ECE2006 Poster Presentations Thyroid (174 abstracts)
Repression of the human NIS upstream enhancer (hNUE) by PTTG
VE Smith 1 , K Boelaert 1 , AL Stratford 1 , SR James 1 , R Susarla 1 , T Kogai 2 , MC Eggo 1 , JA Franklyn 1 & CJ McCabe 1
1Department of Medicine, University of Birmingham, Birmingham, United Kingdom; 2Department of Medicine, UCLA School of Medicine, Los Angeles, United States.
The sodium iodide symporter (NIS) mediates the uptake of iodide into thyroid follicular cells. The pituitary tumor transforming gene (PTTG) is a multifunctional oncogene which stimulates expression of fibroblast growth factor-2 (FGF-2) via the PTTG binding factor (PBF). PTTG, FGF-2 and PBF are all up-regulated in thyroid cancer. PTTG and FGF-2 inhibit NIS mRNA expression and iodide uptake in rat thyroid FRTL5 cells. We have shown previously that both PTTG and PBF repress NIS mRNA expression and iodide uptake in primary human thyroid cultures. To determine whether the regulation of NIS by PTTG and PBF is a direct transcriptional event, we co-transfected primary human thyroid cultures and FRTL5 cells with PTTG and PBF plasmids along with luciferase reporter constructs containing 1) the human NIS proximal promoter, 2) an 879 bp fragment including the human NIS upstream enhancer (hNUE) coupled to the human NIS proximal promoter and 3) the hNUE fragment coupled to the SV40 promoter. In FRTL5 cells, PTTG repressed promoter activity via the hNUE element, whether driven by the SV40 (30% repression; P<0.001; N=9) or the NIS proximal promoter (19% repression; P<0.001; N=9). In primary thyroid cells, PTTG similarly repressed promoter activity via the hNUE element when coupled to the SV40 promoter (45% repression; P=0.003; N=6). PBF also repressed hNUE activity when coupled to either the SV40 (29% repression; P=0.04; N=6) or the NIS proximal promoter (30% repression; P=0.016; N=6). In conclusion, the repression of NIS by PTTG and PBF in human thyroid cells occurs via its upstream enhancer region, hNUE. In thyroid cancer, where PTTG and PBF are up-regulated, NIS activity, and hence radioiodide uptake, are likely to be reduced via a promoter-specific mechanism.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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