Abstract
T4 (3,5,3',5'-tetraiodo-L-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-L-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRα1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T4 as by T3 in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 745-757 |
| Number of pages | 13 |
| Journal | Molecular Endocrinology |
| Volume | 28 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2014 |
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ASJC Scopus subject areas
- Molecular Biology
- Endocrinology
Cite this
The ability of thyroid hormone receptors to sense T4 as an agonist depends on receptor isoform and on cellular cofactors. / Schroeder, Amy; Jimenez, Robyn; Young, Briana; Privalsky, Martin L.
In: Molecular Endocrinology, Vol. 28, No. 5, 2014, p. 745-757.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The ability of thyroid hormone receptors to sense T4 as an agonist depends on receptor isoform and on cellular cofactors
AU - Schroeder, Amy
AU - Jimenez, Robyn
AU - Young, Briana
AU - Privalsky, Martin L.
PY - 2014
Y1 - 2014
N2 - T4 (3,5,3',5'-tetraiodo-L-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-L-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRα1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T4 as by T3 in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.
AB - T4 (3,5,3',5'-tetraiodo-L-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-L-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRα1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T4 as by T3 in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.
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UR - http://www.scopus.com/inward/citedby.url?scp=84899733592&partnerID=8YFLogxK
U2 - 10.1210/me.2013-1335
DO - 10.1210/me.2013-1335
M3 - Article
C2 - 24673558
AN - SCOPUS:84899733592
VL - 28
SP - 745
EP - 757
JO - Molecular Endocrinology
JF - Molecular Endocrinology
SN - 0888-8809
IS - 5
ER -