Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation.
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.
Mesh Terms:
Blotting, Western, Breast Neoplasms, Cell Movement, Estrogen Receptor alpha, Estrogens, Female, Gene Expression Profiling, Humans, Immunoprecipitation, Neoplasm Invasiveness, Oligonucleotide Array Sequence Analysis, Plasminogen Activator Inhibitor 1, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Smad3 Protein, Transcription, Genetic, Transforming Growth Factor beta, Tumor Cells, Cultured, Tumor Markers, Biological, Ubiquitin, Ubiquitin-Protein Ligases
Blotting, Western, Breast Neoplasms, Cell Movement, Estrogen Receptor alpha, Estrogens, Female, Gene Expression Profiling, Humans, Immunoprecipitation, Neoplasm Invasiveness, Oligonucleotide Array Sequence Analysis, Plasminogen Activator Inhibitor 1, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Smad3 Protein, Transcription, Genetic, Transforming Growth Factor beta, Tumor Cells, Cultured, Tumor Markers, Biological, Ubiquitin, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: May. 07, 2010
PubMed ID: 20207742
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