Retinoic acid receptors beta and gamma do not repress, but instead activate target gene transcription in both the absence and presence of hormone ligand

Mol Endocrinol. 2003 Mar;17(3):373-85. doi: 10.1210/me.2002-0340. Epub 2002 Dec 23.

Abstract

Retinoic acid receptors (RARs) are important mediators of retinoid signaling in morphogenesis, development, and cell differentiation. Three major isotypes of RARs, denoted alpha, beta, and gamma, have been identified, each encoded by a distinct genetic locus. Although RARalpha, RARbeta, and RARgamma share many structural and functional features, these three isotypes are known to play unique, as well as overlapping, roles in physiology and development. We report here that the three RAR isotypes display different transcriptional properties in the absence of hormone ligand; under these conditions, RARalpha is a strong repressor of target gene expression, whereas both RARbeta and RARgamma fail to repress and instead are able to mediate substantial levels of hormone-independent transcriptional activation. These differing transcriptional properties appear to reflect the differing abilities of the three RAR isotypes to interact with the SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor protein: RARalpha binds to SMRT strongly both in vitro and in vivo, whereas RARbeta and RARgamma interact only weakly with SMRT. The ability to repress or to activate transcription in the absence of hormone maps predominantly to isotype-specific differences in the sequence of helix 3 within the hormone binding domain of the RARs, and the transcriptional properties of one isotype can be exchanged with that of another by exchanging portions of helix 3. The different transcriptional properties of RARalpha, RARbeta, and RARgamma in the absence of hormone contribute to the distinctive biological functions of these proteins and provide a rationale for the strong conservation of the three distinct isotypes during the vertebrate evolutionary radiation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Blotting, Western
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Nuclear Receptor Co-Repressor 2
  • Protein Isoforms
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Retinoic Acid / physiology*
  • Repressor Proteins / metabolism*
  • Sequence Alignment
  • Transcription, Genetic / physiology*
  • Transcriptional Activation / physiology*

Substances

  • DNA-Binding Proteins
  • Ligands
  • NCOR2 protein, human
  • Nuclear Receptor Co-Repressor 2
  • Protein Isoforms
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • retinoic acid receptor beta
  • retinoic acid receptor gamma