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Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-kappaB-mediated transcription

G C Parry1, N Mackman

  • 1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|April 21, 1998
PubMed

Insights

Elevated cyclic AMP inhibits NF-kappaB transcription by activating protein kinase A. This pathway phosphorylates CREB, which then competes with NF-kappaB p65 for the coactivator CBP, thus blocking gene expression.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Regulation

Background:

  • NF-kappaB transcription factors control inducible gene expression.
  • Elevated cyclic AMP (cAMP) inhibits NF-kappaB transcription in monocytes and endothelial cells without affecting nuclear translocation.
  • The molecular mechanisms underlying cAMP-mediated inhibition of NF-kappaB are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanism by which elevated intracellular cAMP inhibits NF-kappaB-mediated transcription.
  • To determine if protein kinase A (PKA) activation and subsequent CREB phosphorylation play a role in this inhibition by competing for the coactivator CBP.

Main Methods:

  • In vitro and in vivo interaction studies between CBP and NF-kappaB p65 (RelA).
  • Functional studies in human endothelial cells using overexpression of CBP and CREB.
  • Assays to measure NF-kappaB-mediated transcription and transcription mediated by a GAL4-p65 fusion protein.

Main Results:

  • The N-terminal region of CBP (amino acids 1-450) specifically interacts with the C-terminal region of NF-kappaB p65 (amino acids 286-551).
  • Overexpression of CBP rescued cAMP-induced inhibition of NF-kappaB transcription and transcription mediated by GAL4-p65(286-551).
  • Overexpression of CREB inhibited GAL4-p65(286-551)-mediated transcription, suggesting competition for CBP.

Conclusions:

  • Activation of the PKA pathway inhibits NF-kappaB transcription.
  • This inhibition occurs because PKA phosphorylates CREB, which then competes with NF-kappaB p65 for binding to the limiting coactivator CBP.
  • This mechanism explains how cAMP signaling modulates NF-kappaB-dependent gene expression.

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