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J. Biol. Chem., Vol. 279, Issue 25, 26184-26191, June 18, 2004

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The Relative Contribution Exerted by AF-1 and AF-2 Transactivation Functions in Estrogen Receptor Transcriptional Activity Depends upon the Differentiation Stage of the Cell^*

Yohann Mérot, Raphaël Métivier, Graziella Penot, Dominique Manu, Christian Saligaut, Frank Gannon, Farzad Pakdel, Olivier Kah, and Gilles Flouriot¶

From the Endocrinologie Moléculaire de la Reproduction, UMR CNRS 6026, Université de Rennes I, 35042 Rennes cedex, France and the EMBL, Meyerhofstraße 1, D-69117 Heidelberg, Germany

The activity of the transactivation functions (activation function (AF)-1 and AF-2) of the estrogen receptor (ER) is cell-specific. This study aimed to decipher the yet unclear mechanisms involved in this differential cell sensitivity, with particular attention to the specific influence that cell differentiation may have on these processes. Hence, we comparatively evaluated the permissiveness of cells to either ER AFs in two different cases: (i) a series of cell lines originating from a common tissue, but with distinct differentiation phenotypes; and (ii) cell lines that undergo differentiation processes in culture. These experiments demonstrate that the respective contribution that AF-1 and AF-2 make toward ER activity varies in a cell differentiation stage-dependent manner. Specifically, whereas AF-1 is the dominant AF involved in ER transcriptional activity in differentiated cells, the more a cell is de-differentiated the more this cell mediates ER signaling through AF-2. For instance, AF-2 is the only active AF in cells that have achieved their epithelial-mesenchymal transition. Moreover, the stable expression of a functional ER in strictly AF-2 permissive cells restores an AF-1-sensitive cell context. These results, together with data obtained in different ER-positive cell lines tested strongly suggest that the transcriptional activity of ER relies on its AF-1 in most estrogen target cell types.

Received for publication, February 26, 2004 , and in revised form, April 9, 2004.

^* This work was supported by the Association pour la Recherche contre le Cancer, the Ligue contre le cancer, CNRS, and the University of Rennes 1. 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.

^¶ To whom correspondence should be addressed: Endocrinologie Moléculaire de la Reproduction, UMR CNRS 6026, Université de Rennes I, 35042 Rennes cedex, France. Tel.: 33-0-2-23-23-68-04; Fax: 33-0-2-23-23-67-94; E-mail: gilles.flouriot{at}univ-rennes1.fr.

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