Open AccessCytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-κB and the glucocorticoid receptor
Author(s) -
Vassilis Doucas,
Yanhong Shi,
Shigeki Miyamoto,
Andrew B. West,
Inder M. Verma,
Ronald M. Evans
Publication year - 2000
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.220413297
Subject(s) - transactivation , protein subunit , psychological repression , glucocorticoid receptor , transcription factor , biology , protein kinase a , microbiology and biotechnology , cytoplasm , transcription (linguistics) , kinase , biochemistry , receptor , gene , gene expression , linguistics , philosophy
Negative transcriptional regulation or cross-coupling between NF-κB (RelA) and the glucocorticoid receptor (GR) is proposed to play a regulatory role in human physiology and disease. Despite previous advances, the biochemical basis of this phenomenon remains a subject of controversy. We show here that the inhibition of GR activity by RelA does not require the RelA DNA binding, transactivation, or nuclear localization domains. Surprisingly, RelA repression of GR is abolished by mutation of the conserved protein kinase A (PKA) site at amino acid residue 276 of RelA. We show that GR associatesin vivo andin vitro with the catalytic subunit of PKA (PKAc) in a ligand-independent manner and that GR transcription depends on PKA signaling. Indeed, we demonstrated that GR-mediated inhibition of NF-κB transactivation is PKAc-dependent. In contrast to previous models, we suggest that the cross-coupling requires a cytoplasmic step and is regulated by a PKAc-associated signaling.