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J. Biol. Chem., Vol. 279, Issue 5, 3439-3446, January 30, 2004

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The Functional Interaction between the Paired Domain Transcription Factor Pax8 and Smad3 Is Involved in Transforming Growth Factor- Repression of the Sodium/Iodide Symporter Gene^*

Eugenia Costamagna, Bibian García, and Pilar Santisteban¶

From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid. Arturo Duperier 4, 28029 Madrid, Spain

Transforming growth factor- (TGF-) is a secreted protein that regulates proliferation, differentiation, and death in various cell types, including thyroid cells, although few details are known about its mechanisms of action in this cell type. Here, we studied the role of TGF- on the regulation of sodium/iodide symporter (NIS) gene expression in PC Cl3 thyroid cells. TGF- inhibits thyroid-stimulated hormone (TSH)-induced NIS mRNA and protein levels in a dose-dependent manner. This effect takes place at the transcriptional level, as TGF- inhibits TSH-induced transcription of a luciferase reporter construct containing a 2.8-kb DNA fragment of the rat NIS promoter. The inhibitory effect of TGF- was partially overcome by inhibitory Smad7 and mimicked by overexpression of either Smad3 or a constitutively activated mutant of TGF- receptor I (acALK-5). Using internal deletions of the promoter, we defined a region between –2,841 to –1,941, which includes the NIS upstream enhancer (NUE), as responsible for the TGF-/Smad inhibitory effect. NUE contains two binding sites for the paired domain transcription factor Pax8, the main factor controlling NIS transcription. The physical interaction observed between Pax8 and Smad3 appears to be responsible for the decrease in Pax8 binding to DNA. Expression of Pax8 mRNA and protein was also decreased by TGF- treatment. The results suggest that, through activation of Smad3, TGF- decreases Pax8 DNA binding activity as well as Pax8 mRNA and protein levels, which are at least partially involved in TGF--induced down-regulation of NIS gene expression in thyroid follicular cells. Our results thus demonstrate a novel mechanism of Smad3 function in regulating thyroid cell differentiation by functionally antagonizing the action of the paired domain transcription factor Pax8.

Received for publication, July 3, 2003 , and in revised form, November 11, 2003.

^* This study was supported by Ministerio de Ciencia y Tecnología (MCyT) Grant BMC 2001-2087, Comunidad Autónoma de Madrid (CAM) Grant 08.2/0025/97, and Fondo de Investigaciones Sanitarias (FIS) of the Instituto de Salud Carlos III Grants RCMN C03/08 and RGDM G03/212. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Postdoctoral fellow of the Fundación Carolina (Spain).

Postdoctoral fellow of the Comunidad Autónoma de Madrid (Spain).

^¶ To whom correspondence should be addressed. Tel.: 34-91-5854455; Fax: 34-91-5854401. E-mail: psantisteban{at}iib.uam.es.

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