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J. Biol. Chem., Vol. 281, Issue 45, 33959-33970, November 10, 2006

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Glucocorticoids Repress bcl-X Expression in Lymphoid Cells by Recruiting STAT5B to the P4 Promoter^*

Luciana Rocha-Viegas¹, Guillermo P. Vicent, José L. Barañao^¶1, Miguel Beato, and Adali Pecci^¶12

From the Departamentos de ^¶Química Biológica y Fisiología, Biología Molecular y Celular, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE)-Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Intendente Güiraldes 2160, Pab. II, 2do piso, C1428EGA Buenos Aires, Argentina and the Centre de Regulació Genòmica, Universitat Pompeu Fabra, Passeig Marítim, 37-49, 08003 Barcelona, Spain

The bcl-X gene plays a critical role in apoptosis. Six different isoforms generated by tissue-specific promoter usage and alternative splicing were described. Some of them exert opposite effects on cell death. In mammary epithelial cells glucocorticoids induce bcl-X expression and increase the ratio bcl-X_L (antiapoptotic)/bcl-X_S (apoptotic) by activating P4 promoter, which contains two hormone response elements. Here we show that, on mouse thymocytes and T lymphocyte derivative S49 cells, glucocorticoids inhibited transcription from P4 and decreased the ratio bcl-X_L/bcl-X_S favoring apoptosis. Upon hormonal treatment, glucocorticoid receptor (GR), steroid receptor coactivator-1, and RNA polymerase II were transiently recruited to P4 promoter, whereas STAT5B was also recruited but remained bound. Concomitant with the release of GR, silencing mediator for retinoic acid receptor and thyroid hormone receptor and histone deacetylase 3 were recruited, histone H3 was deacetylated, and RNA polymerase II left the promoter. Inhibition of STAT5 activity reverted glucocorticoid repression to activation of transcription and was accompanied by stable recruitment of GR and RNA polymerase II to P4.

Received for publication, March 14, 2006 , and in revised form, September 7, 2006.

^* This work was supported in part by the Ministry of Education and Science (Grant SAF2001-0463 to M. B.) and grants from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), University of Buenos Aires, and the National Agency of Scientific Promotion (Grant BID-1201 PICT 05-09044 to A. P.). 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.

¹ Members of CONICET.

² To whom correspondence should be addressed. Tel.: 54-11-4576-3300 (ext. 483); Fax: 54-11-4576-3342; E-mail: apecci{at}qb.fcen.uba.ar.

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