A unique role of the β-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone: Mapping of a novel amino-terminal domain important for ligand-independent activation

Marie France Langlois, Kerstin Zanger, Tsuyoshi Monden, Joshua D. Safer, Anthony N. Hollenberg, Fredric E. Wondisford

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Negative regulation by thyroid hormone is mediated by nuclear thyroid hormone receptors (TRs) acting on thyroid hormone response elements (TREs). We examine here the role of human TR-β2, a TR isoform with central nervous system-restricted expression, in the regulation of target genes whose expression are decreased by triiodothyronine (T3). Using transient transfection studies, we found that TR-β2 achieved significantly greater ligand-independent activation on the thyrotropin-releasing hormone (TRH) and common glycoprotein α-subunit genes than either TR-β1 or TR-α1. A chimeric TR-β isoform containing the TR-β2 amino terminus linked to the TR-α1 DNA- and ligand-binding domains functioned like the TR-β2 isoform on these promoters, confirming that the amino terminus of TR-β2 was both necessary and sufficient to mediate this effect. By constructing deletion mutants of the TR-β2 amine terminus, we demonstrate that amino acids 89-116 mediate this function. This domain, important in ligand-independent activation on negative TREs, is discrete from a previously described activation domain in the amino-terminal portion of TR-β2. We conclude that the central nervous system-restricted TR-β2 isoform has a unique effect on negative regulation by T3 that can be mapped to amino acids 89-116 of the amino terminus of the human TR-β2.

Original languageEnglish
Pages (from-to)24927-24933
Number of pages7
JournalJournal of Biological Chemistry
Volume272
Issue number40
DOIs
StatePublished - 3 Oct 1997
Externally publishedYes

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