Bone morphogenetic protein and retinoic acid-inducible neural specific protein-3 is expressed in gonadotrope cell pituitary adenomas and induces proliferation, migration, and invasion.

Pituitary tumors are common intracranial neoplasms that often result in endocrine dysfunction due to hormone overproduction or deficiencies from mass effects. Gonadotrope cell or gonadotropinomas are tumors that produce LH and/or FSH and represent 40% of macroadenomas. Little is known about their underlying pathogenic mechanisms. We compared expression profiles of 10 gonadotropinomas with nine normal pituitaries by cDNA array and identified bone morphogenetic protein- and retinoic acid-inducible neural-specific protein-3 (BRINP3) as overexpressed in tumors, compared with normals. BRINP3 is a novel, normally brain restricted protein of unknown function. BRINP3 mRNA was expressed selectively in gonadotropinomas. Subcellular localization studies showed that BRINP3 was targeted to the mitochondria, but BRINP3 overexpression was unable to protect pituitary cells against programmed cell death induced by growth factor withdrawal. However, BRINP3 overexpression in pituitary gonadotrope cells promoted proliferation, migration, and invasion. A BRINP3 antibody was raised that demonstrated clustered expression of BRINP3 protein in gonadotropinomas and not in normal human pituitary samples. Thus, BRINP3 is a mitochondrially localized protein that is selectively up-regulated in human gonadotropinomas. Its actions to increase proliferation, migration, and invasion suggest it may play an important role in pituitary tumorigenesis.

Liganded androgen receptor interaction with beta-catenin: nuclear co-localization and modulation of transcriptional activity in neuronal cells.

A yeast two-hybrid assay was employed to identify androgen receptor (AR) protein partners in gonadotropin-releasing hormone neuronal cells. By using an AR deletion construct (AR-(Delta371-485)) as a bait, beta-catenin was identified as an AR-interacting protein from a gonadotropin-releasing hormone neuronal cell library. Immunolocalization of co-transfected AR and FLAG-beta-catenin demonstrated that FLAG-beta-catenin was predominantly cytoplasmic in the absence of androgen. In the presence of 5alpha-dihydrotestosterone, FLAG-beta-catenin completely co-localized to the nucleus with AR. This effect was specific to AR because liganded progesterone, glucocorticoid, or estrogen alpha receptors did not translocate FLAG-beta-catenin to the nucleus. Agonist-bound AR was required because the AR antagonists casodex and hydroxyflutamide failed to translocate beta-catenin. Time course experiments demonstrated that co-translocation occurred with similar kinetics. Nuclear co-localization was independent of the glycogen synthase kinase-3beta, p42/44 ERK mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways because inhibitors of these pathways had no effect. Transcription assays demonstrated that liganded AR repressed beta-catenin/T cell factor-responsive reporter gene activity. Conversely, co-expression of beta-catenin/T cell factor repressed AR stimulation of AR-responsive reporter gene activity. Our data suggest that liganded AR shuttles beta-catenin to the nucleus and that nuclear interaction of AR with beta-catenin may modulate transcriptional activity in androgen target tissues.