NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK

Biochim Biophys Acta. 2008 May;1783(5):713-27. doi: 10.1016/j.bbamcr.2008.01.002. Epub 2008 Jan 12.


Constitutively activated NF-kappaB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-kappaB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-kappaB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-kappaB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-kappaB in suppressing the expression of anti-inflammatory or anti-tumor genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism
  • CREB-Binding Protein / metabolism*
  • Cell Line
  • Gene Expression Regulation
  • Histone Deacetylases / metabolism*
  • Humans
  • MafK Transcription Factor / metabolism*
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B
  • Response Elements
  • Trans-Activators / antagonists & inhibitors
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic


  • Antioxidants
  • MafK Transcription Factor
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Trans-Activators
  • Transcription Factor RelA
  • CREB-Binding Protein
  • Histone Deacetylases
  • histone deacetylase 3