PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8

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PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8. / Smith, V E; Read, M L; Turnell, A S; Sharma, N; Lewy, G D; Fong, J C W; Seed, R I; Kwan, P; Ryan, G; Mehanna, H; Chan, S Y; Darras, V M; Boelaert, K; Franklyn, J A; McCabe, C J.

In: Endocrinology, Vol. 153, No. 7, 2012, p. 3526-36.

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@article{0115f42b90a84e40b40644984e0f098c,
title = "PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8",
abstract = "Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion.",
author = "Smith, {V E} and Read, {M L} and Turnell, {A S} and N Sharma and Lewy, {G D} and Fong, {J C W} and Seed, {R I} and P Kwan and G Ryan and H Mehanna and Chan, {S Y} and Darras, {V M} and K Boelaert and Franklyn, {J A} and McCabe, {C J}",
year = "2012",
doi = "10.1210/en.2011-2030",
language = "English",
volume = "153",
pages = "3526--36",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "Endocrine Society",
number = "7",

}

RIS

TY - JOUR

T1 - PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8

AU - Smith, V E

AU - Read, M L

AU - Turnell, A S

AU - Sharma, N

AU - Lewy, G D

AU - Fong, J C W

AU - Seed, R I

AU - Kwan, P

AU - Ryan, G

AU - Mehanna, H

AU - Chan, S Y

AU - Darras, V M

AU - Boelaert, K

AU - Franklyn, J A

AU - McCabe, C J

PY - 2012

Y1 - 2012

N2 - Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion.

AB - Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion.

U2 - 10.1210/en.2011-2030

DO - 10.1210/en.2011-2030

M3 - Article

C2 - 22535767

VL - 153

SP - 3526

EP - 3536

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 7

ER -