A Thyroid-Specific Far-Upstream Enhancer in the Human Sodium/Iodide Symporter Gene Requires Pax-8 Binding and Cyclic Adenosine 3′,5′-Monophosphate Response Element-Like Sequence Binding Proteins for Full Activity and Is Differentially Regulated in Normal and Thyroid Cancer Cells

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 16; no. 10; pp. 2266 - 2282
• Main Authors: Taki, Katsumi, Kogai, Takahiko, Kanamoto, Yoko, Hershman, Jerome M, Brent, Gregory A
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.10.2002; Oxford University Press
• Subjects: Activating Transcription Factor 2; Animals; Binding Sites; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Cell Differentiation - genetics; Cells, Cultured; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Gene Expression Regulation; Humans; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Paired Box Transcription Factors; PAX8 Transcription Factor; Promoter Regions, Genetic; Rats; Reference Values; Response Elements - genetics; Sequence Homology, Nucleic Acid; Symporters - drug effects; Symporters - genetics; Symporters - metabolism; Thyroid Gland - cytology; Thyroid Gland - physiology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Nuclear Factor 1; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2002-0109

The sodium/iodide symporter (NIS) gene is highly expressed in the thyroid gland and is important for the diagnosis and radioiodide therapy of differentiated thyroid cancers. We investigated a human NIS (hNIS) gene 5′-far-upstream enhancer (hNUE) (−9847 to −8968). The hNUE is TSH responsive in both FRTL-5 cells and primary normal thyroid cells, but not in human papillary thyroid cancer cells (BHP cells). The hNUE enhanced expression of the basal hNIS promoter 15-fold and required both a Pax-8 binding site and a cAMP response element (CRE)-like sequence for full activity. The hNUE activated transcription in a thyroid-selective and cAMP-dependent manner, mediated by both protein kinase A (PKA)-dependent and PKA-independent pathways. Pax-8 and two CRE-like sequence binding proteins bind to the hNUE. Supershift binding assay indicated that one of the CRE-like sequence binding protein(s) was CRE-binding protein-1, activation transcription factor-1, and/or CRE modulator, and the other was an unknown factor(s) that is absent in BHP 2-7 cells. A far-upstream enhancer is important for hNIS regulation in the thyroid. Deficient CRE-like sequence binding protein(s) that bind to the hNUE in normal thyroid cells may be responsible for reduced NIS gene expression in some thyroid carcinomas.