Blockage of NF-κB Signaling by Selective Ablation of an mRNA target by 2-5A Antisense Chimeras

Maran, Avudaiappan; Maitra, Ratan K.; Kumar, Aseem; Dong, Bin; Xiao, Wei; Li, Guiying; Williams, Bryan R.G.; Torrence, Paul F.; Silverman, Robert H.

doi:10.1126/science.7914032

Cited by 221 publications

(189 citation statements)

References 30 publications

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“…In addition, a long-term and productive collaboration with chemist, Paul Torrence at the National Institutes of Health continued after the move to Cleveland. These efforts were aimed at directing RNase L to cleave target RNAs in vivo [48,49]. Cloning of RNase L provided the first real insight into the enzyme and contributed to, or was complemented by, many interesting and important findings by several different labs.…”

Section: Molecular Cloning Of Rnase Lmentioning

confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

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Section: Molecular Cloning Of Rnase Lmentioning

confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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“…For our initial studies, therefore, we selected U251-MG cells for antisense treatment because they had the highest level of telomerase activity. Previous experience with targeting the PKR mRNA (Maran et al, 1994) and an RSV mRNA (Cirino et al, 1997) using speci®c 2-5A-linked oligonucleotides had demonstrated that the target RNA was degraded after 4 ± 5 h. We therefore treated aliquots of U251-MG cells with the`active' oligonucleotide and the two controls for 5 h. RNA was then prepared from these cells and subjected to RT ± PCR to detect telomerase RNA. GAPDH mRNA was used to demonstrate a lack of non-speci®c activity of these oligonucleotides in these cells.…”

Section: E Ect Of Antisense Telomerase In Vitromentioning

confidence: 99%

“…2-5A antisense refers to a class of oligonucleotide therapeutic agents that cause the catalytic breakdown of target RNA molecules Maran et al, 1994;Maitra et al, 1995;Cirino et al, 1997). These drugs contain a 2',5'-linked tetraadenylate (2-5A) covalently attached through linkers to antisense oligonucleotides.…”

Section: Introductionmentioning

confidence: 99%

“…RNase L is a ubiquitous protein that has no detectable ribonuclease activity until it comes into contact with 2-5A. Attachment of 2-5A to antisense oligonucleotides greatly enhances the degradation rates of target RNA molecules in intact, human cells (Maran et al, 1994;Cirino et al, 1997). In essence, the 2-5A component of the oligonucleotide activates RNase L while the antisense segment of the chimera directs RNase L to the target RNA molecule.…”

Section: Introductionmentioning

confidence: 99%

“…In essence, the 2-5A component of the oligonucleotide activates RNase L while the antisense segment of the chimera directs RNase L to the target RNA molecule. For example, unfacilitated uptake of 2-5A antisense into human HeLa cells resulted in the ablation of a cellular mRNA for protein kinase PKR (Maran et al, 1994). Recently, the recruitment of RNase L by 2-5A antisense to a respiratory syncytial virus (RSV) mRNA resulted in a potent inhibition of RSV replication in human tracheal epithelial cells (Cirino et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA

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Synthetic influenza viral double-stranded RNA induces an acute-phase response in rabbits

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Numerous studies have characterized the physiological effects of synthetic, high-molecular-weight, homopolymeric, double-stranded RNA (dsRNA), particularly polyriboinosinic.polyribocytidylic acid [Carter and De Clercq (1974): Science 186:1172-1178], but limited information exists regarding the physiological effects of dsRNA of viral composition and size. In this report, we determined sleep and fever responses of rabbits to intracerebroventricular injection of different doses of synthetic viral dsRNA (either 108 base pairs or 661 base pairs) derived from the N-terminal sequence of gene segment 3 of the A/PR/8/34-H1N1 (PR8) influenza virus. Both the108-mer and the 661-mer dsRNAs increased nonrapid eye movement sleep, suppressed rapid eye movement sleep, and induced fever. The 661-mer dsRNA had more potent somnogenic and pyrogenic effects than the 108-mer dsRNA on the basis of weight. Neither single-stranded RNA from the corresponding sequences had significant effects on sleep or brain temperature. These results demonstrate for the first time that low-molecular-weight, viral dsRNA has the stability in vivo that is required to induce the fever and sleep changes found in natural viral infections, and the hypothesis is supported that virus-associated dsRNA may be responsible for initiating the acute-phase response during viral infections.

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Blockage of NF-κB Signaling by Selective Ablation of an mRNA target by 2-5A Antisense Chimeras

Cited by 221 publications

References 30 publications

A scientific journey through the 2-5A/RNase L system

A scientific journey through the 2-5A/RNase L system

Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA

Synthetic influenza viral double-stranded RNA induces an acute-phase response in rabbits

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