Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Movement
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Estrogen Receptor alpha / antagonists & inhibitors
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Estrogens / pharmacology*
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Female
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Gene Expression Profiling
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Humans
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Immunoprecipitation
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Neoplasm Invasiveness
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Oligonucleotide Array Sequence Analysis
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Smad2 Protein / metabolism*
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Smad3 Protein / metabolism*
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Transcription, Genetic
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Tumor Cells, Cultured
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Biomarkers, Tumor
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Estrogen Receptor alpha
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Estrogens
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Plasminogen Activator Inhibitor 1
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RNA, Messenger
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RNA, Small Interfering
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SERPINE1 protein, human
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SMAD2 protein, human
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta
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Ubiquitin
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SMURF1 protein, human
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Ubiquitin-Protein Ligases