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J. Biol. Chem., Vol. 281, Issue 26, 17588-17598, June 30, 2006

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Additional Sex Comb-like 1 (ASXL1), in Cooperation with SRC-1, Acts as a Ligand-dependent Coactivator for Retinoic Acid Receptor^*

Yang-Sook Cho, Eun-Joo Kim¹, Ui-Hyun Park¹, Hong-Sig Sin, and Soo-Jong Um¹²

From the Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University and Chebigen Inc., 305-B, Chungmugwan, Sejong University, Seoul 143-747, Korea

Additional sex comb-like 1 (ASXL1, 170 kDa), a mammalian homolog of Drosophila ASX, was identified as a protein that interacts with retinoic acid receptor (RAR) in the presence of retinoic acid (RA). