title: Activation of estrogen receptor α by raloxifene through an activating protein-1-dependent tethering mechanism in human cervical epithelial cancer cells: a role for c-Jun N-terminal kinase.
abstract: Nuclear estrogen receptor α (ERα) regulates target gene expression in response to ligands through two distinct mechanisms: direct binding to DNA and indirect tethering through other DNA-bound transcription factors, such as AP-1. In the studies described herein, we examined the molecular mechanisms underlying the activation of ERα in the AP-1 tethering pathway by the selective estrogen receptor modulator (SERM) raloxifene (Ral). Our results with the MMP1 and PRUNE genes indicate that the c-Fos component of the AP-1 tethering factor and the c-Jun N-terminal kinase 1 (JNK1) are constitutively bound at the promoter regions prior to Ral exposure. Ral then promotes the binding of ERα at the promoter in a c-Fos-dependent manner. Interestingly, we found that JNK1 enzymatic activity is required for Ral-dependent gene activation through ERα. Our results suggest that one role for Ral-dependent recruitment of ERα to the AP-1 binding site is to stimulate JNK1 enzymatic activity. Alternatively, Ral-occupied ERα might recruit protein substrates to promoter-bound JNK1 without any change in JNK1 activity. Collectively, our studies have revealed a new role for JNK1 in determining gene regulatory outcomes by ERα.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fogarty
authors.forename: Christina K
authors.initials: CK
authors.lastname: Matulis
authors.forename: W Lee
authors.initials: WL
authors.lastname: Kraus
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D014453:Glucuronosyltransferase / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial; D010744:Phosphoric Monoester Hydrolases; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms
chemical_list: D002352:Carrier Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D008156:Luciferases; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; D048055:Mitogen-Activated Protein Kinase 8; C438732:PRUNE1 protein, human; D010744:Phosphoric Monoester Hydrolases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1