The promoter of the human sodium/iodide-symporter gene responds to retinoic acid.
It was shown previously that hNIS mRNA expression is stimulated by retinoic acid (RA) in human follicular thyroid carcinoma cell lines FTC-133 and FTC-238, and patients with thyroid carcinomas lacking iodide uptake respond to RA treatment with increased radioiodide transport. Here, in transient transfection experiments using FTC-238 cells, hNIS promoter/luciferase reporter constructs showed an up to 2.5-fold increase in transcriptional activity after incubation with 1 microM RA. Stimulation by 10 nM T3 was up to 2.4-fold. Deletion or block mutation of a putative nuclear receptor recognition site, 'DR10', abolished RA and T3 responses. Four copies of the DR10 cloned 5' to the thymidine kinase promoter gave a 2.6-fold and a 1.4-fold increase in transcriptional activity after RA and T3 stimulation, respectively. In electrophoretic mobility shifts, a wildtype DR10 oligonucleotide, but not block mutants of either DR10 halfsite, interacted with nuclear receptors. Thus, RA redifferentiation of advanced thyroid carcinomas may reinduce iodide uptake by stimulating hNIS expression and thereby make tumours accessible for radioiodide therapy again.
Schmutzler
C
C
Medizinische Poliklinik, Abteilung Molekulare Innere Medizin und Klinische Forschergruppe, Universität Würzburg, Röntgenring 11, D-97070, Würzburg, Germany.
Schmitt
T L
TL
Glaser
F
F
Loos
U
U
Köhrle
J
J
D018263:Adenocarcinoma, Follicular; D000818:Animals; D017930:Genes, Reporter; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D009841:Oligonucleotides / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
D007457:Iodine Radioisotopes; D009841:Oligonucleotides; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014212:Tretinoin; D014284:Triiodothyronine; D000099209:Sodium-Iodide Symporters