title: Lineage-specific restraint of pituitary gonadotroph cell adenoma growth.
abstract: Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p  =  0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth.
authors.affiliation: Department of Medicine, Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Vera
authors.initials: V
authors.lastname: Chesnokova
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zonis
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Shlomo
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.forename: Yoel
authors.initials: Y
authors.lastname: Toledano
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Tong
authors.forename: Kalman
authors.initials: K
authors.lastname: Kovacs
authors.forename: Bernd
authors.initials: B
authors.lastname: Scheithauer
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D016922:Cellular Senescence; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D004249:DNA Damage; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000378:metabolism; D052681:Gonadotrophs / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D010641:Phenotype; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D064249:Securin; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; C495242:CLU protein, human; D051152:Clusterin; D050762:Cyclin-Dependent Kinase Inhibitor p15; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human