cAMP response element-binding protein-binding protein mediates thyrotropin-releasing hormone signaling on thyrotropin subunit genes.
Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). Since cAMP response element-binding protein (CREB)-binding protein (CBP) integrates a number of cell signaling pathways, we investigated whether CBP is important for TRH stimulation of the TSH subunit genes. Cotransfection of E1A in GH(3) cells completely blocked TRH stimulation of the TSH subunit genes, suggesting that CBP is a key factor for TRH signaling in the pituitary. CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-beta promoter, and amino acids 1-450 of CBP were sufficient for the TRH effect. In contrast, on the human alpha-GSU promoter, CREB and P-Lim mediated TRH signaling. Intriguingly, CREB was phosphorylated upon TRH stimulation, leading to CBP recruitment to the alpha-GSU promoter. CBP also interacted with P-Lim in a TRH-dependent manner, suggesting that P-Lim is an important factor for non-cAMP response element-mediated TRH stimulation of this promoter. Distinct domains of CBP were required for TRH signaling by CREB and P-Lim on the alpha-GSU promoter, amino acids 450-700 and 1-450, respectively. Thus, the amino terminus of CBP plays a critical role in TRH signaling in the anterior pituitary via both Pit-1-dependent and -independent pathways, yielding differential regulation of pituitary gene products.
Thyroid Unit, Division of Endocrinology, Beth Israel Deaconess Medical Center and Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
K
K
Hashimoto
K
K
Zanger
A N
AN
Hollenberg
L E
LE
Cohen
S
S
Radovick
F E
FE
Wondisford
D050882:CREB-Binding Protein; D000242:Cyclic AMP / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D013972:Thyrotropin / Q000235:genetics*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D009687:Nuclear Proteins; C494187:POU1F1 protein, human; D021122:Protein Subunits; D015534:Trans-Activators; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human