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J. Biol. Chem., Vol. 278, Issue 22, 20133-20139, May 30, 2003

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The Ski-binding Protein C184M Negatively Regulates Tumor Growth Factor- Signaling by Sequestering the Smad Proteins in the Cytoplasm^*

Kenji Kokura, Hyungtae Kim, Toshie Shinagawa, Md Matiullah Khan, Teruaki Nomura and Shunsuke Ishii 

From the Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan

Ski is a transcriptional co-repressor and is involved in the negative regulation of tumor growth factor- (TGF-) signaling. To understand more fully the role of Ski in TGF- signaling, we searched for novel Ski-interacting proteins. The identified C184M protein consists of 189 amino acids and contains the leucine-rich region. An association between Ski and C184M involving the leucine-rich region of C184M and the C-terminal coiled-coil motif of Ski was confirmed by glutathione S-transferase pull-down and immunoprecipitation assays. The C184M protein is located in the cytosol, and the C184M and Ski signals are co-localized in the cytoplasm when C184M was co-expressed with Ski in CV-1 cells. The cytoplasmic C184M-Ski complex inhibited the nuclear translocation of Smad2. Consistent with this, the activity of promoter containing the Smad-binding sites was repressed by C184M, and the TGF--induced growth inhibition of mink lung Mv1Lu cells was attenuated by the ectopic expression of C184M. Thus, C184M inhibits TGF- signaling in concert with Ski. In hepatocytes, which express significant levels of C184M, the Ski signals were found only in the cytoplasm, supporting the notion that C184M forms a complex with Ski in the cytosol.

Received for publication, October 23, 2002 , and in revised form, February 20, 2003.

^* This work was supported in part by grants-in-aid for Scientific Research and special coordination funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, and by a grant from the Human Frontier Science Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-29-836-9031; Fax: 81-29-836-9030; E-mail: sishii{at}rtc.riken.go.jp.

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