Promoter of FGF8 reveals a unique regulation by unliganded RARalpha

J Mol Biol. 2002 Jun 7;319(3):715-28. doi: 10.1016/S0022-2836(02)00376-5.


We previously reported that retinoids were inducing a complete switch in the expression of two isoforms from the fgf8 gene. In order to gain insight into the transcriptional mechanisms possibly involved in this regulation, we cloned and sequenced a fragment of genomic DNA encompassing 6 kb of the region 5' upstream of the fgf8 coding sequence and investigated its promoter elements. A comprehensive series of biochemical and cellular experiments determined two distinct functional regions cis-responsive to retinoids and/or their receptors: (i) a canonical RARE (type DR2) which is the cis target of a RARalpha-RXRalpha liganded heterodimer; and (ii) a completely novel type of response element composed of two half-binding sites separated by 87 nucleotides, which we demonstrate to be the target of an unliganded RARalpha homodimer phosphorylated on the Ser77 residue. Combined activities of these cis and trans-acting factors support a model of a complex regulation of fgf8 expression: by alternative binding to two distinct promoter elements, phosphorylated-unliganded-RARalpha homodimer or its liganded form have two distinct and mutually exclusive trans-activating activities, explaining the expression of two different isoforms of fgf8.

MeSH terms

  • 3T3 Cells
  • Allosteric Site
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • DNA / genetics
  • DNA / metabolism
  • DNA Footprinting
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Deoxyribonuclease I / metabolism
  • Electrophoretic Mobility Shift Assay
  • Fibroblast Growth Factor 8
  • Fibroblast Growth Factors / chemistry
  • Fibroblast Growth Factors / genetics*
  • Gene Expression Regulation*
  • Humans
  • Ligands
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphoserine / metabolism
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Response Elements / genetics
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • DNA-Binding Proteins
  • FGF8 protein, human
  • Fgf8 protein, mouse
  • Ligands
  • Protein Isoforms
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • Transcription Factors
  • Fibroblast Growth Factor 8
  • Phosphoserine
  • Fibroblast Growth Factors
  • DNA
  • Deoxyribonuclease I

Associated data

  • GENBANK/AF079325