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NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase

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Abstract

Activation of the nuclear transcription factor NF-κB by inflammatory cytokines requires the successive action of NF-κB-inducing kinase (NIK) and an IκB-kinase (IKK) complex composed of IKKα and IKKβ1,2,3,4,5. Here we show that the Akt serine–threonine kinase6 is involved in the activation of NF-κB by tumour necrosis factor (TNF). TNF activates phosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (protein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI(3)K or kinase-dead Akt inhibits TNF-mediated NF-κB activation. Constitutively active Akt induces NF-κB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-κB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-κB. Akt mediates IKKα phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-κB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.

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Figure 1: Activation of PI(3)K and Akt by TNF.
Figure 2: NF-κB activation by a TNF-stimulated PI(3)K–Akt pathway.
Figure 3: NF-κB reporter activity in cells transfected with empty vector, CA-AKT or KD-Akt and then treated with vehicle or TNF.
Figure 4: Association of Akt with IKKα.
Figure 5: Threonine 23 in IKKα is a phosphorylation site for Akt.
Figure 6

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Acknowledgements

L.D.M. is supported by a Hematology Oncology Training Grant from NIH. This work was supported by grants from NIH to D.B.D. and L.M.P.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine and the Walther Oncology Center, Indianapolis, 46202, Indiana, USA

    Osman Nidai Ozes, Lindsey D. Mayo, Jason A. Gustin & David B. Donner

  2. Department of Pathology, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, USA

    Susan R. Pfeffer & Lawrence M. Pfeffer

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  1. Osman Nidai Ozes
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  2. Lindsey D. Mayo
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  3. Jason A. Gustin
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  4. Susan R. Pfeffer
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  5. Lawrence M. Pfeffer
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  6. David B. Donner
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Correspondence to David B. Donner.

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Nidai Ozes, O., Mayo, L., Gustin, J. et al. NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase. Nature 401, 82–85 (1999). https://doi.org/10.1038/43466

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