Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2.
In the human adrenal cortex, the peptide hormone adrenocorticotropin (ACTH) directs cortisol and adrenal androgen biosynthesis by activating a cAMP/cAMP-dependent protein kinase (PKA) pathway. Carboxyl-terminal binding protein 1 (CtBP1) is a corepressor that regulates transcription of the CYP17 gene by periodically interacting with steroidogenic factor-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 steroidogenic factor-1 and the coactivator GCN5 (general control nonderepressed 5) 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 CtBP protein partnering and ACTH-dependent CYP17 transcription.
Dammer
Eric B
EB
School of Biology and Parker H Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
Sewer
Marion B
MB
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000737:chemistry*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D000242:Cyclic AMP / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry*; D005136:Eye Proteins / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins; D009711:Nucleotides / Q000737:chemistry; D010766:Phosphorylation; D011725:Pyridines / Q000737:chemistry; D015398:Signal Transduction; D013254:Steroid 17-alpha-Hydroxylase / Q000737:chemistry / Q000502:physiology*
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D009419:Nerve Tissue Proteins; D009711:Nucleotides; D011725:Pyridines; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; C096794:C-terminal binding protein; D013254:Steroid 17-alpha-Hydroxylase; C023666:pyridine