TAILIEUCHUNG - Báo cáo khoa học: Inhibition of the NF-jB transcriptional activity by protein kinase A

The cAMP-dependent protein kinase (PKA) signaling pathway plays a major role in a number of pathophysio-logical conditions. However, there have been conflicting evidences regarding the action of cAMP/PKA on nuclear factor-jB(NF-jB). Inthis study,wehaveexplored the effect of cAMP/PKA on NF-jBactivity and determined its molecular mechanism. PKA activating agents or expression of thecatalyticsubunitofPKA(PKAc) inhibitedtheNF-jB-dependent reporter gene expression induced by tumor nec-rosis factora(TNFa). . | Eur. J. Biochem. 269 4559-4565 2002 FEBS 2002 doi Inhibition of the NF-kB transcriptional activity by protein kinase A Naoko Takahashi Toshifumi Tetsuka Hiroaki Uranishi and Takashi Okamoto Department of Molecular Genetics Nagoya City University Medical School Japan 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- kB NF-kB . In this study we have explored the effect of cAMP PKA on NF-kB activity and determined its molecular mechanism. PKA activating agents or expression of the catalytic subunit of PKA PKAc inhibited the NF-kB-dependent reporter gene expression induced by tumor necrosis factor a TNFa . PKA activators affected neither I jBa phosphorylation IjBa degradation nor the NF-kB 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-kB appears to be exhibited by modifying the C-terminal transactivation domain of p65 either directly or indirectly. Keywords NF-kB PKA cAMP signal transduction. Nuclear factor kB NF-kB is an inducible cellular transcription factor that regulates a wide variety of cellular and viral genes including several cytokines cell adhesion molecules and human immunodeficiency virus HIV 1-4 . Members of the NF-kB family in mammalian cells include the proto-oncogene c-Rel Rel A p65 Rel B NF-kB1 p50 105 and NF-kB2 p52 p100 . These proteins share a conserved 300 amino acids region known as the

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