Identification of 69-kd and 100-kd forms of 2-5A synthetase in interferon-treated human cells by specific monoclonal antibodies.

Hovanessian, Ara G.; Laurent, A G; Chebath, Judith; Galabru, Julien; Robert, N.; Svab, Josette

doi:10.1002/j.1460-2075.1987.tb02364.x

Cited by 121 publications

(128 citation statements)

References 37 publications

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“…IFN␣ treatment increases the RNase L level in mitochondria (Fig. 1) as it was shown for 2-5A synthetase (35). It was therefore conceivable that IFN␣ treatment could activate the 2-5A/RNase L pathway in mitochondria and promote the destabilization of mitochondrial mRNAs, as described here.…”

Section: -E) No Mitochondrial Mrnas Destabilization Is Observed Aftesupporting

confidence: 72%

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The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Roy¹,

Bisbal²,

Silhol³

et al. 2001

Journal of Biological Chemistry

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Interferon ␣ (IFN␣) belongs to a cytokine family that exhibits antiviral properties, immuno-modulating effects, and antiproliferative activity on normal and neoplasic cells in vitro and in vivo. IFN␣ exerts antitumor action by inducing direct cytotoxicity against tumor cells. This toxicity is at least partly due to induction of apoptosis. Although the molecular basis of the inhibition of cell growth by IFN␣ is only partially understood, there is a direct correlation between the sensitivity of cells to the antiproliferative action of IFN␣ and the down-regulation of their mitochondrial mRNAs. Here, we studied the role of the 2-5A/RNase L system and its inhibitor RLI in this regulation of the mitochondrial mRNAs by IFN␣. We found that a fraction of cellular RNase L and RLI is localized in the mitochondria. Thus, we down-regulated RNase L activity in human H9 cells by stably transfecting (i) RNase L antisense cDNA or (ii) RLI sense cDNA constructions. In contrast to control cells, no post-transcriptional down-regulation of mitochondrial mRNAs and no cell growth inhibition were observed after IFN␣ treatment in these transfectants. These results demonstrate that IFN␣ exerts its antiproliferative effect on H9 cells at least in part via the degradation of mitochondrial mRNAs by RNase L. Interferons (IFNs)1 belong to a family of cytokines produced and secreted by mammalian cells in response to various stimuli. Although originally discovered due to their participation in cellular defense against viral infection (1), IFNs are also known to modulate immune responses as well as control various cellular functions by altering the transcription of a large family of genes involved in cell proliferation and differentiation (2, 3).IFNs are negative regulators of cell proliferation through induction of cell cycle arrest and apoptosis, which has also been suggested to be of central importance in IFN antitumor action. IFN␣ (type I family) has emerged as a tumor suppressor protein. A number of clinical trials were thus carried out in cancer therapy with IFN␣ alone or in combination with other negative regulators of cell proliferation (4, 5). It has been shown to be effective against hematological malignancies including hairy cell leukemia, chronic myelogenous leukemia, and cutaneous T-cell lymphoma (6). IFN␣ has been used successfully in cancer therapy, but development of resistance to IFN␣ therapy has often been observed in patients. Although the molecular basis of the inhibition of cell growth by IFN␣ is partially understood, there is a correlation between the sensitivity of cells to the antiproliferative action of IFN␣ and the down-regulation of their mitochondrial mRNAs and the impairment of mitochondrial function upon IFN␣ treatment (7,8).In this work, we have studied the role of one of the enzymatic pathways induced by IFN␣, the 2-5A/RNase L pathway, in the regulation of mitochondrial mRNAs. The 2-5A/RNase L pathway is an RNA degradation pathway (9). IFN␣ induces the expression of 2-5A synthetase(s) which, upon activation by dou...

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Section: -E) No Mitochondrial Mrnas Destabilization Is Observed Aftesupporting

confidence: 72%

“…These results presented the possibility that RNase L may degrade mitochondrial mRNAs after IFN␣ treatment. Furthermore, previous reports describe the presence of the p69 isoform of 2-5A synthetase in mitochondria (35,36). IFN␣ treatment increases the RNase L level in mitochondria (Fig.…”

Section: -E) No Mitochondrial Mrnas Destabilization Is Observed Aftementioning

confidence: 90%

The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Roy¹,

Bisbal²,

Silhol³

et al. 2001

Journal of Biological Chemistry

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“…Yanase and coworkers have shown that during IFNα induced apoptosis there is a release of cytochrome c from mitochondria, a decline in mitochondrial membrane potential and caspase 3 activation [121]. The different partners of the 2-5A pathway are localized in mitochondria: RNase L, RLI and p69 form of 2-5A-synthetase [100,122,123]. This pathway is induced by IFNα treatment and RNase L participates in mitochondrial mRNA degradation.…”

Section: ) Apoptosismentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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The endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway involved in the molecular mechanism of interferons (IFN). RNase L is a very unusual nuclease with a complex mechanism of regulation. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A. 2-5A is a series of unique 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds. By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism. The 2-5A/RNase L pathway is implicated in mediating apoptosis in response to viral infections and to several types of external stimuli. Several recent studies have suggested that RNase L could have a role in cancer biology and evidence of a tumor suppressor function of RNase L has emerged from studies on the genetics of hereditary prostate cancer. KeywordsInterferon; RNase L; RNA expression; apoptosis; prostate; virus; cancer I) IntroductionThe endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway regulated by interferons (IFN) [1] (Figure 1). The 2-5A system is one of the two antiviral pathways induced by IFN and activated by double stranded RNA (dsRNA), the other is mediated by the dsRNA dependent protein kinase (PKR) [2]. RNase L is a very unusual nuclease. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A ( Figure 1). 2-5A itself is very unusual, consisting of a series of 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds in contrast to the 3′-5′ linkages found in RNA and DNA. The initial and essential observation was made by Ian Kerr's group in 1974 reporting an IFN-induced increase in the sensitivity of protein synthesis to inhibition by dsRNA [3]. Peter Lengyel's group observed increased nuclease activity in extracts of interferon treated cells incubated with dsRNA [4,5]. The identification by Ian Kerr's group of the activators of this nuclease, 2-5A [6] and of the enzyme responsible for their synthesis, the 2-5A-synthetase [7][8][9], led to the discovery of the 2-5A pathway. Clemens and Williams directly demonstrated a nuclease, now recognized as RNase 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, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 2). The N-terminal domain could be considered as the regulatory domain of RNase L. It is composed of eight complete and one partial ankyrin motifs (R1-R9). Two wal...

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“…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.…”

Section: Background On the 2-5a/rnase L Systemmentioning

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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Identification of 69-kd and 100-kd forms of 2-5A synthetase in interferon-treated human cells by specific monoclonal antibodies.

Cited by 121 publications

References 37 publications

The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Diverse functions of RNase L and implications in pathology

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

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