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Molecular and Cellular Biology, March 2004, p. 2251-2262, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2251-2262.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Jab1/CSN5, a Component of the COP9 Signalosome, Regulates Transforming Growth Factor ß Signaling by Binding to Smad7 and Promoting Its Degradation

Byung-Chul Kim,1,2,{dagger} Ho-Jae Lee,1,{dagger} Seok Hee Park,3,{dagger} Sae Ra Lee,1 Tatiana S. Karpova,4 James G. McNally,4 Angelina Felici,1 Dug Keun Lee,1 and Seong-Jin Kim1*

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. E-mail: kims{at}mail.nih.gov.

{dagger} B.-C.K., H.-J.L., and S.H.P. contributed equally to this study.

Molecular and Cellular Biology, March 2004, p. 2251-2262, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2251-2262.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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