Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor

Domingo Barettino, María D.M.Vivanco Ruiz, Hendrik G. Stunnenberg

Research output: Contribution to journalArticlepeer-review

297 Citations (Scopus)

Abstract

Transcriptional activation by nuclear receptors is achieved through autonomous activation functions (AFs), a constitutive N-terminal AF-1 and a C-terminal, ligand-dependent AF-2 that comprises a motif conserved between nuclear receptors. We have performed an extensive mutational analysis of the putative AF-2 domain of chicken thyroid hormone receptor alpha (cT3Rα). We show that the AF-2 region mediates transactivation as well as transcriptional interference (squelching), not only between the thyroid hormone and vitamin (type II) receptors, but also between type II and steroid hormone (type I) receptors. Transcriptional activation and interference require equivalent doses of the cognate ligand, and mutations in the conserved motif that reduce ligand-induced transactivation also impair transcriptional interference. When fused to the Ga14 DNA binding domain, a 35 amino acid long fragment containing the conserved motif is able to transactivate and squelch, albeit in a ligand-independent manner. Our results define the AF-2 of cT3Rα as an autonomous transactivation domain that, in its natural context, is governed by ligand. We propose that AF-2 is probably part of a surface for interaction with either a general transcription factor or a putative bridging factor, that might be utilized by type I and II receptors.

Original languageEnglish
Pages (from-to)3039-3049
Number of pages11
JournalEMBO Journal
Volume13
Issue number13
DOIs
Publication statusPublished - 1994
Externally publishedYes

Keywords

  • Nuclear receptors
  • Thyroid hormone receptor
  • Transactivation domain
  • Transcriptional interference

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