Sterol regulatory element-binding proteins (SREBPs)-1c and -2, which were initially discovered as master transcriptional regulators of lipid biosynthesis and uptake, were recently identified as novel transcriptional regulators of the sodium-iodide symporter gene in the thyroid, which is essential for thyroid hormone synthesis. Based on this observation that SREBPs play a role for thyroid hormone synthesis, we hypothesized that another gene involved in thyroid hormone synthesis, the thyroid peroxidase (TPO) gene, is also a target of SREBP-1c and -2. Thyroid epithelial cells treated with 25-hydroxycholesterol, which is known to inhibit SREBP activation, had about 50% decreased mRNA levels of TPO. Similarly, the mRNA level of TPO was reduced by about 50% in response to siRNA mediated knockdown of both, SREBP-1 and SREBP-2. Reporter gene assays revealed that overexpression of active SREBP-1c and -2 causes a strong transcriptional activation of the rat TPO gene, which was localized to an approximately 80 bp region in the intron 1 of the rat TPO gene. In vitro- and in vivo-binding of both, SREBP-1c and SREBP-2, to this region in the rat TPO gene could be demonstrated using gel-shift assays and chromatin immunoprecipitation. Mutation analysis of the 80 bp region of rat TPO intron 1 revealed two isolated and two overlapping SREBP-binding elements from which one, the overlapping SRE+609/InvSRE+614, was shown to be functional in reporter gene assays. In connection with recent findings that the rat NIS gene is also a SREBP target gene in the thyroid, the present findings suggest that SREBPs may be possible novel targets for pharmacological modulation of thyroid hormone synthesis.
References
[1]
Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter. Nature 379: 458–460. doi: 10.1038/379458a0
[2]
Ruf J, Carayon P (2006) Structural and functional aspects of thyroid peroxidase. Arch Biochem Biophys 445: 269–277. doi: 10.1016/j.abb.2005.06.023
[3]
Colin IM, Denef JF, Lengelé B, Many MC, Gérard AC (2002) Recent insights into the cell biology of thyroid angiofollicular units. Endocr Rev 34: 209–238. doi: 10.1210/er.2012-1015
[4]
Gérard AC, Many MC, Daumerie C, Costagliola S, Miot F, et al. (2002) Structural changes in the angiofollicular units between active and hypofunctioning follicles align with differences in the epithelial expression of newly discovered proteins involved in iodine transport and organification. J Clin Endocrinol Metab 87: 1291–1299. doi: 10.1210/jcem.87.3.8278
[5]
Vassart G, Dumont JE (1992) The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 13: 596–611. doi: 10.1210/edrv-13-3-596
[6]
Laglia G, Zeiger MA, Leipricht A, Caturegli P, Levine MA, et al. (1996) Increased cyclic adenosine 3′,5′-monophosphate inhibits G protein-coupled activation of phospholipase C in rat FRTL-5 thyroid cells. Endocrinology 137: 3170–3176. doi: 10.1210/endo.137.8.8754735
[7]
Levy O, Dai G, Riedel C, Ginter CS, Paul EM, et al. (1997) Characterization of the thyroid Na+/I？ symporter with an anti-COOH terminus antibody. Proc Natl Acad Sci USA 94: 5568–5573. doi: 10.1073/pnas.94.11.5568
[8]
Nicola JP, Nazar M, Mascanfroni ID, Pellizas C-G, Masini-Repiso AM (2010) NF-κB p65 subunit mediates lipopolysaccharide-induced Na(+)/I(-) symporter gene expression by involving functional interaction with the paired domain transcription factor Pax8. Mol Endocrinol 24: 1846–1862. doi: 10.1210/me.2010-0102
[9]
Nazar M, Nicola JP, Vélez ML, Pellizas CG, Masini-Repiso AM (2012) Thyroid peroxidase gene expression is induced by lipopolysaccharide involving nuclear factor (NF)-κB p65 subunit phosphorylation. Endocrinology 153: 6114–6125. doi: 10.1210/en.2012-1567
[10]
Ringseis R, Rauer C, Rothe S, Gessner DK, Schütz LM, et al. (2013) Sterol regulatory element-binding proteins are regulators of the NIS gene in thyroid cells. Mol Endocrinol 27: 781–800. doi: 10.1210/me.2012-1269
[11]
Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109: 1125–1131. doi: 10.1172/jci0215593
[12]
Grieco D, Beg ZH, Romano A, Bifulco M, Aloj SM (1990) Cell cycle progression and 3-hydroxy-3-methylglutaryl coenzyme A reductase are regulated by thyrotropin in FRTL-5 rat thyroid cells. J Biol Chem 265: 19343–19350.
