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The CRE-Like Element Inside the 5'-Upstream Region of the Rat Sodium/Iodide Symporter Gene Interacts with Diverse Classes of b-Zip Molecules that Regulate Transcriptional Activities through Strong Synergy with Pax-8

Department of Biochemistry and Molecular Biology (J.T.C., V.D.D., R.D.L.), Stazione Zoologica ‘Anton Dohrn,’ Villa Comunale, 80121 Napoli, Italy; and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche and Dept. di Biologia e Patologia Cellulare e Molecolare (B.D’A., M.Z.), Universita’ di Napoli Federico II, 80131 Napoli, Italy

Address all correspondence and requests for reprints to: Prof. Roberto Di Lauro, Department of Biochemistry and Molecular Biology, Stazione Zoologica ‘Anton Dohrn,’ Villa Comunale, 80121 Napoli, Italy. E-mail: rdilauro{at}unina.it.

We previously demonstrated that transcription of the rat sodium/iodide symporter (NIS) gene is regulated by NUE, an upstream enhancer located between nucleotides –2264 and –2495 of the 5'-flanking region. To elucidate the mechanism of TSH/cAMP-mediated regulation of NIS gene expression, we have characterized the putative cAMP response element (CRE)/activator protein (AP)-1 site (termed NUC) that is closely located between the two Pax-8 (paired box domain transcription factor-8) binding sites within NUE. In two different approaches using either gel supershift analyses or dominant-negative inhibitors of b-Zip molecules, we have shown that NUC can be recognized by several members of the AP-1 and CREB family transcription factors that modulate the transcriptional activity of NUE. Using tethered dimers of b-Zip molecules, we have also demonstrated that specific homo- or heterodimers of AP-1 can synergistically stimulate NUE activity in concert with Pax-8. To demonstrate further that NUC is a bona fide CRE, we made an artificial promoter with the five-time tandem repeat of this sequence (5xNUC). In comparison to the canonical CRE (5xCRE), 5xNUC manifested greater transcriptional activity and broader response to cAMP signaling. Hence, we postulate that the significance of this evolutionally conserved CRE-like site may lie in its broader cell type specificity.

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