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J. Biol. Chem., Vol. 280, Issue 11, 10164-10173, March 18, 2005

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Daxx Mediates the Small Ubiquitin-like Modifier-dependent Transcriptional Repression of Smad4^*

Che-Chang Chang, Ding-Yen Lin, Hsin-I Fang, Ruey-Hwa Chen¶, and Hsiu-Ming Shih||

From the Graduate Institute of Life Sciences, National Defense Medical Center, the Division of Molecular and Genomic Medicine, National Health Research Institutes, and the ^¶Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 11529 Taiwan, Republic of China

Daxx has been shown to function as an apoptosis regulator and transcriptional repressor via its interaction with various cytoplasmic and nuclear proteins. Here, we showed that Daxx interacts with Smad4 and represses its transcriptional activity via the C-terminal domain of Daxx. In vitro and in vivo interaction studies indicated that the binding of Smad4 to Daxx depends on Smad4 sumoylation. Substitution of Smad4 SUMO conjugation residue lysine 159, but not 113, to arginine not only disrupted Smad4-Daxx interaction but also relieved Daxx-elicited repression of Smad4 transcriptional activity. Furthermore, chromatin immunoprecipitation analyses revealed the recruitment of Daxx to an endogenous, Smad4-targeted promoter in a Lys¹⁵⁹ sumoylation-dependent manner. Finally, down-regulation of Daxx expression by RNA interference enhanced transforming growth factor -induced transcription of reporter and endogenous genes through a Smad4-dependent, but not K159R-Smad4-dependent, manner. Together, these results indicate that Daxx suppresses Smad4-mediated transcriptional activity by direct interaction with the sumoylated Smad4 and identify a novel role of Daxx in regulating transforming growth factor signaling.

Received for publication, August 10, 2004 , and in revised form, January 5, 2005.

^* This work was supported by National Health Research Institutes Intramural Funds Grant MG-093-PP-03 and National Science Council Grants NSC93-3112-B-400-004 and NSC93-2321-B-400-002 (to H.-M. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

^|| To whom correspondence should be addressed. Present address: Institute of Biomedical Sciences, Academia Sinica., 128, Sec. 2, Academia RD, Taipei 11529, Taiwan. Tel.: 886-2-2652-3520; Fax: 886-2-2785-8594; E-mail: hmshih{at}ibms.sinica.edu.tw.

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