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First published online 25 August 2009
doi: 10.1242/jcs.045427

Journal of Cell Science 122, 3393-3402 (2009)
Published by The Company of Biologists 2009
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Research Article

A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer

Vicki E. Smith1, Martin L. Read1, Andrew S. Turnell2, Rachel J. Watkins1, John C. Watkinson1, Greg D. Lewy1, Jim C. W. Fong1, Sally R. James1, Margaret C. Eggo1, Kristien Boelaert1, Jayne A. Franklyn1 and Christopher J. McCabe1,*

1 School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, B15 2TH, UK
2 School of Cancer Sciences, University of Birmingham, B15 2TH, UK

* Author for correspondence (mccabcjz{at}bham.ac.uk)

Accepted 13 June 2009

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.

Key words: PBF, NIS, Iodide uptake, Thyroid cancer


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