA need to be fully characterized. We present measurements of the persistence length of dsRNA using two different single-molecule techniques: magnetic tweezers and atomic force microscopy. We deduce a mean persistence length for long dsRNA molecules of 63.8 +/- 0.7 nm from force-extension measurements with the magnetic tweezers. We present atomic force microscopy images of dsRNA and demonstrate a new method for analyzing these, which yields an independent, yet consistent value of 62 +/- 2 nm for the persistence length. The introduction of these single-molecule techniques for dsRNA analysis opens the way for real-time, quantitative analysis of dsRNA-protein interactions.

Biophysics↗
PubMed2002

Double-stranded RNA cooperates with interferon-gamma and IL-1 beta to induce both chemokine expression and nuclear factor-kappa B-dependent apoptosis in pancreatic beta-cells: potential mechanisms for viral-induced insulitis and beta-cell death in type 1 diabetes mellitus.

Viral infections may trigger the autoimmune assault leading to type 1 diabetes mellitus. Double-stranded RNA (dsRNA) is produced by many viruses during their replicative cycle. The dsRNA, tested as synthetic poly(IC) (PIC), in synergism with the proinflammatory cytokines interferon-gamma (IFN-gamma) and/or IL-1 beta, results in nitric oxide production, Fas expression, beta-cell dysfunction, and death. Activation of the transcription nuclear factor-kappa B (NF-kappa B) is required for PIC-induced inducible nitric oxide synthase expression in beta-cells, and we hypothesized that this transcription factor may also participate in PIC-induced Fas expression and beta-cell apoptosis. This hypothesis, and the possibility that PIC induces expression of additional chemokines and cytokines (previously reported as NF-kappa B dependent) in pancreatic beta-cells, was investigated in the present study. We observed that the PIC-responsive region in the Fas promoter is located between nucleotides -223 and -54. Site-directed mutations at the NF-kappa B and CCAAT/enhancer binding protein-binding sites prevented PIC-induced Fas promoter activity. Increased Fas promoter activity was paralleled by enhanced susceptibility of PIC + cytokine-treated beta-cells to apoptosis induced by Fas ligand. beta-Cell infection with the NF-kappa B inhibitor AdI kappa B((SA)2) prevented both necrosis and apoptosis induced by PIC + IL-1 beta or PIC + IFN-gamma. Messenger RNAs for several chemokines and one cytokine were induced by PIC, alone or in combination with IFN-gamma, in pancreatic beta-cells. These included IP-10, interferon-gamma-inducible protein-10, IL-15, macrophage chemoattractant protein-1, fractalkine, and macrophage inflammatory protein-3 alpha. There was not, however, induction of IL-1 beta expression. We propose that dsRNA, generated during a viral infection, may contribute for beta-cell demise by both inducing expression of chemokines and IL-15, putative contributors for the build-up of insulitis, and by synergizing with locally produced cytokines to induce beta-cell apoptosis. Activation of the transcription factor NF-kappa B plays a central role in at least part of the deleterious effects of dsRNA in pancreatic beta-cells.

Adenoviridae Infections↗
PubMed1983

Interferon-induced biochemical changes in cell membranes: possible role of cellular enzyme superoxide dismutase.

Interferon exhibits pleotropic effects on homologous cells. Interferons may be used clinically for both antiviral and antitumor therapy. A better understanding of how interferon achieves its hormonal effects should be useful in developing more judicious and specific applications of these natural substances in therapy. Interferon induces increased activity of two enzymes, 2'5'-oligoadenylate synthetase and a protein kinase, that depend on double-stranded RNA for activation. 2'5' A polymerizes ATP into a novel 2'5'-linked oligonucleotide, which in turn can activate a latent cellular nuclease (RNase L) which degrades mRNA. The second dsRNA-dependent enzyme, a protein kinase, phosphorylates a protein of approximately 67,000 daltons as well as the small subunit of eukaryotic initiation factor (eIF-2). The phosphorylation of eIF-2 results in the inhibition of protein synthesis. The extent of sensitivity to exogenous interferon could be influenced by several factors, including the number of cell surface receptors for interferon and the rate and efficiency at which ligand binding and "processing" is achieved. Prostaglandins, cyclic nucleotides, and oxygen-free radicals could participate in modulation of interferon action at this level. Interferon induces specific changes in the composition of membrane lipids. These changes included loss of unsaturated fatty acids from phospholipids, significant increases in levels of unesterified fatty acids, and moderate increases in concentrations of triglycerides and cholesterol esters. The changes were absent in cells treated with interferon in the presence of inhibitors of fatty acid cyclooxygenase or superoxide dismutase. Whether or not interferon-associated lipid changes directly participate in interferon action is not yet clear. Apparent diversity in its mechanistic approach to virus inhibition may be the key to the success of interferon as a wide-spectrum antiviral agent. Heterogeneity in molecular species of interferon may signify its molecular evolutionary adaptations to specific needs and the eventual development of a "fool-proof" system that we now perceive as the "interferon-system." The observed pleotropic effects may be due to linkage to a broader cellular machinery that operates to identify and effectively handle "foreign" substances.

Animals↗
PubMed1998

Production, purification, and characterization of recombinant 2', 5'-oligoadenylate synthetases.

2',5'-Oligoadenylate [2-5(A)] synthetases are a family of interferon-induced enzymes that polymerize ATP into 2'-5'-linked oligoadenylates in the presence of double-stranded RNA (dsRNA), their cofactor. The 2-5(A) molecules, in turn, activate the latent ribonuclease RNase L by promoting its dimerization. The 2-5(A) synthetase pathway has been implicated in interferon's antiviral and anticellular activities. In addition to their interesting cellular properties, these enzymes are also enzymologically interesting because they are the only known template and primer independent nucleotide (DNA or RNA)polymerases that synthesize 2'-5'-linked oligonucleotides. Moreover, their mode of activation by dsRNA remains unknown. In the past, biochemical and structure-function studies have been hampered by the lack of a convenient system for expressing recombinant 2-5(A) synthetases. These proteins are toxic to mammalian cells, probably because of RNase L activation, and proteins produced in bacteria do not have full enzymatic activity. To circumvent these problems, we have developed a baculovirus-insect cell system for high-yield expression of the small and medium isozymes. Here, methods are described for the production, purification, and characterization of the mouse small (9-2) (S. K. Ghosh, J. Kusari, S. K. Bandyopadhyay, H. Samanta, R. Kumar, and G. C. Sen, 1991, J. Biol. Chem. 266, 15293-15299) and human medium (P69) (I. Marie and A. G. Hovanessian, 1992, J. Biol. Chem. 267, 9933-9939) 2-5(A) synthetase isozymes and their mutants using the insect cell system. We also report methods for studying 2-5(A) synthetase-dsRNA interactions and protein-protein interactions among the subunits of the two isozymes.

2',5'-Oligoadenylate Synthetase↗