Transcriptional regulation of the human sodium/iodide symporter gene by Pax8 and TTF-1

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Abstract
The regulation of the human Na+/I- symporter (NIS) gene is of considerable interest for both the diagnosis and therapy of thyroid pathologies. We investigated the influence of the thyroid-specific transcription factors TTF-1 and Pax8 on the NIS promoter and its 5′-flanking sequence. Reporter genes containing the corresponding genomic fragments coupled to a luciferase reporter gene were cotransfected with expression vectors carrying the the cDNA's for TTF-1 and Pax8. Transient transfection assays were performed in HeLa and COS-7 cells, which do not express endogenously these transcription factors. The experiments showed, that TTF-1 had no influence on the NIS promoter. Pax8, on the other hand, had a moderate stimulating effect (threefold) on the proximal NIS promoter. ABCD assays indicated an interaction of in vitro-translated Pax8 with the NIS promoter. However, DNase I footprinting experiments with bacterially expressed Pax8 were negative, suggesting an indirect mode of action with the participation of other proteins. A putative NIS upstream enhancer (NUE) 9000 bp upstream of the NIS gene, which was cloned based on its sequence homology to the rat NUE, was not transactivated by either Pax8 or TTF-1. The present data demonstrate, that the combination of Pax8 and TTF-1 is less important for NIS gene transcription than for other thyroid-specific genes. This is presumably related to the fact, that NIS is expressed also in other tissues such as mammary and salivary gland.

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