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      Intronic elements in the Na+/I-symporter gene (NIS) interact with retinoic acid receptors and mediate initiation of transcription

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      Author
      Alotaibi, H.
      Yaman, E.
      Salvatore, D.
      di Dato, V.
      Telkoparan, P.
      di Lauro, R.
      Tazebay, U. H.
      Date
      2010
      Source Title
      Nucleic Acids Research
      Print ISSN
      0305-1048
      Publisher
      Oxford University Press
      Volume
      38
      Issue
      10
      Pages
      3172 - 3185
      Language
      English
      Type
      Article
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      Abstract
      Activity of the sodium/iodide symporter (NIS) in lactating breast is essential for iodide (I-) accumulation in milk. Significant NIS upregulation 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. Indirect tRA stimulation of NIS in breast cancer cells is very well documented; however, direct upregulation by tRA-activated nuclear receptors has not been identified yet. Aiming to uncover cis-acting elements directly regulating NIS expression, we screened evolutionary-conserved non-coding genomic sequences for responsiveness to tRA in MCF-7. 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-α (RARα) and retinoid-X-receptor (RXR) with this enhancer. Moreover, using chromatin immunoprecipitation (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. © The Author(s) 2010. Published by Oxford University Press.
      Keywords
      Cell nucleus receptor
      Retinoic acid
      Retinoic acid receptor
      Retinoic acid receptor alpha
      Retinoid X receptor
      RNA polymerase II
      Sodium iodide symporter
      Permalink
      http://hdl.handle.net/11693/22454
      Published Version (Please cite this version)
      http://dx.doi.org/10.1093/nar/gkq023
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