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

Mol Endocrinol. 2002 Oct;16(10):2266-82. doi: 10.1210/me.2002-0109.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • PAX8 Transcription Factor
  • Paired Box Transcription Factors
  • 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

Substances

  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PAX8 Transcription Factor
  • PAX8 protein, human
  • Paired Box Transcription Factors
  • Pax8 protein, rat
  • Symporters
  • Thyroid Nuclear Factor 1
  • Trans-Activators
  • Transcription Factors
  • sodium-iodide symporter
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases