Inhibition of the NF-kappaB transcriptional activity by protein kinase A.
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.
Takahashi
Naoko
N
Department of Molecular Genetics, Nagoya City University Medical School, Japan.
Tetsuka
Toshifumi
T
Uranishi
Hiroaki
H
Okamoto
Takashi
T
D050882:CREB-Binding Protein; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D009687:Nuclear Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017868:Cyclic AMP-Dependent Protein Kinases