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Abstract
Laboratory of Cell Regulation and Carcinogenesis,1 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055,4 Division of Life Science, College of Natural Science, Kangwon National University, Chuncheon, Kangwon-do,2 Inha University College of Medicine, Incheon, Korea3
Received 25 September 2003/ Returned for modification 11 November 2003/ Accepted 16 December 2003
Smad7 inhibits responses mediated by transforming growth factor ß (TGF-ß) and acts in a negative-feedback loop to regulate the intensity or duration of the TGF-ß signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-ß resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-ß-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-ß signaling.
* Corresponding author. Mailing address: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH Building 41, Room B1106, Bethesda, MD 20892-5055. Phone: (301) 496-8350. Fax: (301) 496-8395.
B.-C.K., H.-J.L., and S.H.P. contributed equally to this study.
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