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Dipartimento di Scienze e Tecnologie Biomediche (C.P., G.T., G.D.), University of Udine, 33100 Udine, Italy; Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore" and Dipartimento di Scienze Farmacobiologiche, University of Catanzaro (F.A., D.R., R.S.), 88100 Catanzaro, Italy; and Dipartimento di Scienze Cliniche and Dipartimento di Medicina Sperimentale e Patologia (E.F., S.F.), University of Rome "La Sapienza," 00161 Rome, Italy
Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Dipartimento di Scienze Cliniche-Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico, 155, 00161 Roma, Italy. 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 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.
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