Thyroid hormone response element organization dictates the composition of active receptor.
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.
Velasco
Lara F R
LF
Molecular Pharmacology Laboratory, Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brasília, DF, Brazil.
Togashi
Marie
M
Walfish
Paul G
PG
Pessanha
Rutinéia P
RP
Moura
Fanny N
FN
Barra
Gustavo B
GB
Nguyen
Phuong
P
Rebong
Rachelle
R
Yuan
Chaoshen
C
Simeoni
Luiz A
LA
Ribeiro
Ralff C J
RC
Baxter
John D
JD
Webb
Paul
P
Neves
Francisco A R
FA
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
D047488:Retinoid X Receptors; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine