title: Thyroid hormone response element organization dictates the composition of active receptor.
abstract: Thyroid hormone (triiodothyronine, T(3)) is known to activate transcription by binding heterodimers of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs). RXR-TRs bind to T(3) response elements (TREs) composed of direct repeats of the sequence AGGTCA spaced by four nucleotides (DR-4). In other TREs, however, the half-sites can be arranged as inverted palindromes and palindromes (Pal). Here we show that TR homodimers and monomers activate transcription from representative TREs with alternate half-site placements. TR beta activates transcription more efficiently than TR alpha at an inverted palindrome (F2), and this correlates with preferential TR beta homodimer formation at F2 in vitro. Furthermore, reconstruction of TR transcription complexes in yeast indicates that TR beta homodimers are active at F2, whereas RXR-TRs are active at DR-4 and Pal. Finally, analysis of TR beta mutations that block homodimer and/or heterodimer formation reveal TRE-selective requirements for these surfaces in mammalian cells, which suggest that TR beta homodimers are active at F2, RXR-TRs at DR-4, and TR monomers at Pal. TR beta requires higher levels of hormone for activation at F2 than other TREs, and this differential effect is abolished by a dimer surface mutation suggesting that it is related to composition of the TR.TRE complex. We propose that interactions of particular TR oligomers with different elements play unappreciated roles in TRE-selective actions of liganded TRs in vivo.
authors.affiliation: Molecular Pharmacology Laboratory, Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brasília, DF, Brazil.
authors.forename: Lara F R
authors.initials: LF
authors.lastname: Velasco
authors.forename: Marie
authors.initials: M
authors.lastname: Togashi
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
authors.forename: Rutinéia P
authors.initials: RP
authors.lastname: Pessanha
authors.forename: Fanny N
authors.initials: FN
authors.lastname: Moura
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Barra
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Rachelle
authors.initials: R
authors.lastname: Rebong
authors.forename: Chaoshen
authors.initials: C
authors.lastname: Yuan
authors.forename: Luiz A
authors.initials: LA
authors.lastname: Simeoni
authors.forename: Ralff C J
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Francisco A R
authors.initials: FA
authors.lastname: Neves
mesh_terms: D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D047488:Retinoid X Receptors; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine