Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation

J Biol Chem. 2010 May 7;285(19):14747-55. doi: 10.1074/jbc.M109.093039. Epub 2010 Mar 5.


Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ERalpha and ERbeta, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-beta acts as a cell growth inhibitor, and its signaling is transduced by Smads. Although a number of studies have been made on the cross-talk between estrogen/ERalpha and TGF-beta/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ERalpha inhibits TGF-beta signaling by decreasing Smad protein levels. ERalpha-mediated reductions in Smad levels did not require the DNA binding ability of ERalpha, implying that ERalpha opposes the effects of TGF-beta via a novel non-genomic mechanism. Our analysis revealed that ERalpha formed a protein complex with Smad and the ubiquitin ligase Smurf, and enhanced Smad ubiquitination and subsequent degradation in an estrogen-dependent manner. Our observations provide new insight into the molecular mechanisms governing the non-genomic functions of ERalpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Movement
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogens / pharmacology*
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunoprecipitation
  • Neoplasm Invasiveness
  • Oligonucleotide Array Sequence Analysis
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Transcription, Genetic
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Biomarkers, Tumor
  • Estrogen Receptor alpha
  • Estrogens
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • RNA, Small Interfering
  • SERPINE1 protein, human
  • SMAD2 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Ubiquitin
  • SMURF1 protein, human
  • Ubiquitin-Protein Ligases