Activin Inhibits the Human Pit-1 Gene Promoter through the p38 Kinase Pathway in a Smad-Independent Manner

• Published in: Endocrinology (Philadelphia) 2006-09, Vol.147 (9), p.4351-4362
• Main Authors: de Guise, Chantal, Lacerte, Annie, Rafiei, Shahrzad, Reynaud, Rachel, Roy, Melanie, Brue, Thierry, Lebrun, Jean-Jacques
• Format: Article
• Language: English
• Subjects: Activin; Activins - pharmacology; Animals; Biological and medical sciences; Blotting, Western; Cell Line; CHO Cells; Cricetinae; Enzyme Activation - drug effects; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression - drug effects; Gene regulation; Humans; Kinases; Luciferases - genetics; MAP kinase; Mutagenesis; p38 Mitogen-Activated Protein Kinases - metabolism; Pit1 protein; Pituitary (anterior); Pituitary gland; Pituitary Gland - metabolism; Prolactin; Prolactin - biosynthesis; Promoter Regions, Genetic - drug effects; Rats; Recombinant Fusion Proteins; Smad protein; Smad Proteins, Receptor-Regulated - physiology; Transcription Factor Pit-1 - genetics; Transfection; Transforming Growth Factor beta - pharmacology; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-0444

The pituitary transcription factor Pit-1 regulates hormonal production from the anterior pituitary gland. However, the mechanisms by which Pit-1 gene expression is regulated in humans are poorly understood. Activin, a member of the TGFβ superfamily, acts as a negative regulator of cell growth and prolactin gene expression in lactotrope cells. In this study, we show that activin negatively regulates the human Pit-1 gene promoter. We defined a 117-bp element within the Pit-1 promoter that is sufficient to relay these inhibitory effects. We further investigated the signaling pathways that mediate activin-induced inhibition of Pit-1 gene promoter in pituitary lactotrope cells. We found that the activin effects on Pit-1 gene regulation are Smad independent and require the p38 MAPK pathway. Specifically, blocking p38 kinase activity reverses activin-mediated inhibition of the Pit-1 gene promoter. Together, our results highlight the p38 MAPK pathway as a key regulator of activin function in pituitary lactotrope cells and further emphasizes the critical role played by activin in regulating hormonal production in the pituitary gland.