Activation of AHR mediates the ubiquitination and proteasome degradation of c-Fos through the induction of Ubcm4 gene expression

Toxicology. 2015 Nov 4:337:47-57. doi: 10.1016/j.tox.2015.08.008. Epub 2015 Aug 28.


The ubiquitin-proteasome system (UPS) is a specific, non-lysosomal pathway responsible for the controlled degradation of abnormal and short-half-life proteins. Despite its relevance in cell homeostasis, information regarding control of the UPS component gene expression is lacking. Data from a recent study suggest that the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, might control the expression of several genes encoding for UPS proteins. Here, we showed that activation of AHR by TCDD and β-naphthoflavone (β-NF) results in Ubcm4 gene induction accompanied by an increase in protein levels. UbcM4 is an ubiquitin-conjugating enzyme or E2 protein that in association with ubiquitin ligase enzymes or E3 ligases promotes the ubiquitination and 26S proteasome-mediated degradation of different proteins, including p53, c-Myc, and c-Fos. We also present data demonstrating increased c-Fos ubiquitination and proteasomal degradation through the AHR-mediated induction of UbcM4 expression. The present study shows that AHR modulates the degradation of proteins involved in cell cycle control, consistent with previous reports demonstrating an essential role of the AHR in cell cycle regulation.

Keywords: Aryl hydrocarbon receptor; TCDD; UbcM4; Ubiquitination; c-Fos.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Gene Expression / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Plasmids / drug effects
  • Polychlorinated Dibenzodioxins / pharmacology
  • Proteasome Endopeptidase Complex / drug effects*
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Receptors, Aryl Hydrocarbon / drug effects*
  • Transfection
  • Ubiquitin-Conjugating Enzymes / biosynthesis*
  • Ubiquitin-Conjugating Enzymes / drug effects
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitination / drug effects*
  • beta-Naphthoflavone / pharmacology


  • Polychlorinated Dibenzodioxins
  • Proto-Oncogene Proteins c-fos
  • Receptors, Aryl Hydrocarbon
  • UBE2L4 protein, human
  • beta-Naphthoflavone
  • Ubiquitin-Conjugating Enzymes
  • Proteasome Endopeptidase Complex