Sterol regulatory element-binding proteins are transcriptional regulators of the thyroglobulin gene in thyroid cells.
The genes encoding sodium/iodide symporter (NIS) and thyroid peroxidase (TPO), both of which are essential for thyroid hormone (TH) synthesis, were shown to be regulated by sterol regulatory element-binding proteins (SREBP)-1c and -2. In the present study we tested the hypothesis that transcription of a further gene essential for TH synthesis, the thyroglobulin (TG) gene, is under the control of SREBP. To test this hypothesis, we studied the influence of inhibition of SREBP maturation and SREBP knockdown on TG expression in FRTL-5 thyrocytes and explored transcriptional regulation of the TG promoter by reporter gene experiments in FRTL-5 and HepG2 cells, gel shift assays and chromatin immunoprecipitation. Inhibition of SREBP maturation by 25-hydroxycholesterol and siRNA-mediated knockdown of either SREBP-1c or SREBP-2 decreased mRNA and protein levels of TG in FRTL-5 thyrocytes. Reporter gene assays with wild-type and mutated TG promoter reporter truncation constructs revealed that the rat TG promoter is transcriptionally activated by nSREBP-1c and nSREBP-2. DNA-binding assays and chromatin immunoprecipitation assays showed that both nSREBP-1c and nSREBP-2 bind to a SREBP binding motif with characteristics of an E-box SRE at position -63 in the rat TG promoter. In connection with recent findings that NIS and TPO are regulated by SREBP in thyrocytes the present findings support the view that SREBP are regulators of essential steps of TH synthesis in the thyroid gland such as iodide uptake, iodide oxidation and iodination of tyrosyl residues of TG. This moreover suggests that SREBP may be molecular targets for pharmacological modulation of TH synthesis.
Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Gießen, 35392 Gießen, Germany.
Gaiping
G
Wen
Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Gießen, 35392 Gießen, Germany.
Klaus
K
Eder
Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Gießen, 35392 Gießen, Germany. Electronic address: Robert.ringseis@ernaehrung.uni-giessen.de.
Robert
R
Ringseis
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013954:Thyroglobulin / Q000235:genetics* / Q000378:metabolism; D000072637:Thyroid Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism; D000099209:Sodium-Iodide Symporters
D006888:Hydroxycholesterols; D007453:Iodide Peroxidase; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D027981:Symporters; D013954:Thyroglobulin; D014284:Triiodothyronine; D000099209:Sodium-Iodide Symporters; C497389:Srebf1 protein, rat; C007997:25-hydroxycholesterol
Functional SRE; SREBP; Thyroglobulin; Thyroid hormone synthesis