Involvement of Double-stranded RNA-activated Protein Kinase in the Synergistic Activation of Nuclear Factor-κB by Tumor Necrosis Factor-α and γ-Interferon in Preneuronal Cells

Cheshire, Jeanette L.; Williams, Bryan R.G.; Baldwin, Albert S.

doi:10.1074/jbc.274.8.4801

Cited by 64 publications

(65 citation statements)

References 66 publications

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“…The need of PKR kinase activity for NF-kB activation is also supported by the previous observation that 2-aminopurine, an inhibitor of PKR catalytic activity, is able to inhibit NF-kB activation induced by PKR (Kumar et al, 1994;Cheshire et al, 1999). However, another study has suggested that PKR kinase dead mutant is able to activate NF-kB (Chu et al, 1999).…”

Section: Discussionsupporting

confidence: 54%

“…It has been shown that PKR-mediated activation of NF-kB can be inhibited by blocking PKR catalytic activity using the chemical inhibitor 2-aminopurine (Kumar et al, 1994;Cheshire et al, 1999). However, more recently another study suggested that expression of a PKR K296R point mutant lacking catalytic activity, was able to activate the IKK complex, (Chu et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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The catalytic activity of dsRNA-dependent protein kinase, PKR, is required for NF-κB activation

et al. 2001

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The double stranded RNA-dependent protein kinase (PKR), in addition to its role as a translational controlling factor, is a key transcriptional regulator exerting antiviral and antitumoral activities. We have previously shown that induction of NF-kB by PKR is involved in apoptosis commitment and this process is mediated through activation of the IKK complex. To gain insights into the mechanism of activation of NF-kB by PKR, we have analysed the domains of PKR involved in IKK activation and subsequent NF-kB induction. In PKR 0/0 cells infected with a collection of vaccinia virus (VV) recombinants expressing di erent mutant forms of PKR, we found that only PKR forms conserving the catalytic activity are able to activate NF-kB. An inactive PKR mutant (K296R), was unable to induce NF-kB activation despite full expression of the protein in a wide range of concentrations, as de®ned by Western blot, EMSA, IKK kinase activity and NF-kB transactivation assays. Moreover, the mutant PKR (K296R) acts as a dominant negative of PKR-induced eIF-2a phosphorylation and NF-kB activation. However, PKR mutants unable to activate NF-kB still retain their ability to associate with the IKK complex, as con®rmed by immunoprecipitation analysis. We conclude that the catalytic activity of PKR and not only a protein-protein interaction with the IKK complex, is needed for activation of the transcription factor NF-kB. Oncogene (2001) 20, 385 ± 394.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

The catalytic activity of dsRNA-dependent protein kinase, PKR, is required for NF-κB activation

et al. 2001

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“…Published studies have shown that combined TNF and IFNg treatment enhanced NF-kB activation in preneuronal cells and fibroblasts. 31,33,34 Ouaaz et al 31 demonstrated that cytotoxicity of TNF was enhanced by addition of IFN-g in mouse embryonic fibroblasts. This cytotoxicity was shown to be because of apoptosis induced by interaction of Fas and FasL, and the activation of NF-kB induced by combined treatment with TNF and IFN-g was demonstrated to function in a proapoptotic manner.…”

Section: Discussionmentioning

confidence: 99%

TNF combined with IFN-α accelerates NF-κB-mediated apoptosis through enhancement of Fas expression in colon cancer cells

et al. 2003

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Immunostaining and EMSA revealed that NF-jB was activated strongly by TNF/IFN-a compared to TNF alone in a human colon adenocarcinoma cell line, RPMI4788. Although inhibition of activated NF-jB, by using an NF-jB decoy, reduced cell viability after treatment with TNF only, NF-jB decoy resulted in recovery of cell viability after TNF/IFN-a treatment. Caspase-3 activity was increased in cells induced by TNF/IFNa, while suppression of caspase-3 activity was observed in cells transfected with NF-jB decoy and then treated by TNF/ IFN-a. On the other hand, Fas expression was strongly enhanced by TNF/IFN-a, and inhibition of TNF/IFN-a-induced NF-jB activation, by using NF-jB decoy, decreased Fas expression. Cell viability and caspase-3 activity decreased in cells treated with TNF/IFN-a and anti-FasL antibody. Taken together, our findings suggest that activated NF-jB induced by the crosstalk between TNF and IFN-a is a novel proapoptotic signal acting via enhancement of Fas expression.

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“…The link between the TNF signaling pathway and PKR activation also remains to be determined. There is a de®ciency in TNF signaling of NF-kB in PKR null cells or in cells expressing transdominant mutants of PKR that is manifest in an inability to sustain NF-kB activation (ZamanianDaryoush et al, 1999;Chesire et al, 1999). Therefore, the defect in apoptosis induction by TNFa in PKR null cells could be due in part to a failure to upregulate the expression of antiapoptotic genes dependent on NF-kB.…”

Section: Signaling Via Pkrmentioning

confidence: 99%

PKR; a sentinel kinase for cellular stress

1999

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Involvement of Double-stranded RNA-activated Protein Kinase in the Synergistic Activation of Nuclear Factor-κB by Tumor Necrosis Factor-α and γ-Interferon in Preneuronal Cells

Abstract: Tumor necrosis factor-␣ (TNF-␣) and ␥-interferon

Cited by 64 publications

References 66 publications

The catalytic activity of dsRNA-dependent protein kinase, PKR, is required for NF-κB activation

The catalytic activity of dsRNA-dependent protein kinase, PKR, is required for NF-κB activation

TNF combined with IFN-α accelerates NF-κB-mediated apoptosis through enhancement of Fas expression in colon cancer cells

PKR; a sentinel kinase for cellular stress

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