Ribotoxic Stress Response: Activation of the Stress-Activated Protein Kinase JNK1 by Inhibitors of the Peptidyl Transferase Reaction and by Sequence-Specific RNA Damage to the α-Sarcin/Ricin Loop in the 28S rRNA

Iordanov, Mihail S.; Pribnow, David; Magun, Jennifer L.; Dinh, Thanh Hoai; Pearson, Jean A.; Chen, Steven Li Ye; Magun, Bruce E.

doi:10.1128/mcb.17.6.3373

Cited by 434 publications

(520 citation statements)

References 51 publications

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“…To explore the relationship between these two phenomena, we first checked the activation status of mitogen-activated protein kinase family because mitogen-activated protein kinases, especially c-Jun NH 2 -terminal kinase, were reported to be activated by a ribotoxic stress response (Iordanov et al, 1997;Laskin et al, 2002). Interestingly, we only detected p38 activation, but not either c-Jun NH 2 -terminal kinase or ERK, in rpS3 depleted cells ( Figure 2a).…”

Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 97%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

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Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 97%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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“…By comparison, the fungal ribonuclease, α-sarcin, and the RNA modifying enzyme, ricin A chain, and uv light each lead to ribotoxic stress responses involving damage to the 3′-end of the large ribosomal RNA. These treatments activate the stress-activate protein kinases, c-jun NH2-terminal kinases (JNKs) [113,114]. JNK activation in response to uv irradiation has been linked to apoptosis through Bax [115].…”

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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“…Induction of the MIC-1 gene in response to 2-5A required stimulation of the MAP kinases, JNK and ERK, and the catalytic function of RNase L. There are significant gaps in our understanding of the transcriptional signaling pathways mediated by 2-5A activation of RNase L. For example, how RNase L activity stimulates JNK and ERK and the downstream events to gene induction are unknown. However, JNK is activated in response to different treatments that cleave or modify rRNA in intact ribosomes (including ricin A, alpha sarcin, uv light, and RNase L) [81,87,88]. Because some of the RNase L-induced genes have antiviral functions, this phenomenon could be contributing to the antiviral effect of 2-5A.…”

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

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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Ribotoxic Stress Response: Activation of the Stress-Activated Protein Kinase JNK1 by Inhibitors of the Peptidyl Transferase Reaction and by Sequence-Specific RNA Damage to the α-Sarcin/Ricin Loop in the 28S rRNA

Cited by 434 publications

References 51 publications

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Diverse functions of RNase L and implications in pathology

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

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