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J. Biol. Chem., Vol. 279, Issue 3, 2005-2011, January 16, 2004

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PIAS Represses the Transcriptional Activation Induced by the Nuclear Receptor Nurr1^*

Danny Galleguillos, Andrea Vecchiola, José Antonio Fuentealba, Viviana Ojeda, Karin Alvarez, Andrea Gómez, and María Estela Andrés

From the Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, P. O. Box 114-D, Santiago, Chile

Nurr1 is a transcription factor essential for the development of ventral dopaminergic neurons. In search for regulatory mechanisms of Nurr1 function, we identified the SUMO (small ubiquitin-like modifier)-E3 ubiquitin-protein isopeptide ligase, PIAS, as an interaction partner of Nurr1. Overexpressed PIAS and Nurr1 co-localize in the nuclei of transfected cells, and their interaction is demonstrated through co-immunoprecipitation and glutathione S-transferase pulldown assays. Co-expression of PIAS with Nurr1 results in a potent repression of Nurr1-dependent transcriptional activation of an artificial NGFI-B response element (NBRE) reporter as well as of a reporter driven by the native tyrosine hydroxylase promoter. We identified two consensus sumoylation sites in Nurr1. The substitution of lysine 91 by arginine in one SUMO site enhanced the transcriptional activity of Nurr1, whereas the substitution of lysine 577 by arginine in the second SUMO site decreased transcriptional activity of Nurr1. Interestingly, PIAS-induced repression of Nurr1 activity does not require the two sumoylation sites, because each mutant is repressed as efficiently as the wild type Nurr1. In addition, the mutations do not alter Nurr1 nuclear localization. Finally, we provide evidence that Nurr1 and PIAS co-exist in several nuclei of the rodent central nervous system by demonstrating the co-expression of Nurr1 protein and PIAS mRNA in the same cells. In conclusion, our studies identified PIAS as a transcriptional co-regulator of Nurr1 and suggest that this interaction may have a physiological role in regulating the expression of Nurr1 target genes.

Received for publication, July 25, 2003 , and in revised form, October 9, 2003.

^* This work was supported by FONDECYT Grants 1000722 and 1030496. 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.

These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: mandres{at}bio.puc.cl.

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