Ligand-independent and -dependent functions of thyroid hormone receptor isoforms depend upon their distinct amino termini

A. N. Hollenberg, T. Monden, F. E. Wondisford

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70 Scopus citations

Abstract

Isoform specificity likely plays a large role in the ability of the thyroid hormone receptor (TR) to specifically regulate gene expression in both the presence and absence of its cognate ligand, triiodothyronine. To investigate further the mechanism of isoform specificity of human TRs (TRα1 and TRβ1), we have examined their functional effects on positive thyroid hormone response elements (TREs) both in the presence and absence of ligand. TRα1 was greater than 2-fold more potent than TRβ1 on both TREs studied, in terms of both ligand-independent repression and ligand-dependent stimulation. By creating a number of chimeric and mutant receptors, we have established that the increased functional potency of TRα1 is due to its unique amino terminus. Deletion or substitution of the TRα1 amino terminus leads to a loss of both its ligand-independent and -dependent functions on positive TREs. Furthermore, the TRα1 amino terminus antagonizes homodimer formation on the positive TREs studied. TR constructs, which contain the TRα1 amino terminus, are unable to form homodimers and form exclusively heterodimers with RXRα on direct repeat and palindromic TREs. Deletion of the amino terminus from either TR isoform leads to preferential homodimer formation, which suggests that the TR amino terminus is important for relative heterodimerization capability. From these data, we conclude that TRα1 isoform specificity on positive TREs resides predominantly in its amino terminus through its ability to favor heterodimerization with the retinoid X receptor or other nuclear proteins.

Original languageEnglish (US)
Pages (from-to)14274-14280
Number of pages7
JournalJournal of Biological Chemistry
Volume270
Issue number24
DOIs
StatePublished - 1995

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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