[13]
Aloj SM, Grieco D, Kohn AD, Nikodem VM, Kohn LD (1990) Thyrotropin regulation of malic enzyme in FRTL-5 rat thyroid cells. Mol Endocrinol 4: 611–622. doi: 10.1210/mend-4-4-611
[14]
Bifulco M, Perillo B, Saji M, Laezza C, Tedesco I, et al. (1995) Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in FRTL-5 cells. I. Identification and characterization of a cyclic AMP-responsive element in the rat reductase promoter. J Biol Chem 270: 15231–15236. doi: 10.1074/jbc.270.25.15231
[15]
Espenshade PJ, Li WP, Yabe D (2002) Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc Natl Acad Sci U S A 99: 11694–11699. doi: 10.1073/pnas.182412799
[16]
Goldstein JL, Rawson RB, Brown MS (2002) Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch Biochem Biophys 397: 139–148. doi: 10.1006/abbi.2001.2615
[17]
Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, et al. (2005) MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21: 2933–2942. doi: 10.1093/bioinformatics/bti473
[18]
Inoue S, Yoshinari K, Sugawara M, Yamazoe Y (2011) Activated sterol regulatory element-binding protein-2 suppresses hepatocyte nuclear factor-4-mediated Cyp3a11 expression in mouse liver. Mol Pharmacol 79: 148–156. doi: 10.1124/mol.110.068577
[19]
Wen G, Ringseis R, Eder K (2010) Mouse OCTN2 is directly regulated by peroxisome proliferator-activated receptor α (PPARα) via a PPRE located in the first intron. Biochem Pharmacol 79: 768–776. doi: 10.1016/j.bcp.2009.10.002
[20]
Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ (2000) Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102: 315–323. doi: 10.1016/s0092-8674(00)00037-4
[21]
Sheng Z, Otani H, Brown MS, Goldstein JL (1995) Independent regulation of sterol regulatory element-binding proteins 1 and 2 in hamster liver. Proc Natl Acad Sci U S A 92: 935–938. doi: 10.1073/pnas.92.4.935
[22]
DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS (2001) Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci U S A 98: 1477–1482. doi: 10.1073/pnas.98.4.1477
[23]
Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, et al. (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev 14: 2819–2830. doi: 10.1101/gad.844900
[24]
Sato R (2010) Sterol metabolism and SREBP activation. Arch Biochem Biophys 501: 177–181. doi: 10.1016/j.abb.2010.06.004
[25]
Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS (1997) Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 99: 838–845. doi: 10.1172/jci119247
[26]
Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, et al. (2002) Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res 43: 1220–1235.
[27]
Briggs MR, Yokoyama C, Wang X, Brown MS, Goldstein JL (1993) Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence. J Biol Chem 268: 14490–14496.
[28]
Nara TY, He WS, Tang C, Clarke SD, Nakamura MT (2002) The E-box like sterol regulatory element mediates the suppression of human Delta-6 desaturase gene by highly unsaturated fatty acids. Biochem Biophys Res Commun 296: 111–117. doi: 10.1016/s0006-291x(02)00851-3
[29]
Amemiya-Kudo M, Shimano H, Yoshikawa T, Yahagi N, Hasty AH, et al. (2000) Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J Biol Chem 275: 31078–31085. doi: 10.1074/jbc.m005353200
[30]
Rozman D, Fink M, Fimia GM, Sassone-Corsi P, Waterman MR, et al. (1999) Cyclic adenosine 3′,5′-monophosphate(cAMP)/cAMP-responsiv？eelement modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. Mol Endocrinol 13: 1951–1962. doi: 10.1210/mend.13.11.0377
[31]
Dubchak I, Brudno M, Loots GG, Pachter L, Mayor C, et al. (2000) Active conservation of noncoding sequences revealed by three-way species comparisons. Genome Res 10: 1304–1306. doi: 10.1101/gr.142200
[32]
Ericsson J, Jackson SM, Kim JB, Spiegelman BM, Edwards PA (1997) Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1- and sterol regulatory element-binding protein-responsive gene. J Biol Chem 272: 7298–7305. doi: 10.1074/jbc.272.11.7298
[33]
Guan G, Dai PH, Osborne TF, Kim JB, Shechter I (1997) Multiple sequence elements are involved in the transcriptional regulation of the human squalene synthase gene. J Biol Chem 272: 10295–10302. doi: 10.1074/jbc.272.15.10295
[34]
Tabor DE, Kim JB, Spiegelman BM, Edwards PA (1999) Identification of conserved cis-elements and transcription factors required for sterol-regulated transcription of stearoyl-CoA desaturase 1 and 2. J Biol Chem 274: 20603–20610. doi: 10.1074/jbc.274.29.20603
[35]
Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, et al. (1993) SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75: 187–197. doi: 10.1016/s0092-8674(05)80095-9
[36]
Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, et al. (1993) SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA 90: 11603–11607. doi: 10.1073/pnas.90.24.11603
