Selenium increases thyroid-stimulating hormone-induced sodium/iodide symporter expression through thioredoxin/apurinic/apyrimidinic endonuclease 1-dependent regulation of paired box 8 binding activity

[Aims]: The sodium–iodide symporter (NIS) mediates the uptake of I− by the thyroid follicular cell and is essential for thyroid hormone biosynthesis. Nis expression is stimulated by thyroid-stimulating hormone (TSH) and also requires paired box 8 (Pax8) to bind to its promoter. Pax8 binding activity depends on its redox state by a mechanism involving thioredoxin/thioredoxin reductase-1 (Txn/TxnRd1) reduction of apurinic/apyrimidinic endonuclease 1 (Ape1). In this study, we investigate the role of Se in Nis expression. [Results]: Selenium increases TSH-induced Nis expression and activity in rat thyroid cells. The stimulatory effect of Se occurs at the transcriptional level and is only observed for Nis promoters containing a Pax8 binding site in the Nis upstream enhancer, suggesting that Pax8 is involved in this effect. In fact, Se increases Pax8 expression and its DNA-binding capacity, and in Pax8-silenced rat thyroid cells, Nis is not Se responsive. By inhibiting Ape1 and TxnRd1 functions, we found that both enzymes are crucial for TSH and TSH plus Se stimulation of Pax8 activity and mediate the Nis response to Se treatment. [Innovation]: We describe that Se increases Nis expression and activity. We demonstrate that this effect is dependent on the redox functions of Ape1 and Txn/TxnRd1 through control of the DNA binding activity of Pax8. [Conclusion]: Nis expression is controlled by Txn/Ape1 through a TSH/Se-dependent mechanism. These findings open a new field of study regarding the regulation of Nis activity in thyroid cellsThis work was supported by grants, BFU2010-16025 and SAF2013-44709R, from the Dirección General de Ciencia y Tecnología, Ministerio de Economía y Competitividad and S2011/BMD- 2328-Tironet from the Comunidad de Madrid (to P.S.); grant PI12-01201 from the Instituto de Salud Carlos III and grant FSEEN (to A.D.l.V.); and grant, RETICC RD12/0036/0030, from the Instituto de Salud Carlos III (to A.D.l.V. and P.S.). S.G.L. was supported, in part, by a JAE-Doc Intramural CSIC Project grant, 2011-20E101, and a postdoctoral contract from grant S2011/BMD-2328 Tironet and PI12/01201.Peer reviewe