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

Hormones and Cancer Research Unit (C.d.G., A.L., S.R., R.R., M.R., J.-J.L.), Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A 1A1; and Department of Endocrinology (R.R., T.B.), Hopital de la Timone, 13005 Marseille, France

Address all correspondence and requests for reprints to: Dr. Jean-Jacques Lebrun, Hormones and Cancer Research Unit, Department of Medicine, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. 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 TGFß 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.

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