Activin inhibits pituitary prolactin expression and cell growth through Smads, Pit-1 and menin.
Activin, a member of the TGFbeta superfamily, is a negative regulator of cell growth and prolactin (PRL) production in pituitary lactotrope cells. However, the mechanisms by which this growth factor exerts its growth-inhibitory and -repressive effect on PRL remain unclear. In this study, we show that activin negatively regulates PRL expression at the transcriptional level through the Smad pathway and the multiple endocrine neoplasia type 1 gene product, menin. Our results also demonstrate that the tumor suppressor menin is required for activin-induced growth arrest of somatolactotrope cells. Moreover, we show that activin represses transcription and expression of Pit-1, a pituitary transcription factor that is essential for maintenance and development of lactotrope cells. We defined two Pit-1 DNA-binding sites in the proximal region of the PRL promoter as critical for the activin-mediated inhibition. Together, our results highlight the Smad pathway and the tumor suppressor menin as key regulators of activin effects on PRL and Pit-1 expression, as well as on cell growth inhibition, and emphasize the critical role of activin in the regulation of pituitary function.
Lacerte
Annie
A
Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, H3A 1A1, Canada.
Lee
Eun-Hye
EH
Reynaud
Rachel
R
Canaff
Lucie
L
De Guise
Chantal
C
Devost
Dominic
D
Ali
Suhad
S
Hendy
Geoffrey N
GN
Lebrun
Jean-Jacques
JJ
D028341:Activins / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D016296:Mutagenesis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010902:Pituitary Gland / Q000378:metabolism*; D011388:Prolactin / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D051785:Smad Proteins; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D004396:Coloring Agents; D004268:DNA-Binding Proteins; C105373:MEN1 protein, human; D016376:Oligonucleotides, Antisense; C494187:POU1F1 protein, human; C494186:Pou1f1 protein, rat; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051785:Smad Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D015534:Trans-Activators; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D028341:Activins; D011388:Prolactin; C022616:thiazolyl blue