Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1

作者：Cheung E; Acevedo ML; Cole PA; Kraus WL^*

来源：Proceedings of the National Academy of Sciences, 2005, 102(3): 559-564.

DOI：10.1073/pnas.0407113102

• chromatin
• enhancer
• Fos/Jun heterodimers
• histone acetyltransferase
• selective estrogen receptor modulator

Estrogen signaling occurs through at least two distinct molecular pathways: (i) direct binding of liganded estrogen receptors (ERs) to estrogen- responsive DNA elements (EREs) (the -ER/ERE pathway") and (h) indirect recruitment of liganded ERs to activating protein-1 (AP-1)-responsive DNA elements via heterodimers of Fos and Jun (the "ER/AP-1 pathway"). We have developed a biochemical assay for examining ligand-regulated transcription by ERs in the ER/AP-1 pathway. This assay recapitulates the altered (i.e., agonistic) pharmacology of selective estrogen receptor modulator drugs in this pathway reported previously by using various cell-based assays. We used our biochemical assay to examine the detailed mechanisms of ER/AP-1-dependent transcription. Our studies indicate that (i) ERalpha/AP-1 complexes play a critical role in promoting the formation of stable RNA polymerase 11 preinitiation complexes leading to transcription initiation, (ii) chromatin is a key determinant of estrogen and selective estrogen receptor modulator signaling in the ERalpha/AP-1 pathway, (iii) distinct domains of ERalpha are required for recruitment to DNA-bound Fos/Jun heterodimers and transcriptional activation at AP-1 sites, and (iv) different enhancer/ activator combinations in the ERalpha and AP-1 pathways use coactivators in distinct ways. These studies have increased our understanding of the molecular mechanisms underlying ligand-dependent signaling in the ER/AP-1 pathway and demonstrate the usefulness of this biochemical approach.

• 出版日期2005-1-18