title: Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.
abstract: Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized proto-oncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.
authors.affiliation: School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, United Kingdom.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Read
authors.forename: Greg D
authors.initials: GD
authors.lastname: Lewy
authors.forename: Jim C W
authors.initials: JC
authors.lastname: Fong
authors.forename: Neil
authors.initials: N
authors.lastname: Sharma
authors.forename: Robert I
authors.initials: RI
authors.lastname: Seed
authors.forename: Vicki E
authors.initials: VE
authors.lastname: Smith
authors.forename: Erica
authors.initials: E
authors.lastname: Gentilin
authors.forename: Adrian
authors.initials: A
authors.lastname: Warfield
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Eggo
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Leadbeater
authors.forename: John C
authors.initials: JC
authors.lastname: Watkinson
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: Kristien
authors.initials: K
authors.lastname: Boelaert
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006044:Goiter, Nodular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007455:Iodine / Q000378:metabolism; D007457:Iodine Radioisotopes; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D000099209:Sodium-Iodide Symporters
chemical_list: D019938:Cyclin D1; D047908:Intracellular Signaling Peptides and Proteins; D007455:Iodine; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C000715470:MAS1 protein, human; C112633:PTTG1IP protein, human