Two distinct actions of retinoid-receptor ligands

Nature. 1996 Aug 29;382(6594):819-22. doi: 10.1038/382819a0.


Signalling by all-trans retinoic acid is mediated through RXR-RAR retinoid receptor heterodimers, in which RXR has been considered to act as a transcriptionally silent partner. However, we show here that in cultured NB4 (ref. 6) human acute promyelocytic leukaemia cells treated with either an RAR-alpha-selective agonist alone, or certain RAR-alpha antagonists in combination with an RXR agonist, receptor-DNA binding is induced in vivo, resulting in expression of the target genes of retinoic acid as well as acute promyelocytic leukaemia protein (PML) relocation to nuclear bodies and differentiation before apoptosis. These results indicate that RAR-alpha ligands can induce two separate events: one enables RXR-RAR-alpha heterodimers to bind to DNA in vivo and allows RXR agonists to act; the other induces transcriptional activity of RAR-alpha. The availability of receptor-specific synthetic retinoids that can induce distinct receptor functions has potential in extending the therapeutic repertoire of retinoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Drug Synergism
  • Humans
  • Ligands
  • Mice
  • Neoplasm Proteins*
  • Nuclear Proteins*
  • Promyelocytic Leukemia Protein
  • Protein Binding
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / antagonists & inhibitors
  • Receptors, Retinoic Acid / metabolism*
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • Retinoids / pharmacology
  • Transcription Factors / metabolism
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins


  • DNA-Binding Proteins
  • Ligands
  • Neoplasm Proteins
  • Nuclear Proteins
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • Retinoids
  • Transcription Factors
  • Tumor Suppressor Proteins
  • retinoic acid receptor beta
  • PML protein, human
  • Tretinoin
  • DNA