title: Sterol regulatory element-binding proteins are regulators of the NIS gene in thyroid cells.
abstract: The uptake of iodide into the thyroid, an essential step in thyroid hormone synthesis, is an active process mediated by the sodium-iodide symporter (NIS). Despite its strong dependence on TSH, the master regulator of the thyroid, the NIS gene was also reported to be regulated by non-TSH signaling pathways. In the present study we provide evidence that the rat NIS gene is subject to regulation by sterol regulatory element-binding proteins (SREBPs), which were initially identified as master transcriptional regulators of lipid biosynthesis and uptake. Studies in FRTL-5 thyrocytes revealed that TSH stimulates expression and maturation of SREBPs and expression of classical SREBP target genes involved in lipid biosynthesis and uptake. Almost identical effects were observed when the cAMP agonist forskolin was used instead of TSH. In TSH receptor-deficient mice, in which TSH/cAMP-dependent gene regulation is blocked, the expression of SREBP isoforms in the thyroid was markedly reduced when compared with wild-type mice. Sterol-mediated inhibition of SREBP maturation and/or RNA interference-mediated knockdown of SREBPs reduced expression of NIS and NIS-specific iodide uptake in FRTL-5 cells. Conversely, overexpression of active SREBPs caused a strong activation of the 5'-flanking region of the rat NIS gene mediated by binding to a functional SREBP binding site located in the 5'-untranslated region of the rat NIS gene. These findings show that TSH acts as a regulator of SREBP expression and maturation in thyroid epithelial cells and that SREBPs are novel transcriptional regulators of NIS.
authors.affiliation: Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 26-32, 35392 Gießen, Germany. robert.ringseis@ernaehrung.uni-giessen.de
authors.forename: Robert
authors.initials: R
authors.lastname: Ringseis
authors.forename: Christine
authors.initials: C
authors.lastname: Rauer
authors.forename: Susanne
authors.initials: S
authors.lastname: Rothe
authors.forename: Denise K
authors.initials: DK
authors.lastname: Gessner
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Schütz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Luci
authors.forename: Gaiping
authors.initials: G
authors.lastname: Wen
authors.forename: Klaus
authors.initials: K
authors.lastname: Eder
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D007454:Iodides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011989:Receptors, Thyrotropin / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D013261:Sterols / Q000494:pharmacology; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D000099209:Sodium-Iodide Symporters
chemical_list: D020121:5' Untranslated Regions; D005576:Colforsin; D000242:Cyclic AMP; D007454:Iodides; D011989:Receptors, Thyrotropin; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; D027981:Symporters; D013972:Thyrotropin; D000099209:Sodium-Iodide Symporters
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