The 2′-5′ Oligoadenylate/RNase L/RNase L Inhibitor Pathway Regulates Both MyoD mRNA Stability and Muscle Cell Differentiation

Bisbal, Catherine; Silhol, Michelle; Laubenthal, H.; Kaluza, T.; Carnac, Gilles; Milligan, Laura; Roy, Florence Le; Salehzada, Tamim

doi:10.1128/mcb.20.14.4959-4969.2000

Cited by 84 publications

(78 citation statements)

References 44 publications

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“…Studies of subcellular localization of RNase L showed that RNase L could be associated with polysomes [24], mitochondria [100], cytoskeleton [101] and nuclei [102], suggesting that RNase L could regulates the stability of different cellular RNA species in different cellular compartments. Conditional expression of RNase L showed that RNase L regulates MyoD mRNA stability and muscle cell differentiation [103]. RNase L in mitochondria regulates mitochondrial mRNA stability and possibly contributing to the antiproliferative activity of IFNs [100].…”

Section: ) Regulation Of Cellular Mrna Stabilitymentioning

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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Section: ) Regulation Of Cellular Mrna Stabilitymentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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“…12 RNase L is an endoribonuclease which has little sequence specificity as it cleaves RNA 3 0 of UpNp nucleotides. 6,7 On the other hand, only a few cellular RNAs have been identified as regulated by RNase L: rRNA, 16 IFN-induced genes ISG43 and ISG15 mRNAs, 17 mitochondrial mRNAs, 12,18 MyoD mRNA during C2 myoblast differentiation 19 and PKR mRNA. 20 RNase L activity is regulated not only by 2-5A binding, but also by interaction with other proteins.…”

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confidence: 99%

Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNα-induced apoptosis

et al. 2007

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Interferons (IFNs) inhibit the growth of many different cell types by altering the expression of specific genes. IFNs activities are partly mediated by the 2 0 -5 0 oligoadenylates-RNase L RNA decay pathway. RNase L is an endoribonuclease requiring activation by 2 0 -5 0 oligoadenylates to cleave single-stranded RNA. Here, we present evidence that degradation of mitochondrial mRNA by RNase L leads to cytochrome c release and caspase 3 activation during IFNa-induced apoptosis. We identify and characterize the mitochondrial translation initiation factor (IF2mt) as a new partner of RNase L. Moreover, we show that specific inhibition of mitochondrial translation with chloramphenicol inhibits the IFNa-induced degradation of mitochondrial mRNA by RNase L. Finally, we demonstrate that overexpression of IF2mt in human H9 cells stabilizes mitochondrial mRNA, inhibits apoptosis induced by IFNa and partially reverses IFNa-cell growth inhibition. On the basis of our results, we propose a model describing how RNase L regulates mitochondrial mRNA stability through its interaction with IF2mt. Apoptosis is a regulated cell death process that plays a central role in the control of many physiological events. Cells die by apoptosis during embryonic development, tissue homeostasis or immune regulation and defects in the apoptotic pathway during these events can lead to excessive cell accumulation with dramatic consequences. 1-3 Interferons (IFNs) are among the regulators of apoptosis. They belong to a family of cytokines produced and secreted by mammalian cells in response to various inducers. They are negative regulators of cell proliferation through induction of cell-cycle arrest and apoptosis, but the mechanisms are not yet fully understood. The 2-5A/RNase L pathway is a single-stranded RNA (ssRNA) decay pathway induced by IFNs: the 2-5A synthetases are induced by IFNs and upon activation by doublestranded RNA (dsRNA), convert ATP into a series of oligomers known as 2 0 -5 0 oligoadenylates (2-5A). 4,5 The 2-5A activates RNase L, a latent endoribonuclease, which inhibits protein synthesis by cleaving ssRNA. 6,7 RNase L plays a central role in IFNs cell growth inhibition and in IFN-induced apoptosis. [8][9][10][11][12] Activation of RNase L causes caspase-dependent apoptosis accompanied by cytochrome c release from the mitochondria. 13 20 RNase L activity is regulated not only by 2-5A binding, but also by interaction with other proteins. It has been shown previously that RNase L can form a heterodimer with the RNase L inhibitor (RLI), a protein that inhibits 2-5A binding to RNase L, resulting in an inhibition of RNase L activity. 21,22 More recently, we demonstrated that RNase L interacts with the translation termination release factor eRF3/GSPT1 and that their interaction is important for its role in translation termination regulation. 23 We set out to identify other potential RNase L partners to better comprehend its mechanism of action. In the present study, a yeast two-hybrid screening, using human RNase L as bait identifies ...

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“…This pathway is reviewed by Silverman and Bisbal in this same issue. In recent years, it has been accepted that RNase L participates in the degradation of selected cellular mRNAs [63][64][65][66][67]. Specifically, RNase L has been shown to downregulate PKR mRNA [64].…”

Section: The Role Of Ifn-regulated Rnase L and Pkr In The Post-transcmentioning

confidence: 99%

Section: The Role Of Ifn-regulated Rnase L and Pkr In The Post-transcmentioning

confidence: 99%

“…RNase L and its inhibitor RLI are sequentially induced during C2 cell line myoblast differentiation to myotubes [63]. Inhibition or over-expression of RNAse L prolongs or decreases MyoD mRNA half life, respectively [63]. Activated by the localization of a fraction of RNase L in mitochondria that increases with IFN-α treatment, a role of RNAse L in down-regulating miotchondria mRNAs such as those of CYTB), ATPase 6 (ATP6), and cytochrome oxidase II (CO) has been established and proposed as a mechanism of the anti-proliferative action of IFN [66].…”

Section: The Role Of Ifn-regulated Rnase L and Pkr In The Post-transcmentioning

confidence: 99%

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Post-transcriptional control of the interferon system

Khabar

Young

2007

Biochimie

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The interferon (IFN) system is a well-controlled network of signaling, transcriptional, and posttranscriptional processes that orchestrate host defense against microbes. The IFN response comprises a multi-array of IFN-stimulated gene products that mediate a variety of biological processes designed to control infection and regulate specific immune responses. In this review, we focus on posttranscriptional mechanisms of gene regulation that occur during the course of IFN induction and during the response of cells to IFN. Post-transcriptional mechanisms involve different levels of regulation such as mRNA stability, alternative splicing, and translation. Such controls offer a fine tuning mechanism for efficient and rapid response and as a negative feedback control in IFN biosynthesis and response.

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The 2′-5′ Oligoadenylate/RNase L/RNase L Inhibitor Pathway Regulates Both MyoD mRNA Stability and Muscle Cell Differentiation

Cited by 84 publications

References 44 publications

Diverse functions of RNase L and implications in pathology

Diverse functions of RNase L and implications in pathology

Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNα-induced apoptosis

Post-transcriptional control of the interferon system

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