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1.
Cancer Res ; 71(19): 6153-64, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21844185

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.


Subject(s)
Membrane Proteins/metabolism , Symporters/metabolism , Thyroid Gland , Animals , Cell Proliferation , Cyclin D1/genetics , Cyclin D1/metabolism , Gene Expression Regulation , Goiter, Nodular/metabolism , Goiter, Nodular/pathology , Humans , Hyperplasia/metabolism , Hyperplasia/pathology , Intracellular Signaling Peptides and Proteins , Iodine/metabolism , Iodine Radioisotopes , Membrane Proteins/genetics , Mice , Mice, Transgenic , Proto-Oncogene Mas , Symporters/genetics , Thyroid Gland/metabolism , Thyroid Gland/pathology
2.
J Cell Sci ; 122(Pt 18): 3393-402, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19706688

ABSTRACT

Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.


Subject(s)
Cell Differentiation , Repressor Proteins/metabolism , Symporters/metabolism , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Animals , Antigens, CD/metabolism , Caveolins/metabolism , Cell Line , Gene Deletion , Humans , Intracellular Signaling Peptides and Proteins , Iodides/metabolism , Membrane Proteins/metabolism , Platelet Membrane Glycoproteins/metabolism , Protein Binding , Protein Transport , Proto-Oncogene Mas , Rats , Subcellular Fractions/metabolism , Tetraspanin 30
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