Transcriptional regulation of human sodium/iodide symporter gene: a role for redox factor-1.
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.
Puppin
Cinzia
C
Dipartimento di Scienze e Tecnologie Biomediche,University of Udine, Italy.
Arturi
Franco
F
Ferretti
Elisabetta
E
Russo
Diego
D
Sacco
Rosario
R
Tell
Gianluca
G
Damante
Giuseppe
G
Filetti
Sebastiano
S
D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D011401:Promoter Regions, Genetic / Q000502:physiology; D027981:Symporters / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000503:physiopathology; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D000099209:Sodium-Iodide Symporters
D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D027981:Symporters; D015534:Trans-Activators; D000099209:Sodium-Iodide Symporters; C083325:PAX8 protein, human; C085108:APEX1 protein, human