Ribosomal protein L22 inhibits regulation of cellular activities by the Epstein‐Barr virus small RNA EBER‐1

Elia, Androulla; Vyas, Jashmin J.; Laing, Ken; Clemens, Michael J.

doi:10.1111/j.1432-1033.2004.04099.x

Cited by 40 publications

(27 citation statements)

References 69 publications

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“…First, replication of vesicular stomatitis virus, a virus sensitive to the antiviral function of PKR (37), is equivalent in B-cell lines immortalized with either a wild-type EBV or a mutant virus lacking the EBER genes and is equivalently repressed in both lines by IFN-␣ treatment (38). Second, the EBERs are normally in a complex with rpL22, an interaction that in vitro can exclude binding by PKR (4), and third, activation of PKR is not prevented upon infection of EBV/EBERpositive cells with mutant adenovirus that does not express the PKR-inhibiting VAI small RNA (43). We conclude, therefore, that EBER inhibition of IFN-␣-induced apoptosis in latently infected cells must occur downstream of PKR activation.…”

Section: Ebv and Eber Inhibition Of Ifn-␣-induced Apoptosismentioning

confidence: 85%

Protection from Interferon-Induced Apoptosis by Epstein-Barr Virus Small RNAs Is Not Mediated by Inhibition of PKR

Ruf

Lackey

Warudkar

et al. 2005

J Virol

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The Epstein-Barr virus (EBV) EBER transcripts are small, highly structured RNAs able to bind to and inhibit activation of the double-stranded RNA-dependent protein kinase PKR in cell-free systems, and within latently infected B-cell lines they inhibit alpha interferon-induced apoptosis that is believed to be mediated through PKR. Here, we address the consequences of EBER expression for PKR activation in vivo in response to alpha interferon. In agreement with published findings, either EBV infection or the EBERs alone protected Burkitt lymphoma cells from alpha-interferon-induced apoptosis. However, utilizing multiple phosphorylation state-specific antibodies to monitor PKR activation within cells in response to interferon, we demonstrate that the EBERs are unable to inhibit phosphorylation of either cytoplasmic or nuclear PKR. Concordantly, a direct substrate of PKR, the ␣ subunit of eukaryotic initiation factor 2 (eIF-2␣), was equally phosphorylated in EBV-positive and EBV-negative cells following interferon treatment. Therefore, EBER inhibition of alphainterferon-induced apoptosis, and potentially other PKR-mediated events, is unlikely to be mediated through direct inhibition of PKR, as previously thought.

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Section: Ebv and Eber Inhibition Of Ifn-␣-induced Apoptosismentioning

confidence: 85%

Protection from Interferon-Induced Apoptosis by Epstein-Barr Virus Small RNAs Is Not Mediated by Inhibition of PKR

Ruf

Lackey

Warudkar

et al. 2005

J Virol

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“…There is no published evidence to support a role for most genes in the region (Table 1) as TSGs in cancer generally, or neuroblastomas in particular. RPL22 recruits the EpsteinBarr early RNA and is linked to lymphoma associated with Epstein-Barr virus (Elia et al, 2004;Fok et al, 2006). ICMT is an isoprenylcysteine methyltransferase that has been implicated in carcinogenesis and as a target for anticancer therapy (Bergo et al, 2004;WinterVann et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas

et al. 2007

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Neuroblastomas are characterized by 1p deletions, suggesting that a tumor suppressor gene (TSG) resides in this region. We have mapped the smallest region of deletion (SRD) to a 2 Mb region of 1p36.31 using microsatellite and single nucleotide polymorphisms. We have identified 23 genes in this region, and we have analysed these genes for mutations and RNA expression patterns to identify candidate TSGs. We sequenced the coding exons of these genes in 30 neuroblastoma cell lines. Although rare mutations were found in 10 of the 23 genes, none showed a pattern of genetic change consistent with homozygous inactivation. We examined the expression of these 23 genes in 20 neuroblastoma cell lines, and most showed readily detectable expression, and no correlation with 1p deletion. However, 7 genes showed uniformly low expression in the lines, and 2 genes (CHD5, RNF207) had virtually absent expression, consistent with the expected pattern for a TSG. Our mutation and expression analysis in neuroblastoma cell lines, combined with expression analysis in normal tissues, putative function and prior implication in neuroblastoma pathogenesis, suggests that the most promising TSG deleted from the 1p36 SRD is CHD5, but TNFRSF25, CAMTA1 and AJAP1 are also viable candidates.

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“…Comparison of EBER-positive and -negative viruses demonstrated that the small RNA contributes significantly to the efficiency of EBV growth transformation of B cells (385). Ribosomal protein L22 competes with PKR for binding to RNA, thereby halting the PKR inhibition by EBER-1 (89). As a result of this competition, L22 interferes with the ability of the small RNA to inhibit PKR activation by dsRNA, suggesting that L22 may exert a protective effect in vivo against the transforming potential of EBER-1 and EBV.…”

Section: Herpesviruses (I) Hsv-1mentioning

confidence: 99%

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

García

Gil

Ventoso

et al. 2006

Microbiol Mol Biol Rev

694

731

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SUMMARY The double-stranded RNA-dependent protein kinase PKR is a critical mediator of the antiproliferative and antiviral effects exerted by interferons. Not only is PKR an effector molecule on the cellular response to double-stranded RNA, but it also integrates signals in response to Toll-like receptor activation, growth factors, and diverse cellular stresses. In this review, we provide a detailed picture on how signaling downstream of PKR unfolds and what are the ultimate consequences for the cell fate. PKR activation affects both transcription and translation. PKR phosphorylation of the alpha subunit of eukaryotic initiation factor 2 results in a blockade on translation initiation. However, PKR cannot avoid the translation of some cellular and viral mRNAs bearing special features in their 5′ untranslated regions. In addition, PKR affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-κB. In particular, how PKR triggers a cascade of events involving IKK phosphorylation of IκB and NF-κB nuclear translocation has been intensively studied. At the cellular and organism levels PKR exerts antiproliferative effects, and it is a key antiviral agent. A point of convergence in both effects is that PKR activation results in apoptosis induction. The extent and strength of the antiviral action of PKR are clearly understood by the findings that unrelated viral proteins of animal viruses have evolved to inhibit PKR action by using diverse strategies. The case for the pathological consequences of the antiproliferative action of PKR is less understood, but therapeutic strategies aimed at targeting PKR are beginning to offer promising results.

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Ribosomal protein L22 inhibits regulation of cellular activities by the Epstein‐Barr virus small RNA EBER‐1

Cited by 40 publications

References 69 publications

Protection from Interferon-Induced Apoptosis by Epstein-Barr Virus Small RNAs Is Not Mediated by Inhibition of PKR

Protection from Interferon-Induced Apoptosis by Epstein-Barr Virus Small RNAs Is Not Mediated by Inhibition of PKR

Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

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