Transcriptional regulation of human sodium/iodide symporter gene: a role for redox factor-1.

Abstract

The transcriptional regulation of the human sodium/iodide symporter (NIS) gene in normal and transformed thyroid cells is a crucial issue in attempting to restore iodide uptake and use radioiodine as a therapeutic treatment of thyroid cancer. Previous investigations have shown that the multifunctional protein apurinic apyrimidinic endonuclease/redox factor 1 (APE/Ref-1) plays an important role in regulation of thyroid-specific gene transcription. In this study, we investigated the effects of APE/Ref-1 on human NIS promoter activity. Cotransfection experiments performed in nonthyroid HeLa cells demonstrated that APE/Ref-1 exerts both PAX8-dependent and PAX8-independent effects. In fact, in the absence of PAX8, overexpression of APE/Ref-1 enhanced NIS promoter activity 2-fold. When the expression plasmid of APE/Ref-1 was transfected together with an expression plasmid for PAX8, a strong cooperative effect was detected with an increase of NIS promoter activity 9-fold over control. The PAX8-independent effect of APE/Ref-1 was specific for the NIS promoter, resulting not present for the promoter of the thyroperoxidase (TPO) gene. It was, at least in part, due to the up-regulation of the transcriptional activity of the ubiquitous factor early growth response-1 (Egr-1). In the thyroid tumor cell lines TPC-1 and B-CPAP, APE/Ref-1 was not effective by itself, and it also failed to increase PAX8 stimulation on NIS promoter activity. These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. However, restoring the PAX8-APE/Ref-1 expression in tumor cells may not be sufficient to obtain adequate levels of NIS gene expression.

• Authors: Cinzia Puppin, Franco Arturi, Elisabetta Ferretti, Diego Russo, Rosario Sacco, Gianluca Tell, Giuseppe Damante, Sebastiano Filetti
• Journal: Endocrinology (Endocrinology) Vol. 145 Issue 3 Pg. 1290-3 (Mar 2004) ISSN: 0013-7227 [Print] United States
• PMID: 14630715 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Nuclear Proteins
• PAX8 Transcription Factor
• PAX8 protein, human
• Paired Box Transcription Factors
• Symporters
• Trans-Activators
• sodium-iodide symporter
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• DNA-(Apurinic or Apyrimidinic Site) Lyase (genetics, metabolism)
• DNA-Binding Proteins (genetics)
• HeLa Cells
• Humans
• Nuclear Proteins
• PAX8 Transcription Factor
• Paired Box Transcription Factors
• Promoter Regions, Genetic (physiology)
• Symporters (genetics)
• Thyroid Neoplasms (physiopathology)
• Trans-Activators (genetics)
• Transcription, Genetic (physiology)
• Transfection