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Cited by 529NF-κB Signaling PathwaysPI3K/AKT/mTOR signaling in cancerSignaling Pathways in Disease

Akt‐mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt

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Bai, Dong, Ueno, Lynn, Vogt, Peter K.·2009·International Journal of Cancer
DOI 10.1002/ijc.24748PMC PMC2767458
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Abstract

The serine/threonine kinase Akt (cellular homolog of murine thymoma virus akt8 oncogene), also known as PKB (protein kinase B), is activated by lipid products of phosphatidylinositol 3‐kinase (PI3K). Akt phosphorylates numerous protein targets that control cell survival, proliferation and motility. Previous studies suggest that Akt regulates transcriptional activity of the nuclear factor‐κB (NFκB) by inducing phosphorylation and subsequent degradation of inhibitor of κB (IκB). We show here that NFκB‐driven transcription increases in chicken embryonic fibroblasts (CEF) transformed by myristylated Akt (myrAkt). Accordingly, both a dominant negative mutant of Akt and Akt inhibitors repress NFκB‐dependent transcription. The degradation of the IκB protein is strongly enhanced in Akt‐transformed cells, and the loss of NFκB activity by introduction of a super‐repressor of NFκB, IκBSR, interferes with PI3K‐ and Akt‐induced oncogenic transformation of CEF. The phosphorylation of the p65 subunit of NFκB at serine 534 is also upregulated in Akt‐transformed cells. Our data suggest that the stimulation of NFκB by Akt is dependent on the phosphorylation of p65 at S534, mediated by IKK (IκB kinase) α and β. Akt phosphorylates IKKα on T23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at S534 by IKKα and β. Our results demonstrate two separate functions of the IKK complex in NFκB activation in cells with constitutive Akt activity: the phosphorylation and consequent degradation of IκB and the phosphorylation of p65. The data further support the conclusion that NFκB activity is essential for PI3K‐ and Akt‐induced oncogenic transformation. © 2009 UICC

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  • Activated NF-kB translocates to the nucleus and stimulates transcription of target genes, some of which include immune response genes and inflammasome components.

    “Activated NF-kB can then translocate to the nucleus, where it stimulates the transcription of its target genes, some of which include immune response genes and inflammasome components [88].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [88]

    The Introduction (page not provided) says that NFκB translocates to the nucleus, binds target-gene sites, and regulates transcription; it also links NFκB to innate and adaptive immune responses. Our copy does not identify inflammasome components as NFκB target genes, so that part of the attributed claim is unsupported. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Bai, D., Ueno, L., & Vogt, P. K.
Affiliations
Scripps Research Institute (US)
Corresponding author
Vogt, Peter K.
ORCID
Venue
International Journal of Cancer
Publisher
Wiley
Published
2009-09
Volume
125
Issue
12
Pages
2863-2870
ISSN
  • 0020-7136 (ISSN-L)
  • 1097-0215
DOI
10.1002/ijc.24748
PMC
PMC2767458
OpenAlex
W1965627667
Cited by
529
References
3
Citations by year
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FWCI
3.69
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • International Journal of Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA078230, P01CA078045)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
Akt, NF-κB, phosphatidylinositol 3-kinase, oncogenic transformation, IκB degradation, p65 phosphorylation, IkappaB kinase alpha, IκB kinase β, chicken embryo fibroblasts, transcriptional regulation, AKT inhibitors
MeSH terms
Animals, Cell Nucleus, Cell Transformation, Neoplastic, Chick Embryo, Fibroblasts, Gene Expression Regulation, Luciferases, Phosphorylation, Transcription, Genetic, Blotting, Western, Signal Transduction, NF-kappa B, Phosphatidylinositol 3-Kinases, Immunoprecipitation, Proto-Oncogene Proteins c-akt, Mice, I-kappa B Kinase

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