title: Increased acetylation in the DNA-binding domain of TR4 nuclear receptor by the coregulator ARA55 leads to suppression of TR4 transactivation.
abstract: The nuclear receptor TR4 is a key regulator for many physiological processes, including growth, development, and metabolism. However, how the transcriptional activity of TR4 is regulated in the absence of ligand(s) remains largely unknown. Here we found that an androgen receptor (AR) coactivator, ARA55, might function as a corepressor to suppress TR4 transactivation. Molecular mechanistic dissection with mutation analysis found that ARA55 could enhance TR4 acetylation at the conserved acetylation sites of lysine 175 and lysine 176 in the DNA-binding domain via recruiting proteins with histone acetyl transferase activity, which might then reduce significantly the TR4 DNA binding activity that resulted in the suppression of TR4 transactivation. These results are in contrast to the classic ARA55 coactivator function to enhance AR transactivation partially via increased AR acetylation in the hinge/ligand-binding domain. Together, these results not only provide a novel functional mechanism showing that acetylation of different nuclear receptors at different domains by coregulator may lead to differential receptor transactivation activity but also provide a new way for small molecules to control TR4 transactivation via altering TR4 acetylation levels, and such small molecules may have potential therapeutic applications in the future.
authors.affiliation: George Whipple Lab for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Shaozhen
authors.initials: S
authors.lastname: Xie
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D060588:LIM Domain Proteins; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D051379:Mice; D016297:Mutagenesis, Site-Directed; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000737:chemistry*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation; D016896:Treatment Outcome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008024:Ligands; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; C490351:TGFB1I1 protein, human; D004247:DNA; D008239:Lysine