2024-03-29T01:38:06Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1139572021-12-27T16:07:02Zcom_10261_41com_10261_1com_10261_134col_10261_294col_10261_387
00925njm 22002777a 4500
dc
Subtil-Rodríguez, Alicia
author
Millán-Ariño, Lluis
author
Quiles, Ignacio
author
Ballaré, Cecilia
author
Beato, Miguel
author
Jordan, Albert
author
2008-06
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.
Molecular and Cellular Biology 28(11): 3830-3849 (2008)
http://hdl.handle.net/10261/113957
10.1128/MCB.01217-07
18378698
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