title: Estrogen receptor β (ERβ1) transactivation is differentially modulated by the transcriptional coregulator Tip60 in a cis-acting element-dependent manner.
abstract: Estrogen receptor (ER) β1 and ERα have overlapping and distinct functions despite their common use of estradiol as the physiological ligand. These attributes are explained in part by their differential utilization of coregulators and ligands. Although Tip60 has been shown to interact with both receptors, its regulatory role in ERβ1 transactivation has not been defined. In this study, we found that Tip60 enhances transactivation of ERβ1 at the AP-1 site but suppresses its transcriptional activity at the estrogen-response element (ERE) site in an estradiol-independent manner. However, different estrogenic compounds can modify the Tip60 action. The corepressor activity of Tip60 at the ERE site is abolished by diarylpropionitrile, genistein, equol, and bisphenol A, whereas its coactivation at the AP-1 site is augmented by fulvestrant (ICI 182,780). GRIP1 is an important tethering mediator for ERs at the AP-1 site. We found that coexpression of GRIP1 synergizes the action of Tip60. Although Tip60 is a known acetyltransferase, it is unable to acetylate ERβ1, and its coregulatory functions are independent of its acetylation activity. In addition, we showed the co-occupancy of ERβ1 and Tip60 at ERE and AP-1 sites of ERβ1 target genes. Tip60 differentially regulates the endogenous expression of the target genes by modulating the binding of ERβ1 to the cis-regulatory regions. Thus, we have identified Tip60 as the first dual-function coregulator of ERβ1.
authors.affiliation: From the Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health.
authors.forename: Ming-Tsung
authors.initials: MT
authors.lastname: Lee
authors.affiliation: From the Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health,; Center for Environmental Genetics, and; Cancer Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 and.
authors.forename: Yuet-Kin
authors.initials: YK
authors.lastname: Leung
authors.affiliation: From the Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health.
authors.forename: Irving
authors.initials: I
authors.lastname: Chung
authors.affiliation: From the Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health,; Center for Environmental Genetics, and; Cancer Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 and.
authors.forename: Pheruza
authors.initials: P
authors.lastname: Tarapore
authors.affiliation: From the Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health,; Center for Environmental Genetics, and; Cancer Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 and; the Cincinnati Veteran Affairs Medical Center, Cincinnati, Ohio 45220. Electronic address: shuk-mei.ho@uc.edu.
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
mesh_terms: D000107:Acetylation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D047629:Estrogen Receptor beta; C491310:GRIP1 protein, human; D009419:Nerve Tissue Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5
keywords: AP-1; Acetyltransferase; Coregulator; ERβ1; Estrogen Receptor; Estrogen-response Element; Protein-Protein Interactions; Transcription; Transcription Enhancers; Transcription Repressor