Specific ubiquitin-conjugating enzymes promote degradation of specific nuclear receptor coactivators

Mol Endocrinol. 2003 Jul;17(7):1315-31. doi: 10.1210/me.2002-0209. Epub 2003 Mar 27.


Nuclear receptor coactivators (NRCoAs) are nuclear hormone receptor-associated regulatory proteins that interact with members of the nuclear receptor superfamily in the presence of their cognate ligand, enhancing their transcriptional activity. The identification of ubiquitin-proteasome pathway proteins as coactivators provides evidence that ubiquitin-proteasome-mediated protein degradation plays an integral role in eukaryotic gene transcription. It has also been observed that nuclear receptors themselves are ubiquitinated and degraded in a hormone-dependent manner and that ubiquitin-proteasome function is essential for most nuclear receptors to function as transactivators. Here, we show that specific ubiquitin-proteasome pathway enzymes target specific NRCoA proteins in vivo and in vitro. First, using a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, we confirmed that NRCoA proteins are targets of the ubiquitin-proteasome pathway. Then using coimmunoprecipitation studies, we also demonstrate that in vivo, NRCoA proteins are ubiquitinated. Finally, we illustrate that in vitro, NRCoA ubiquitination and degradation depend on the ubiquitin-activating enzyme (E1) and on specific ubiquitin-conjugating enzymes (E2) for each of the coactivators.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • CREB-Binding Protein
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • HeLa Cells
  • Histone Acetyltransferases
  • Humans
  • Leupeptins / pharmacology
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • Mutation
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Coactivator 3
  • Proteasome Endopeptidase Complex
  • Proteins / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism
  • Ubiquitin / metabolism*
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism*
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism*


  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Multienzyme Complexes
  • Nuclear Proteins
  • Nuclear Receptor Coactivator 2
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Trans-Activators
  • Transcription Factors
  • Ubiquitin
  • CREB-Binding Protein
  • CREBBP protein, human
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 3
  • Ubiquitin-Conjugating Enzymes
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Ubiquitin-Activating Enzymes
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde