CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression.
Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) gene expression in anterior pituitary somatotrophs by binding to the GHRH receptor, a G-protein-coupled transmembrane receptor, and by mediating a cAMP-mediated protein kinase A (PKA) signal-transduction pathway. Two nonclassical cAMP-response element motifs (CGTCA) are located at nucleotides -187/-183 (distal cAMP-response element; dCRE) and -99/-95 (proximal cAMP-response element; pCRE) of the human GH promoter and are required for cAMP responsiveness, along with the pituitary-specific transcription factor Pit-1 (official nomenclature, POU1F1). Although a role for cAMP-response element 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 binds other nuclear proteins. We determined that CBP interacts with Pit-1 and is a cofactor for Pit-1-dependent activation of the human GH promoter. This pathway appears to be independent of CREB, with CPB being the likely target of phosphorylation by PKA.
Cohen
L E
LE
Division of Endocrinology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. COHEN_L@A1.TCH.HARVARD.EDU
Hashimoto
Y
Y
Zanger
K
K
Wondisford
F
F
Radovick
S
S
D001483:Base Sequence; D050882:CREB-Binding Protein; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000502:physiology*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C494187:POU1F1 protein, human; D015534:Trans-Activators; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D019382:Human Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017868:Cyclic AMP-Dependent Protein Kinases