title: CEBPD suppresses prolactin expression and prolactinoma cell proliferation.
abstract: Hyperprolactinemia, usually caused by a pituitary lactotroph tumor, leads to galactorrhea and infertility. Increased prolactin (PRL) levels may be due to enhanced PRL expression or proliferation of PRL-secreting cells. We hypothesize that PRL expression and PRL-secreting cell proliferation are linked. Using microarray-based gene expression profiling, we identified CCAAT-enhancer-binding protein δ (CEBPD) transcription factor as a critical gene that regulates both PRL expression and lactotroph cell proliferation. CEBPD expression levels are decreased approximately 7-fold in experimental rat prolactinoma cells. Forced expression of this transcription factor in PRL-secreting cells (GH3 and MMQ) inhibited PRL expression and cellular proliferation, and CEBPD knockdown by small interfering RNA leads to increased PRL expression in both cell lines. To determine mechanisms underlying this observation, we determined binding of CEBPD to the PRL promoter and also showed marked suppression (96%) of PRL promoter activity. CEBPD and Pit1 interact and attenuate each other's binding to the PRL promoter. CEBPD also suppresses expression of proliferation-related genes, including c-Myc, survivin, as well as cyclins B1, B2, and D1. These results show that PRL expression and cell proliferation are controlled in part by CEBPD.
authors: Academic Affairs, Los Angeles, California 90048, USA.
authors: Yunguang
authors: Y
authors: Tong
authors: Jin
authors: J
authors: Zhou
authors: Jun
authors: J
authors: Mizutani
authors: Hidenori
authors: H
authors: Fukuoka
authors: Song-Guang
authors: SG
authors: Ren
authors: Arthur
authors: A
authors: Gutierrez-Hartmann
authors: H Phillip
authors: HP
authors: Koeffler
authors: Shlomo
authors: S
authors: Melmed
mesh_terms: D000818:Animals; D015153:Blotting, Western; D051743:CCAAT-Enhancer-Binding Protein-delta; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D056765:Cyclin B2 / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D013006:Growth Hormone / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011388:Prolactin / Q000235:genetics / Q000378:metabolism*; D015175:Prolactinoma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D011863:Radioimmunoassay; D051381:Rats; D050817:Transcription Factor Pit-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C497254:Cebpd protein, rat; D056744:Cyclin B1; D056765:Cyclin B2; D004967:Estrogens; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D050817:Transcription Factor Pit-1; D019938:Cyclin D1; D051743:CCAAT-Enhancer-Binding Protein-delta; D011388:Prolactin; D013006:Growth Hormone