Tumor necrosis factor alpha induction of NF-κB requires the novel coactivator SIMPL

Hyung Joo Kwon, Erin Haag Breese, Eva Vig-Varga, Yong Luo, Younghee Lee, Mark G. Goebl, Maureen A. Harrington

Research output: Contribution to journalArticle

25 Scopus citations


A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of IκB kinase β (IKK-β), IKK-α, and IKK-γ/N leading to changes in NF-κB-dependent gene expression. However, it is not clear how the NF-κB response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-α)-dependent but not interleukin-1-dependent NF-κB activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNT receptor-induced NF-κB activity. SIMPL interacts with nuclear p65 in a TNF-α- dependent manner to promote endogenous NF-κB-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-α activation of NF-κB dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-α-specific induction of gene expression.

Original languageEnglish (US)
Pages (from-to)9317-9326
Number of pages10
JournalMolecular and cellular biology
Issue number21
StatePublished - Nov 1 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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