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J. Biol. Chem., Vol. 279, Issue 50, 52087-52094, December 10, 2004

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Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A^*

Rafael Toro, Irfan Saadi¶, Adisa Kuburas||, Mona Nemer**, and Andrew F. Russo||

From the Genetics Program and the ^||Department of Physiology and Biophysics University of Iowa, Iowa City, Iowa 52242 and the ^**Institut de Recherches Cliniques de Montreal, Montreal, Quebec H2W-1R7, Canada

The PITX2 homeodomain protein is mutated in patients with Axenfeld-Rieger syndrome and is involved in the development of multiple organ systems, including the heart. We have examined the interaction of PITX2 isoforms with myocyte-enhancing factor 2A (MEF2A), which is a known regulator of cardiac development. A direct interaction between PITX2a and MEF2A was demonstrated using yeast two-hybrid and GST pull-down assays. To study the functional significance of this interaction, we used the atrial natriuretic factor (ANF) promoter. Coexpression of MEF2A and PITX2a or Pitx2c resulted in a strong synergistic activation of the ANF promoter in LS8 oral epithelial cells but not in other cell lines (NIH/3T3, Chinese hamster ovary, or C2C12). The synergism was dependent on promoter context, because it required MEF2 binding sites and was not seen with two other PITX2 target promoters. DNA binding by MEF2A was required but not sufficient for synergism. Upstream activators of p38 MAP kinases, MKK3 and MKK6, increased PITX2a and Pitx2c activity to yield up to 90-fold activation of the ANF promoter in LS8 cells. Because Axenfeld-Rieger syndrome is autosomal dominant and affects development of the oral epithelium, we tested one of the known PITX2 mutants. The PITX2a-K88E mutant protein suppressed wild type PITX2a synergism with MEF2A. These results demonstrate a promoter- and cell-specific functional interaction between PITX2 and MEF2A and suggest the possibility of coordinate control by these factors in the oral epithelium.

Received for publication, April 29, 2004 , and in revised form, September 8, 2004.

^* This work was supported by National Institutes of Health Grant DE13076 (to A. F. R.), the Canadian Institutes of Health Research (to M. N.), and predoctoral fellowships from the American Heart Association (to I. S.) and the University of Iowa (R. T.). 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.

^¶ Present address: Brigham and Women's Hospital, Harvard Medical School-New Research Bldg., Boston, MA 02115.

To whom correspondence should be addressed. Tel.: 319-335-7872; Fax: 319-335-7330; E-mail: andrew-russo{at}uiowa.edu.

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