p54nrb/NONO Regulates Glucocorticoid Production by Controlling the Capacity for cAMP Signaling

Glucocorticoid production is a finely tuned integrated process that is activated by the cAMP/protein kinases A (PKA) signaling pathways. Previous studies have demonstrated that p54nrb/NONO is a transcriptional coregulator of genes required for glucocorticoid production. Moreover, p54nrb/NONO is implicated in bridging transcription and splicing. Thus, we sought to define the molecular mechanism by which p54nrb/NONO regulates glucocorticoid biosynthesis. Silencing p54nrb/NONO expression in H295R human adrenocortical cells attenuated adrenocorticotropin‐stimulated cAMP production. In addition to a decrease in intracellular cAMP concentrations p54nrb/NONO knockdown cells exhibited reduced expressions of multiple genes required for cAMP signaling, including the catalytic subunits of PKA, members of the activating transcription factors (ATF)/cAMP response element binding (CREB) family of transcription factors, and members of the nuclear receptor 4A family. Reduced cAMP signaling capacity was concomitant with a decrease in the expressions of key enzymes required for steroid hormone production, CYP17A1 and CYP11B1. Finally, suppressing p54nrb/NONO reduced the secretion of cortisol and dehydroepiandrosterone. In summary, we identify p54nrb/NONO as a novel regulator of cAMP concentrations, and thus the cAMP signal transduction cascade.