c-Ski Acts as a Transcriptional Co-repressor in Transforming Growth Factor-β Signaling through Interaction with Smads

doi:10.1074/jbc.274.49.35269

c-Ski Acts as a Transcriptional Co-repressor in Transforming Growth Factor-β Signaling through Interaction with Smads*

From the^‡Department of Biochemistry, The Cancer Institute of Japanese Foundation for Cancer Research, and Research for the Future Program, Japan Society for Promotion of Science, 1-37-1, Kami-ikebukuro, Toshima-ku, Tokyo 170-8455 and^§Department of Toxicology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan

Abstract

Smads are intracellular signaling mediators of the transforming growth factor-β (TGF-β) superfamily that regulates a wide variety of biological processes. Among them, Smads 2 and 3 are activated specifically by TGF-β. We identified c-Ski as a Smad2 interacting protein. c-Ski is the cellular homologue of thev-ski oncogene product and has been shown to repress transcription by recruiting histone deacetylase (HDAC). Smad2/3 interacts with c-Ski through its C-terminal MH2 domain in a TGF-β-dependent manner. c-Ski contains two distinct Smad-binding sites with different binding properties. c-Ski strongly inhibits transactivation of various reporter genes by TGF-β. c-Ski is incorporated in the Smad DNA binding complex, interferes with the interaction of Smad3 with a transcriptional co-activator, p300, and in turn recruits HDAC. c-Ski is thus a transcriptional co-repressor that links Smads to HDAC in TGF-β signaling.

Footnotes

↵* This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, and Special Coordination Funds for Promoting Science and Technology from the Science and Technology Agency.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¶ The first two authors equally contributed to this work.
↵‖ To whom correspondence should be addressed: Dept. of Biochemistry, The Cancer Institute of Japanese Foundation for Cancer Research, 1-37-1, Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. Tel.: and Fax: 3-3918-0342; E-mail: miyazono-ind@umin.ac.jp.
↵** Supported by Princess Takamatsu Cancer Research Foundation and Sagawa Cancer Research Promotion Foundation.
↵2 A. Nishihara, J.-i. Hanai, T. Imamura, K. Miyazono, and M. Kawabata, unpublished work.
Abbreviations:

TGF-β

transforming growth factor-β

BMP

bone morphogenetic protein

Dpp

decapentaplegic

R-Smad

receptor-regulated Smad

Co-Smad

common Smad

I-Smad

inhibitory Smad

TβR-I

TGF-β type I receptor

BMPR-I

BMP type I receptor

MH

Mad homology

HAT

histone acetyltransferase

HD

histone deacetylase

Rb

retinoblastoma

HA

hemagglutinin
- Received July 28, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.