Abstract
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.
Highlights
Thyrotropin (TSH)1 is a member of a pituitary and placental glycoprotein hormone family, which includes follicle-stimulating hormone, luteinizing hormone, and chorionic gonadotropin
Since cAMP response element-binding protein (CREB)-binding protein (CBP) integrates a number of cell signaling pathways, we investigated whether CREB-binding protein (CBP) is important for thyrotropin-releasing hormone (TRH) stimulation of the TSH subunit genes
Since we hypothesized that CBP would play an important role in TRH stimulation of the TSH subunit genes, we cotransfected E1A12S and an E1A mutant (E1A⌬CR1, where CR1 is conserved region 1) [23] that lacks CBP binding into a rat pituitary cell line (GH3 cells)
Summary
Thyrotropin (TSH)1 is a member of a pituitary and placental glycoprotein hormone family, which includes follicle-stimulating hormone, luteinizing hormone, and chorionic gonadotropin. 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.
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