Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Lee, Jee Hoon; Park, Eun Jung; Kim, Ohn Soon; Kim, Hee Young; Joe, Eun‐Hye; Jou, Ilo

doi:10.1002/glia.20156

Cited by 45 publications

(32 citation statements)

References 37 publications

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“…Consistent with the observation that PKR does not phosphorylate STAT1 directly, the role of PKR seems to be to control a kinase cascade in which ERK2 is the kinase phosphorylating STAT1 (290). STAT1 is also a target for PKR-mediated activation in response to LPS in glial cells (213). PKR also associates with STAT3, and it is required for full STAT3 activation in response to PDGF (73).…”

Section: Statsupporting

confidence: 64%

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

García

Gil

Ventoso

et al. 2006

Microbiol Mol Biol Rev

695

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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Section: Statsupporting

confidence: 64%

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

García

Gil

Ventoso

et al. 2006

Microbiol Mol Biol Rev

695

731

View full text Add to dashboard Cite

show abstract

“…In addition to eIF2-a phosphorylation and inhibition of translation, PKR was reported to control the activation of several transcription factors such as NF-kB, p53, and STATs. 5,13,14 Together with TRAF6, TAK1 and TAB2, PKR is also recruited to TLR3 upon binding of dsRNA. 25 As seen before with RIP1, 34 the catalytic activity of PKR is not required for NF-kB activation.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, apoptosis induced by LPS, tumor-necrosis factor a (TNF-a), viral infection, or serum starvation was suggested to require PKR, 5,13,14 whereas induction of apoptosis by PKR was suggested to involve the activation of the FADD/caspase-8 pathway by a mechanism independent of Fas and TNFR. 15 We demonstrated before that cleavage of PKR by caspases at aspartate 251 occurs in apoptosis and leads to PKR activation, eIF2-a phosphorylation, and inhibition of translation.…”

mentioning

confidence: 99%

The caspase-generated fragments of PKR cooperate to activate full-length PKR and inhibit translation

Kalai¹,

Suin²,

Festjens³

et al. 2007

Cell Death Differ

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We have studied the involvement of receptor interacting protein kinase-1 (RIP1) and dsRNA-activated protein kinase (PKR) in external dsRNA-induced apoptotic and necrotic cell death in Jurkat T cell lymphoma. Our results suggest that RIP1 plays an imported role in dsRNA-induced apoptosis and necrosis. We demonstrated that contrary to necrosis, protein synthesis is inhibited in apoptosis. Here, we show that phosphorylation of translation initiation factor 2-a (eukaryotic initiation factor 2-a (eIF2-a)) and its kinase, PKR, occur in dsRNA-induced apoptosis but not in necrosis. These events are caspase-dependent and coincide with the appearance of the caspase-mediated PKR fragments, N-terminal domain (ND) and kinase domain (KD). Our immunoprecipitation experiments demonstrated that both fragments could independently co-precipitate with full-length PKR. Expression of PKR-KD leads to PKR and eIF2-a phosphorylation and inhibits protein translation, whereas that of PKR-ND does not. Co-expression of PKR-ND and PKR-KD promotes their interaction with PKR, PKR and eIF2-a phosphorylation and suppresses protein translation better than PKR-KD alone. Our findings suggest a caspase-dependent mode of activation of PKR in apoptosis in which the PKR-KD fragment interacts with and activates intact PKR. PKR-ND facilitates the interaction of PKR-KD with full-length PKR and thus the activation of the kinase and amplifies the translation inhibitory signal.

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“…Media nitrite concentration was measured as an indication of NO release, as we have described previously [17]. Data were expressed as mean7SEM.…”

Section: Determination Of Nitric Oxide Releasementioning

confidence: 99%

Oxysterols suppress inducible nitric oxide synthase expression in lipopolysaccharide-stimulated astrocytes through liver X receptor

Lee

Joe²,

Jou³

2006

NeuroReport

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Cholesterols are enriched in the brain and can be oxidized to oxysterols by several processes. Oxysterols are transport forms of cholesterols across cell membranes and the blood^brain barrier. Here, to elucidate the roles of oxysterols in brain in£ammation, we treated lipopolysaccharide-stimulated rat brain astrocytes with two oxysterols, 7-ketocholesterol and 22(R)-hydroxycholesterol. Both oxysterols suppressed inducible nitric oxide synthase expression and nitric oxide release as well as upstream signaling molecules including interferon-b, phosphorylated signal transducer and activator of transcription 1/3, and interferon regulatory factor-1. Oxysterols are known as liver X receptor agonists, and inhibitory e¡ects were also observed with synthetic agonists of liver X receptor and retinoid X receptor. Thus, we conclude that it is most likely mediated by liver X receptor/retinoid X receptor heterodimers. NeuroReport 17:183^187

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Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Cited by 45 publications

References 37 publications

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

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

The caspase-generated fragments of PKR cooperate to activate full-length PKR and inhibit translation

Oxysterols suppress inducible nitric oxide synthase expression in lipopolysaccharide-stimulated astrocytes through liver X receptor

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