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Title: | 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 |
Authors: | Subtil-Rodríguez, Alicia ![]() ![]() ![]() |
Issue Date: | Jun-2008 |
Publisher: | American Society for Microbiology |
Citation: | Molecular and Cellular Biology 28(11): 3830-3849 (2008) |
Abstract: | 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. Copyright © 2008, American Society for Microbiology. All Rights Reserved. |
Publisher version (URL): | http://dx.doi.org/10.1128/MCB.01217-07 |
URI: | http://hdl.handle.net/10261/113957 |
DOI: | 10.1128/MCB.01217-07 |
Identifiers: | doi: 10.1128/MCB.01217-07 issn: 0270-7306 |
Appears in Collections: | (IBMB) Artículos (CABIMER) Artículos |
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File | Description | Size | Format | |
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Subtil-MCB-2008-v28-n11-p3830.pdf | 2,08 MB | Adobe PDF | ![]() View/Open | |
Subtil-MCB-2008-v28-n11-Supplementary-1.pdf | 83,22 kB | Adobe PDF | ![]() View/Open | |
Subtil-MCB-2008-v28-n11-Supplementary-2.pdf | 147,13 kB | Adobe PDF | ![]() View/Open |
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