Activin inhibits the human Pit-1 gene promoter through the p38 kinase pathway in a Smad-independent manner.
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 TGFbeta 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.
de Guise
Chantal
C
Hormones and Cancer Research Unit, Department of Medicine, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
Lacerte
Annie
A
Rafiei
Shahrzad
S
Reynaud
Rachel
R
Roy
Melanie
M
Brue
Thierry
T
Lebrun
Jean-Jacques
JJ
D028341:Activins / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016296:Mutagenesis; D010902:Pituitary Gland / Q000378:metabolism; D011388:Prolactin / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D051381:Rats; D011993:Recombinant Fusion Proteins; D051896:Smad Proteins, Receptor-Regulated / Q000502:physiology*; D050817:Transcription Factor Pit-1 / Q000235:genetics*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; D051896:Smad Proteins, Receptor-Regulated; D050817:Transcription Factor Pit-1; D016212:Transforming Growth Factor beta; D028341:Activins; D011388:Prolactin; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases