Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 22, Pages 11893-11898Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.220413297
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- NICHD NIH HHS [R01 HD027183, HD27183] Funding Source: Medline
- NIGMS NIH HHS [GM26444] Funding Source: Medline
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Negative transcriptional regulation or cross-coupling between NF-kappaB (RelA) and the glucocorticoid receptor (CR) 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 on is abolished by mutation of the conserved protein kinase A (PKA) site at amino acid residue 276 of RelA, We show that CR associates in vivo and in 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-kappaB 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.
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