title: Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines.
abstract: Pax proteins are transcriptional regulators that control a variety of developmental decisions in vertebrates. During development, the paired-box gene 8 (PAX8) is expressed in the thyroid, kidney, and several areas of the central nervous system. It is also expressed in the adult thyroid gland, in which it mediates TSH-induced modulation of the expression of important genes, such as those encoding thyroglobulin, thyroperoxidase, and the sodium/iodide symporter (NIS). Thus far, placental expression of PAX8 has been described only in mice. In the present study, we show that PAX8 is also expressed in the human placenta at term. In an in vitro model of placental cancer, the JAR choriocarcinoma cell line, human chorionic gonadotropin (hCG) increased levels of PAX8 mRNA and protein, and gel retardation assays indicated that the up-regulation of PAX8 protein expression is associated with an increase in its DNA-binding activity. The effects of hCG were mimicked by forskolin, indicating that they are cAMP dependent. Levels of mRNA for the Wilms' tumor 1 (WT1) and NIS genes were increased in JAR cells by hCG treatment, whereas overexpression of PAX8 increased only levels of WT1 mRNA. In cells transfected with PAX8-specific small interfering RNA, the stimulatory effects of hCG on WT1 mRNA levels were abolished, but hormonal enhancement of NIS mRNA levels was unchanged. These findings indicate that, in JAR cells, hCG activates a cAMP-dependent pathway that can up-regulate WT1 expression through PAX8.
authors.affiliation: Department of Clinical Science, University of Rome, La Sapienza, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Franco
authors.initials: F
authors.lastname: Arturi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mattei
authors.forename: Angela
authors.initials: A
authors.lastname: Scipioni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
authors.forename: Emanuele
authors.initials: E
authors.lastname: Tosi
authors.forename: Ivan
authors.initials: I
authors.lastname: Presta
authors.forename: Roberta
authors.initials: R
authors.lastname: Morisi
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
mesh_terms: D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000503:physiopathology*; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010920:Placenta / Q000166:cytology / Q000502:physiology*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D027981:Symporters / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014594:Uterine Neoplasms / Q000503:physiopathology*; D025721:WT1 Proteins / Q000235:genetics; D000099209:Sodium-Iodide Symporters
chemical_list: D006063:Chorionic Gonadotropin; D000242:Cyclic AMP; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D027981:Symporters; D015534:Trans-Activators; D025721:WT1 Proteins; D000099209:Sodium-Iodide Symporters; C083325:PAX8 protein, human