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NGFI‐B Is Important for Induction of SF‐1 Dependent Transcription in Response to cAMP

Agents that stimulate cAMP production in adrenocortical cells rapidly induce the levels of the orphan nuclear receptor NGFI-B. We previously demonstrated that the activity of a cAMP responsive sequence (CRS2) in the promoter of the bovine CYP17 gene is partly determined by the two nuclear receptors COUP-TF and SF-1 that compete for overlapping binding sites in this element. We now show that NGFI-B activates transcription through CRS2 by the formation of a NGFI-B/COUP-TF heterodimeric complex that apparently is unable to bind DNA. In this way, NGFI-B removes the repressor COUP-TF from CRS2 allowing binding of, and subsequent transactivation by, SF-1. Interestingly, overexpression of NGFI-B and knockdown of NGFI-B and COUP-TF by siRNA abrogate the cAMP-induced transcription from CRS2. These results strongly indicate that NGFI-B is important for cAMP-dependent regulation of the CYP17 gene, and strengthens the hypothesis that NGFI-B is an important player in the transcriptional responses to ACTH. In addition to the classical cAMP-signaling pathway via PKA, cAMP also induces Epac-dependent activation of the G-protein Rap in adrenocortical cells. By the use of cAMP-analogues that specifically activate either PKA or Epac we are currently determining how these pathways individually affect NGFI-B activity in the adrenal cortex.