PTTG-Binding Factor (PBF) Is a Novel Regulator of the Thyroid Hormone Transporter MCT8
PTTG-Binding Factor (PBF) Is a Novel Regulator of the Thyroid Hormone Transporter MCT8
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DOI：
10.1210/en.2011-2030
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
McCabe, C. J.
中科院分区：
文献类型：
--
作者：
Smith, V. E.;Read, M. L.;McCabe, C. J.
在甲状腺滤泡上皮细胞的基底膜内，两种转运蛋白对甲状腺激素（TH）的生物合成和分泌起着重要作用。钠碘同向转运体（NIS）将碘从血流递送到甲状腺中，并且在TH生物合成之后，单羧酸转运体8（MCT 8）介导甲状腺的TH分泌。甲状腺肿瘤转化基因结合因子（PBF; PTTG 1 IP）是一种在甲状腺癌中上调的原癌基因，与NIS结合并调节其亚细胞定位和功能。我们现在表明，PBF结合MCT 8在体外，引起一个显着的转变MCT 8亚细胞定位，并导致在一个显着的减少量的MCT 8在质膜细胞表面生物素化测定。在由牛甲状腺球蛋白（Tg）启动子（PBF-Tg）驱动的甲状腺特异性PBF过表达的小鼠模型中，也观察到PBF和Mct 8之间的共定位和相互作用。甲状腺Mct 8 mRNA和蛋白表达水平与野生型小鼠相似。然而，关键的是，PBF-Tg小鼠表现出显着增强甲状腺TH积累和减少TH分泌TSH刺激后。重要的是，Mct 8基因敲除小鼠也具有这种表型。这些数据表明，PBF在体外结合并改变了MCT 8的亚细胞定位，PBF过表达导致体内甲状腺内TH的积累。总体而言，这些研究确定PBF是第一个与关键TH转运蛋白MCT 8相互作用并调节其体内功能的蛋白质。此外，除了NIS抑制，PBF因此可能代表TH生物合成和分泌的新调节剂。（内分泌学153：3526-3536，2012）
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 anew regulator of TH biosynthesis and secretion. (Endocrinology 153: 3526-3536, 2012)