Inhibition of the NF-kappaB transcriptional activity by protein kinase A

Eur J Biochem. 2002 Sep;269(18):4559-65. doi: 10.1046/j.1432-1033.2002.03157.x.


The cAMP-dependent protein kinase (PKA) signaling pathway plays a major role in a number of pathophysiological conditions. However, there have been conflicting evidences regarding the action of cAMP/PKA on nuclear factor- kappaB (NF-kappaB). In this study, we have explored the effect of cAMP/PKA on NF-kappaBeta activity and determined its molecular mechanism. PKA activating agents or expression of the catalytic subunit of PKA (PKAc) inhibited the NF-kappaBeta-dependent reporter gene expression induced by tumor necrosis factor alpha (TNFalpha). PKA activators affected neither IkappaBalpha phosphorylation, IkappaBetaalpha degradation, nor the NF-kappaBeta/DNA binding. Expression of PKAc inhibited the transactivation potential of Gal4-p65 (286-551) suggesting that the inhibitory action of PKA is through the C-terminal transactivation domain of p65 but not by phosphorylation of the consensus PKA recognition site containing serine at position 276. Overexpression of coactivators, CBP (CREB-binding protein) and p300, failed to reverse the PKA-mediated inhibition of p65 transactivation. Thus, the inhibitory action of the cAMP/PKA pathway on the transcriptional activity of NF-kappaB appears to be exhibited by modifying the C-terminal transactivation domain of p65, either directly or indirectly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CREB-Binding Protein
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Humans
  • Jurkat Cells
  • MAP Kinase Signaling System
  • NF-kappa B / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Trans-Activators / metabolism
  • Transcription Factor RelA
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / metabolism


  • Cyclic AMP Response Element-Binding Protein
  • NF-kappa B
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factor RelA
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Cyclic AMP
  • CREB-Binding Protein
  • CREBBP protein, human
  • Cyclic AMP-Dependent Protein Kinases