Clusterin and FOXL2 act concordantly to regulate pituitary gonadotroph adenoma growth.
Pituitary tumors grow slowly and despite their high prevalence are invariably benign. We therefore studied mechanisms underlying pituitary tumor growth restraint. Pituitary tumor transforming gene (PTTG), the index human securin, a hallmark of pituitary tumors, triggers pituitary cell proliferation and murine pituitary tumor development. We show that human gonadotroph cell pituitary tumors, unlike other secreting tumor types, express high levels of gonadotroph-specific forkhead transcription factor FOXL2, and both PTTG and Forkhead box protein L2 (FOXL2) stimulate gonadotroph clusterin (Clu) expression. Both Clu RNA isoforms are abundantly expressed in these nonhormone-secreting human tumors, and, when cultured, these tumor cells release highly abundant levels of secreted Clu. FOXL2 directly stimulates the Clu gene promoter, and we show that PTTG triggers ataxia telangiectasia mutated kinase/IGF-I/p38MAPK DNA damage/chromosomal instability signaling, which in turn also induces Clu expression. Consequently, Clu restrains pituitary cell proliferation by inducing cyclin dependent kinase inhibitors p16 and p27, whereas Clu deletion down-regulates p16 and p27 in the Clu(-/-) mouse pituitary. FOXL2 binds and suppresses the PTTG promoter, and Clu also suppresses PTTG expression, thus neutralizing protumorigenic PTTG gonadotroph tumor cell properties. In vivo, murine gonadotroph LβT2 tumor cell xenografts overexpressing Clu and FOXL2 both grow slower and elicit smaller tumors. Thus, gonadotroph tumor cell proliferation is determined by the interplay between cell-specific FOXL2 with PTTG and Clu.
Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Vera
V
Chesnokova
Svetlana
S
Zonis
Kolja
K
Wawrowsky
Yuji
Y
Tani
Anat
A
Ben-Shlomo
Vladimir
V
Ljubimov
Adam
A
Mamelak
Serguei
S
Bannykh
Shlomo
S
Melmed
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D043171:Chromosomal Instability / Q000235:genetics; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D052681:Gonadotrophs / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059368:RNA Isoforms / Q000096:biosynthesis; D064249:Securin; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D051152:Clusterin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D059368:RNA Isoforms; D064249:Securin; D025521:Tumor Suppressor Proteins; C578002:pituitary tumor-transforming protein 1, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases