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Submitted on September 18, 2003
Accepted on November 10, 2003
1 Dipartimento di Scienze e Tecnologie Biomediche, University of Udine, Udine, Italy; Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore" and Dipartimento di Scienze Farmacobiologiche, University of Catanzaro, Catanzaro, Italy; Dipartimento di Scienze Cliniche and Dipartimento di Medicina Sperimentale e Patologia, University of Rome "La Sapienza", Rome, Italy.
* To whom correspondence should be addressed. E-mail: sebastiano.filetti{at}uniroma1.it.
The transcriptional regulation of the human sodium/iodide symporter (NIS) gene in normal and transformed thyroid cells is a crucial issue for the attempts 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 the human NIS promoter activity. Cotransfection experiments performed in non-thyroid HeLa cells demonstrated that APE/Ref-1 exerts both PAX8-dependent and PAX8-independent effects. In fact, in absence of PAX8, overexpression of APE/Ref-1 enhanced NIS promoter activity of 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 the NIS promoter activity of 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 TPO gene. It was, at least in part, due to the up-regulation of the transcriptional activity of the ubiquitous factor Egr-1. In the thyroid tumor cell lines TPC-1and B-CPAP, APE/Ref-1 was not effective by itself and 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 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.
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