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This version published online on June 1, 2006
Endocrinology, doi:10.1210/en.2006-0444
A more recent version of this article appeared on September 1, 2006
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Submitted on April 6, 2006
Accepted on May 24, 2006

Activin inhibits the human Pit-1 gene promoter through the p38 kinase pathway in a Smad-independent manner

Chantal de Guise, Annie Lacerte, Sharzad Rafiei, Rachel Reynaud, Melanie Roy, Thierry Brue, and Jean-Jacques Lebrun*

Hormones and Cancer Research Unit, Department of Medicine, Royal Victoria Hospital, McGill University, 687 Pine Avenue West, H3A 1A1, Montreal, Quebec, Canada; Department of Endocrinology, Hopital de la Timone, Marseille, France

* To whom correspondence should be addressed. E-mail: JJ.Lebrun{at}MUHC.McGill.CA.

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 TGF{beta} 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 MAP kinase 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.
Key words: Activin • Pit-1 • p38 MAP kinase • signal transduction




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