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Phosphorylation of CtBP1 by PKA Induces CYP17 by Promoting CtBP Heterooligomerization
Author(s) -
Dammer Eric B,
Sewer Marion B
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1016.1
Subject(s) - corepressor , phosphorylation , transcription factor , chemistry , adrenal cortex , protein kinase a , transcription (linguistics) , psychological repression , kinase , microbiology and biotechnology , gene , biology , biochemistry , gene expression , nuclear receptor , linguistics , philosophy
In the human adrenal cortex, the peptide hormone adrenocorticotropin (ACTH) directs cortisol and adrenal androgen biosynthesis by activating a cAMP/protein kinase A (PKA) pathway. Carboxy terminal binding protein 1 (CtBP1) is a corepressor that regulates transcription of the CYP17 gene by periodically interacting with steroidogenic factor‐1 (SF‐1) in response to ACTH signaling. Given that CtBP1 function is regulated by NADH binding, we hypothesized that ACTH‐stimulated changes in cellular pyridine nucleotide concentrations modulate the ability of CtBP1 to repress CYP17 transcription. Further, we postulated that PKA evokes changes in the phosphorylation status of CtBP1 that control the ability of the protein to bind to SF‐1 and repress CYP17 gene expression. We show that ACTH alters pyridine nucleotide redox state and identify amino acid residues in CtBP1 that are targeted by PKA and PAK6. Both ACTH/cAMP signaling and NADH/NAD + ratio stimulate nuclear‐cytoplasmic oscillation of both CtBP proteins. We provide evidence that PKA 1) induces metabolic changes in the adrenal cortex and 2) phosphorylates CtBP proteins, particularly CtBP1 at T144, resulting in ACTH‐dependent CYP17 transcription.