title: Inhibition of Bcl3 gene expression mediates the anti-proliferative action of estrogen in pituitary lactotrophs in primary culture.
abstract: In addition to their well-known stimulatory action, estrogens have an anti-proliferative effect. The present study was undertaken to investigate the mechanism by which 17β-estradiol (E2) inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation in vitro in the rat pituitary lactotroph, a typical estrogen-responsive cell. E2 treatment of pituitary cells did not change levels of IGF-1-induced phosphorylation of proliferation-related protein kinases such as Erk1/2 and Akt. We performed global gene expression profiling by DNA microarray analysis and identified 177 genes regulated by E2 in the presence of IGF-1. These results were verified by quantitative real time PCR. The estrogen-regulated genes included several NFκB family related genes. As pharmacological inhibition of the NFκB pathway blocked IGF-1-induced lactotroph proliferation, we chose to investigate whether one NFκB pathway gene, Bcl3, was involved in the anti-proliferative action of E2. RNA interference-mediated knockdown of Bcl3 expression attenuated IGF-1-induced lactotroph proliferation. Even minimal induced overexpression of Bcl3 blocked the anti-proliferative action of E2. In contrast, Nfkb2, another E2-downregulated protein, required maximal overexpression to block the anti-proliferative action of E2. These results suggest that inhibition of Bcl3 expression is involved in the anti-proliferative action of estrogens in pituitary lactotrophs in culture.
authors.affiliation: Department of Physiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Mitsui
authors.forename: Maho
authors.initials: M
authors.lastname: Ishida
authors.forename: Michi
authors.initials: M
authors.lastname: Izawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kagami
authors.forename: Jun
authors.initials: J
authors.lastname: Arita
mesh_terms: D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D052682:Lactotrophs / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases