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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

AuthorsSubtil-Rodríguez, Alicia ; Millán-Ariño, Lluis ; Quiles, Ignacio; Ballaré, Cecilia; Beato, Miguel; Jordan, Albert
Issue DateJun-2008
PublisherAmerican Society for Microbiology
CitationMolecular and Cellular Biology 28(11): 3830-3849 (2008)
AbstractSteroid 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. Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Publisher version (URL)http://dx.doi.org/10.1128/MCB.01217-07
Identifiersdoi: 10.1128/MCB.01217-07
issn: 0270-7306
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