Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1.
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 (ii) 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 II 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.
Cheung
Edwin
E
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Acevedo
Mari Luz
ML
Cole
Philip A
PA
Kraus
W Lee
WL
D002843:Chromatin / Q000378:metabolism / Q000502:physiology; D019281:Dimerization; D004742:Enhancer Elements, Genetic; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008024:Ligands; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D002843:Chromatin; D047628:Estrogen Receptor alpha; D008024:Ligands; D016761:Oncogene Proteins v-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1