Uygar H Tazebay
Gebze Technical University, Turkey
Posters & Accepted Abstracts: J Nutr Food Sci
Activity of the sodium/iodide symporter (NIS) in lactating breast is essential for iodide (I-) accumulation in milk. This is an essential activity for the proper development of the suckling newborn, as I- in milk is the babyâ�?�?s only source for thyroid hormone synthesis. Independent of lactation, significant NIS up-regulation was also reported in breast cancer, indicating a potential use of radioiodide treatment. All trans-retinoic acid (tRA) is a potent ligand that enhances NIS expression in a subset of breast cancer cell lines and in experimental breast cancer models. Aiming to uncover genetic elements directly regulating NIS expression, we screened evolutionary conserved non coding genomic sequences for responsiveness to tRA in mammary epithelial model cell lines. Here, we report that a potent enhancer in the first intron of NIS mediates direct regulation by tRA stimulated nuclear receptors. In vitro as well as in vivo DNA-protein interaction assays revealed direct association between retinoic acid receptor-a (RARa) and retinoid-X-receptor (RXR) with this enhancer. Moreover, using ChIP we uncovered early events of NIS transcription in response to tRA, which require the interaction of several novel intronic tRA responsive elements. These findings indicate a complex interplay between nuclear receptors, RNA Pol-II and multiple intronic RAREs in NIS gene and they establish a novel mechanistic model for tRA induced gene transcription.