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J. Biol. Chem., Vol. 281, Issue 51, 39169-39178, December 22, 2006

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Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor- Signaling by Repressing SMAD3 Transactivation^*

Ji Ho Suh¹, Jiansheng Huang, Yun-Yong Park¹, Hyun-A Seong^¶, Dongwook Kim^||, Minho Shong^||, Hyunjung Ha^¶, In-Kyu Lee^**, Keesook Lee, Li Wang, and Hueng-Sik Choi²

From the Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Kwangju 500-757, Republic of Korea, the ^¶Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea, ^||Laboratory of Endocrine Cell Biology, the Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Republic of Korea, the ^**Department of Internal Medicine, Kyungpook University School of Medicine, Daegu 702-701, Republic of Korea, and the Department of Medicine and Pharmacology, the University of Kansas Medical Center, Kansas City, Kansas 66160

Orphan nuclear receptor small heterodimer partner (SHP) is an atypical member of the nuclear receptor superfamily; SHP regulates the nuclear receptor-mediated transcription of target genes but lacks a conventional DNA binding domain. In this study, we demonstrate that SHP represses transforming growth factor- (TGF-)-induced gene expression through a direct interaction with Smad, a transducer of TGF- signaling. Transient transfection studies demonstrate that SHP represses Smad3-induced transcription. In vivo and in vitro protein interaction assays revealed that SHP directly interacts with Smad2 and Smad3 but not with Smad4. Mapping of domains mediating the interaction between SHP and Smad3 showed that the entire N-terminal domain (1–159 amino acids) of SHP and the linker domain of Smad3 are involved in this interaction. In vitro glutathione S-transferase pulldown competition experiments revealed the SHP-mediated repression of Smad3 transactivation through competition with its co-activator p300. SHP also inhibits the activation of endogenous TGF--responsive gene promoters, the p21, Smad7, and plasminogen activator inhibitor-1 (PAI-1) promoters. Moreover, adenovirus-mediated overexpression of SHP decreases PAI-1 mRNA levels, and down-regulation of SHP by a small interfering RNA increases both the transactivation of Smad3 and the PAI-1 mRNA levels. Finally, the PAI-1 gene is expressed in SHP^–/– mouse hepatocytes at a higher level than in normal hepatocytes. Taken together, these data indicate that SHP is a novel co-regulator of Smad3, and this study provides new insights into regulation of TGF- signaling.

Received for publication, June 21, 2006 , and in revised form, October 2, 2006.

^* This work was supported by National Research Laboratory Grant M1-0500-4705J-4710, KRF Grant C00126 [GenBank] , a Marine Bio21 grant (to H.-S. C.), by funds from the Kansas Masonic Cancer Research Institute, National Institutes of Health Grant P20 RR016475 from the INBRE Program of the NCRR, a Liver Scholar Award from ALF/AASLD, and a BGIA Award from the American Heart Association (to L. W.). 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.

¹ Members of the post Brain Korea 21 program.

² To whom correspondence and reprint requests should be addressed. Tel.: 82-62-530-0503; Fax: 82-62-530-0500; E-mail: hsc{at}chonnam.ac.kr.

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