OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity

J Biol Chem. 2009 Jun 12;284(24):16135-16145. doi: 10.1074/jbc.M109.007484. Epub 2009 Apr 21.

Abstract

Estrogen receptor (ER) alpha is an essential component in human physiology and is a key factor involved in the development of breast and endometrial cancers. ERalpha protein levels and transcriptional activity are tightly controlled by the ubiquitin proteasome system. Deubiquitinating enzymes, a class of proteases capable of removing ubiquitin from proteins, are increasingly being seen as key modulators of the ubiquitin proteasome system, regulating protein stability and other functions by countering the actions of ubiquitin ligases. Using mass spectrometry analysis of an ERalpha protein complex, we identified OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) as a novel ERalpha-interacting protein capable of deubiquitinating ERalpha in cells and in vitro. We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells. We also show that OTUB1 regulates the availability and functional activity of ERalpha in Ishikawa cells by affecting the transcription of the ERalpha gene and by stabilizing the ERalpha protein in the chromatin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Chromatin / physiology
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism*
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism*
  • Endometrial Neoplasms / pathology
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • GPI-Linked Proteins
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Isoenzymes / metabolism
  • Kidney / cytology
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Receptors, Progesterone / genetics
  • Solubility
  • Transcriptional Activation / physiology*
  • Ubiquitination

Substances

  • Chromatin
  • Estrogen Receptor alpha
  • GPI-Linked Proteins
  • Isoenzymes
  • RNA, Messenger
  • Receptors, Progesterone
  • Alkaline Phosphatase
  • alkaline phosphatase, placental
  • OTUB1 protein, human
  • Cysteine Endopeptidases