IKKγ (NEMO) is involved in the coordination of the AP-1 and NF-κB pathways

Amde Selassie Shifera, Joshua M. Friedman, Marshall S. Horwitz

Research output: Contribution to journalArticle

Abstract

Tumor necrosis factor alpha (TNFα) activates the nuclear factor-kappaB (NF-κB) pathway in various cell types, leading to expression of cell survival and inflammatory proteins. One mechanism of cell survival brought about by NF-κB is the inhibition of Activator Protein-1 (AP-1), which when activated, could lead to cell death. However, TNFα can also induce the AP-1 pathway, and the mechanisms by which these two pathways are regulated in response to TNFα are poorly understood. We proposed that Inhibitor of κB Kinase gamma (IKKγ) (which is also known as NF-κB essential modulator, NEMO) plays a key role in integrating and coordinating these two pathways. Our results showed that IKKγ activates the AP-1 pathway, via a mechanism that is dependent on the first leucine zipper (LZ) domain of IKKγ, by interacting with two proteins of the AP-1 complex, c-Jun and c-Fos, and changing the phosphorylation status of c-Jun. Even though IKKγ is required for the activation of NF-κB, we found that it reduced the activity of NF-κB when it was overexpressed. In summary, we demonstrated that transfected IKKγ, while inhibiting the NF-κB pathway, directly interacts with the AP-1 proteins and activates the AP-1 pathway independent of its effects on NF-κB. Our results indicate that IKKγ regulates TNFα signaling by coordinating cell responses mediated by the AP-1 and NF-κB pathways.

Original languageEnglish (US)
Pages (from-to)181-190
Number of pages10
JournalMolecular and Cellular Biochemistry
Volume310
Issue number1-2
DOIs
StatePublished - Mar 2008
Externally publishedYes

Fingerprint

Transcription Factor AP-1
Modulators
Tumor Necrosis Factor-alpha
Cell Survival
I-kappa B Kinase
Cells
Leucine Zippers
Phosphorylation
Proteins
Cell death
Cell Death
Phosphotransferases
Chemical activation

Keywords

  • Apoptosis
  • c-Fos
  • c-Jun
  • TNFα

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

IKKγ (NEMO) is involved in the coordination of the AP-1 and NF-κB pathways. / Shifera, Amde Selassie; Friedman, Joshua M.; Horwitz, Marshall S.

In: Molecular and Cellular Biochemistry, Vol. 310, No. 1-2, 03.2008, p. 181-190.

Research output: Contribution to journalArticle

Shifera, Amde Selassie ; Friedman, Joshua M. ; Horwitz, Marshall S. / IKKγ (NEMO) is involved in the coordination of the AP-1 and NF-κB pathways. In: Molecular and Cellular Biochemistry. 2008 ; Vol. 310, No. 1-2. pp. 181-190.
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