Estrogen Inhibits Transforming Growth Factor β Signaling by Promoting Smad2/3 Degradation

• Published in: The Journal of biological chemistry 2010-05, Vol.285 (19), p.14747-14755
• Main Authors: Ito, Ichiaki, Hanyu, Aki, Wayama, Mitsutoshi, Goto, Natsuka, Katsuno, Yoko, Kawasaki, Shohei, Nakajima, Yuka, Kajiro, Masashi, Komatsu, Yoko, Fujimura, Akiko, Hirota, Ryuichi, Murayama, Akiko, Kimura, Keiji, Imamura, Takeshi, Yanagisawa, Junn
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - metabolism; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Movement; Estrogen; 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; Protein Degradation; Protein Synthesis and Degradation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction; Signal Transduction - drug effects; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Transcription Factors; Transcription, Genetic; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor β (TGFβ); Tumor Cells, Cultured; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.093039

Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ERα and ERβ, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-β 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/ERα and TGF-β/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ERα inhibits TGF-β signaling by decreasing Smad protein levels. ERα-mediated reductions in Smad levels did not require the DNA binding ability of ERα, implying that ERα opposes the effects of TGF-β via a novel non-genomic mechanism. Our analysis revealed that ERα 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 ERα.