Intracellular receptors use a common mechanism to interpret signaling information at response elements

D. Barry Starr, William Matsui, Jay R. Thomas, Keith R. Yamamoto

Research output: Contribution to journalArticle

Abstract

The glucocorticoid receptor (GR) activates transcription in certain glucocorticoid response element (GRE) contexts, and represses or displays no activity in others. We isolated point mutations in one GRE, plfG, at which GR activated transcription under conditions in which the wild-type element was inactive or conferred repression, implying that GREs may carry signals that are interpreted by bound receptors. Consistent with this notion, we identified a mutant rat GR, K461A, which activated transcription in all GRE contexts tested, implying that this residue is important in interpretation of GRE signals. In a yeast screen of 60,000 GR mutants for strong activation from plfG, all 13 mutants isolated contained substitutions at K461. This lysine residue is highly conserved in the zinc-binding region (ZBR) of the intracellular receptor (IR) superfamily; when it was mutated in MR and RARβ, the resulting receptors similarly activated transcription at response elements that their wild-type counterparts repressed or were inactive. We suggest that IR response elements serve in part as signaling components, and that a critical lysine residue serves as an allosteric "lock" that restricts IRs to inactive or repressing configurations except in response element contexts that signal their conversion to transcriptional activators. Therefore, mutation of this residue produces altered receptors that activate in many or all response element contexts.

Original languageEnglish (US)
Pages (from-to)1271-1283
Number of pages13
JournalGenes & development
Volume10
Issue number10
StatePublished - May 15 1996
Externally publishedYes

Keywords

  • Context-dependent activity
  • DNA-binding domain
  • Glucocorticoid receptor
  • Intracellular receptor
  • Transcriptional repression

ASJC Scopus subject areas

  • Developmental Biology
  • Genetics

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  • Cite this

    Starr, D. B., Matsui, W., Thomas, J. R., & Yamamoto, K. R. (1996). Intracellular receptors use a common mechanism to interpret signaling information at response elements. Genes & development, 10(10), 1271-1283.