1. Estrogen Inhibits Transforming Growth Factor β Signaling by Promoting Smad2/3 Degradation
- Author
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Masashi Kajiro, Keiji Kimura, Yuka Nakajima, Shohei Kawasaki, Mitsutoshi Wayama, Yoko Komatsu, Takeshi Imamura, Aki Hanyu, Ichiaki Ito, Yoko Katsuno, Natsuka Goto, Junn Yanagisawa, Akiko Fujimura, Ryuichi Hirota, and Akiko Murayama
- Subjects
Transcription, Genetic ,Ubiquitin-Protein Ligases ,Blotting, Western ,Estrogen receptor ,Breast Neoplasms ,Smad2 Protein ,SMAD ,Protein degradation ,Biochemistry ,Cell Movement ,Transforming Growth Factor beta ,Plasminogen Activator Inhibitor 1 ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,Immunoprecipitation ,Neoplasm Invasiveness ,RNA, Messenger ,Smad3 Protein ,RNA, Small Interfering ,Molecular Biology ,Transcription factor ,Estrogen receptor beta ,Oligonucleotide Array Sequence Analysis ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Ubiquitin ,Gene Expression Profiling ,Estrogen Receptor alpha ,Estrogens ,Cell Biology ,Ubiquitin ligase ,biology.protein ,Cancer research ,Female ,Estrogen receptor alpha ,Signal Transduction ,Transforming growth factor - 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.
- Published
- 2010