Thyroid Hormone-independent Interaction between the Thyroid Hormone Receptor β2 Amino Terminus and Coactivators

Koshi Hashimoto,Corinna Oberste-Berghaus,Ronald N Cohen,Anthony N Hollenberg,Fredric E Wondisford,Kerstin Zanger

doi:10.1074/jbc.275.3.1787

Koshi Hashimoto, Corinna Oberste-Berghaus + Show 4 more

Open Access

https://doi.org/10.1074/jbc.275.3.1787

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Abstract

Thyroid hormone receptors (TRs) mediate hormone action by binding to DNA response elements (TREs) and either activating or repressing gene expression in the presence of ligand, T(3). Coactivator recruitment to the AF-2 region of TR in the presence of T(3) is central to this process. The different TR isoforms, TR-beta1, TR-beta2, and TR-alpha1, share strong homology in their DNA- and ligand-binding domains but differ in their amino-terminal domains. Because TR-beta2 exhibits greater T(3)-independent activation on TREs than other TR isoforms, we wanted to determine whether coactivators bound to TR-beta2 in the absence of ligand. Our results show that TR-beta2, unlike TR-beta1 or TR-alpha1, is able to bind certain coactivators (CBP, SRC-1, and pCIP) in the absence of T(3) through a domain which maps to the amino-terminal half of its A/B domain. This interaction is specific for certain coactivators, as TR-beta2 does not interact with other co-factors (p120 or the CBP-associated factor (pCAF)) in the absence of T(3). The minimal TR-beta2 domain for coactivator binding is aa 21-50, although aa 1-50 are required for the full functional response. Thus, isoform-specific regulation by TRs may involve T(3)-independent coactivator recruitment to the transcription complex via the AF-1 domain.

Highlights

Thyroid hormone receptors (TRs)1 belong to the superfamily of nuclear receptors and contain at least five discrete domains: 1) the amino-terminal A/B domain containing AF-1 function; 2) the DNA-binding or C domain, which is highly conserved among nuclear receptors; 3) the hinge region or D domain, where corepressors bind; 4) the ligand-binding or E domain; and 5) the carboxyl-terminal AF-2 or F domain [1]
On positively regulated to DNA response elements (TREs), gene expression is repressed in the absence of T3 and stimulated when T3 binds to the TR (6 – 8)
Cotransfection of CBP, SRC-1, or pCIP expression vectors with the amino terminus of TR-␤2 enhanced transcriptional activation 42, 50, and 43-fold, respectively. Cotransfection of these coactivators with the amino-terminal domains of the TR-␣1 or TR-␤1 did not increase reporter gene expression over base-line activity observed with a GAL4 “empty vector.”

Summary

Introduction

Thyroid hormone receptors (TRs)1 belong to the superfamily of nuclear receptors and contain at least five discrete domains: 1) the amino-terminal A/B domain containing AF-1 function; 2) the DNA-binding or C domain, which is highly conserved among nuclear receptors; 3) the hinge region or D domain, where corepressors bind; 4) the ligand-binding or E domain; and 5) the carboxyl-terminal AF-2 or F domain [1]. The ligand-independent activation of transcription by the TR-␤2 isoform could be mediated by binding of these cofactors to the amino terminus (AF-1 domain) of the receptor.

Results

Conclusion