CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression

Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth horm one (GH) gene expression in anterior pituitary somatotrophs by binding to t he GHRH receptor, a G-protein-coupled transmembrane receptor, and by mediat ing a cAMP-mediated protein kinase A (PKA) signal-transduction pathway. Two nonclassical cAMP-response element motifs (CGTCA) are located at nucleotid es -187/-183 (distal cAMP-response element; dCRE) and -99/-95 (proximal cAM P-response element; pCRE) of the human GH promoter and are required for cAM P responsiveness, along with the pituitary-specific transcription factor Pi t-1 (official nomenclature, POU1F1). Although a role for cAMP-response elem ent binding protein (CREB) in GH stimulation by PKA has been suggested, it is unclear how the effect may be mediated. CREB binding protein (CBP) is a nuclear cofactor named for its ability to bind CREB. However, CBP also bind s other nuclear proteins. We determined that CBP interacts with Pit-1 and i s a cofactor for Pit-1-dependent activation of the human GH promoter. This pathway appears to be independent of CREB, with CBP being the likely target of phosphorylation by PKA.