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NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.
Nature. 1999 Sep 02; 401(6748):82-5.Nat

Abstract

Activation of the nuclear transcription factor NF-kappaB by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and an IKB-kinase (IKK) complex composed of IKKalpha and IKKbeta. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-kappaB 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-kappaB activation. Constitutively active Akt induces NF-kappaB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-kappaB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappaB. Akt mediates IKKalpha phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.

Authors+Show Affiliations

Department of Microbiology and Immunology, Indiana University School of Medicine, the Walther Oncology Center, Indianapolis 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10485710

Citation

Ozes, O N., et al. "NF-kappaB Activation By Tumour Necrosis Factor Requires the Akt Serine-threonine Kinase." Nature, vol. 401, no. 6748, 1999, pp. 82-5.
Ozes ON, Mayo LD, Gustin JA, et al. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999;401(6748):82-5.
Ozes, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., & Donner, D. B. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature, 401(6748), 82-5.
Ozes ON, et al. NF-kappaB Activation By Tumour Necrosis Factor Requires the Akt Serine-threonine Kinase. Nature. 1999 Sep 2;401(6748):82-5. PubMed PMID: 10485710.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. AU - Ozes,O N, AU - Mayo,L D, AU - Gustin,J A, AU - Pfeffer,S R, AU - Pfeffer,L M, AU - Donner,D B, PY - 1999/9/15/pubmed PY - 2001/3/23/medline PY - 1999/9/15/entrez SP - 82 EP - 5 JF - Nature JO - Nature VL - 401 IS - 6748 N2 - Activation of the nuclear transcription factor NF-kappaB by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and an IKB-kinase (IKK) complex composed of IKKalpha and IKKbeta. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-kappaB 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-kappaB activation. Constitutively active Akt induces NF-kappaB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-kappaB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappaB. Akt mediates IKKalpha phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses. SN - 0028-0836 UR - https://www.unboundmedicine.com/medline/citation/10485710/NF_kappaB_activation_by_tumour_necrosis_factor_requires_the_Akt_serine_threonine_kinase_ L2 - https://doi.org/10.1038/43466 DB - PRIME DP - Unbound Medicine ER -