title: Signaling events associated with gonadotropin releasing hormone-agonist-induced hormonal castration and its reversal in canines.
abstract: A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c-Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c-Raf-Erk1/2-p53 signaling cascade that triggers growth arrest or apoptosis. GnRH-A also suppressed the anti-apoptotic protein Bcl-xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down-regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH-A treatment, levels of ZIP9, a membrane-bound Zn2+transporter that mediates non-classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant-dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 83: 1092-1101, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute for Veterinary Physiology and Biochemistry, Giessen, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bulldan
authors.affiliation: Institute for Veterinary Physiology and Biochemistry, Giessen, Germany.
authors.forename: Mazen
authors.initials: M
authors.lastname: Shihan
authors.affiliation: Clinic for Obstetrics, Gynecology, and Andrology of Large and Small Animals, Justus-Liebig-University, Giessen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Goericke-Pesch
authors.affiliation: Institute for Veterinary Physiology and Biochemistry, Giessen, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Scheiner-Bobis
mesh_terms: D000818:Animals; D017209:Apoptosis; D004285:Dogs; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D020935:MAP Kinase Signaling System; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009919:Orchiectomy; D013245:Sterilization, Reproductive; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D007987:Gonadotropin-Releasing Hormone; D048052:Mitogen-Activated Protein Kinase 3