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Endocrine Abstracts (2013) 32 JP1 | DOI: 10.1530/endoabs.32.JP1

School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Ablative radioiodine therapy is critical to the treatment of differentiated thyroid cancers and their metastases, and relies on the innate ability of thyroid cells to uptake iodide via the sodium iodide symporter (NIS). As tumours with reduced avidity for radioiodine have a poorer prognosis,it is critical to identify ways to induce NIS activity and hence radioiodine uptake.

Pituitary tumor transforming gene (PTTG) and its interacting partner, PTTG-binding factor (PBF), areproto-oncogenes that are significantly upregulated in thyroid tumours and have been identified as potent repressors of iodide uptake. Higher levels of PTTG and PBF expression are independently associated with early tumour recurrence and an overall poorer disease outcome. Both PTTG and PBF can inhibit NIS transcriptional regulation via an upstream enhancerelement (hNUE).

NIS can also be post-translationally regulated through an interaction with PBF that internalises it away from its functional localisation at the cell surface. PBF elicits a similar mechanism of post-translational regulation on the monocarboxylate transporter 8 (MCT8), which mediates the secretion of thyroid hormone, suggesting a role for PBF in the overall regulation of thyroid hormone biosynthesis and secretion.

Recent studies have focused on inhibiting NIS repression by PBF. PBF has been identified as a phospho-protein that can bind the proto-oncogene tyrosine-protein kinase Src. Src significantly induces phosphorylation of PBF residue Y174 and, conversely, Src inhibition reduces Y174 phosphorylation. Of direct clinical importance to the treatment of thyroid cancer, Src inhibition entirely overcomes PBF repression of iodide uptake in human primary thyroid cells. Hence, targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid tumours.

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