Journal
EUROPEAN JOURNAL OF BIOCHEMISTRY
Volume 269, Issue 18, Pages 4559-4565Publisher
BLACKWELL PUBLISHING LTD
DOI: 10.1046/j.1432-1033.2002.03157.x
Keywords
NF-kappa B; PKA; cAMP; signal transduction
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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-kappaB activity and determined its molecular mechanism. PKA activating agents or expression of the catalytic subunit of PKA (PKAc) inhibited the NF-kappaB-dependent reporter gene expression induced by tumor necrosis factor alpha (TNFalpha). PKA activators affected neither IkappaBalpha phosphorylation, IkappaBalpha degradation, nor the NF-kappaB/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.
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