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

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@article{a4bddec4ab8b49258dc06ba82e312ac3,
title = "A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer",
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 protooncogene 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.",
keywords = "PBF, Iodide uptake, Thyroid cancer, NIS",
author = "Vicki Smith and Martin Read and Andrew Turnell and Rachel Watkins and John Watkinson and Gregory Lewy and Jim Fong and SR James and Margaret Eggo and Kristien Boelaert and Jayne Franklyn and Christopher McCabe",
note = "Rachel Spruce published under Rachel Watkins",
year = "2009",
month = sep,
day = "1",
doi = "10.1242/jcs.045427",
language = "English",
volume = "122",
pages = "3393--3402",
journal = "J. Cell Sci",
issn = "0021-9533",
publisher = "The Company of Biologists Ltd.",
number = "18",

}

RIS

TY - JOUR

T1 - A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer

AU - Smith, Vicki

AU - Read, Martin

AU - Turnell, Andrew

AU - Watkins, Rachel

AU - Watkinson, John

AU - Lewy, Gregory

AU - Fong, Jim

AU - James, SR

AU - Eggo, Margaret

AU - Boelaert, Kristien

AU - Franklyn, Jayne

AU - McCabe, Christopher

N1 - Rachel Spruce published under Rachel Watkins

PY - 2009/9/1

Y1 - 2009/9/1

N2 - 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 protooncogene 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.

AB - 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 protooncogene 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.

KW - PBF

KW - Iodide uptake

KW - Thyroid cancer

KW - NIS

U2 - 10.1242/jcs.045427

DO - 10.1242/jcs.045427

M3 - Article

C2 - 19706688

VL - 122

SP - 3393

EP - 3402

JO - J. Cell Sci

JF - J. Cell Sci

SN - 0021-9533

IS - 18

ER -