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Molecular and Cellular Biology, June 2008, p. 3830-3849, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.01217-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Progesterone Induction of the 11β-Hydroxysteroid Dehydrogenase Type 2 Promoter in Breast Cancer Cells Involves Coordinated Recruitment of STAT5A and Progesterone Receptor to a Distal Enhancer and Polymerase Tracking{triangledown} ,{dagger}

Alicia Subtil-Rodríguez,{ddagger} Lluís Millán-Ariño, Ignacio Quiles, Cecilia Ballaré, Miguel Beato, and Albert Jordan*

Centre de Regulació Genòmica, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, E-08003 Barcelona, Spain

Received 9 July 2007/ Returned for modification 17 August 2007/ Accepted 7 March 2008

Steroid hormone receptors regulate gene expression, interacting with target DNA sequences but also activating cytoplasmic signaling pathways. Using the human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) gene as a model, we have investigated the contributions of both effects on a human progesterone-responsive promoter in breast cancer cells. Chromatin immunoprecipitation has identified two different mechanisms of hormone-induced progesterone receptor (PR) recruitment to the 11β-HSD2 promoter: (i) direct PR binding to DNA at the proximal promoter, abrogated when PR contains a mutated DNA binding domain (DBD), and (ii) STAT5A (signal transducer and activator of transcription 5A)-mediated recruitment of PR to an upstream distal region, impaired by AG490, a JAK/STAT pathway inhibitor. The JAK/STAT inhibitor, as well as expression of dominant-negative STAT5A, impairs hormone induction of 11β-HSD2. On the other hand, the DBD-mutated PR fully supports 11β-HSD2 expression. These results, along with data from a deletion analysis, indicate that the distal region is crucial for hormone regulation of 11β-HSD2. We show active RNA polymerase II tracking from the distal region upon PR and STAT5A binding, concomitant with synthesis of noncoding, hormone-dependent RNAs, suggesting that this region works as a hormone-dependent transcriptional enhancer. In conclusion, coordination of PR transcriptional effects and cytoplasmic signaling activation, in particular the JAK/STAT pathway, are critical in regulating progestin-induced endogenous 11β-HSD2 gene expression in breast cancer cells. This is not unique to this promoter, as AG490 also alters the expression of other progesterone-regulated genes.

* Corresponding author. Present address: Institute of Molecular Biology of Barcelona, CSIC, Parc Cientific de Barcelona, Baldiri Reixac 10, E-08028 Barcelona, Spain. Phone: 34-93-403 4668. Fax: 34-93-403 4979. E-mail: ajvbmc{at}ibmb.csic.es

{triangledown} Published ahead of print on 31 March 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Centro Andaluz de Biología Molecular y Medicina Regenerativa, CSIC, Sevilla, Spain.

Molecular and Cellular Biology, June 2008, p. 3830-3849, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.01217-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Quiles, I., Millan-Arino, L., Subtil-Rodriguez, A., Minana, B., Spinedi, N., Ballare, C., Beato, M., Jordan, A. (2009). Mutational Analysis of Progesterone Receptor Functional Domains in Stable Cell Lines Delineates Sets of Genes Regulated by Different Mechanisms. Mol. Endocrinol. 23: 809-826 [Abstract] [Full Text]  
  • Abdel-Hafiz, H., Dudevoir, M. L., Horwitz, K. B. (2009). Mechanisms Underlying the Control of Progesterone Receptor Transcriptional Activity by SUMOylation. J. Biol. Chem. 284: 9099-9108 [Abstract] [Full Text]  


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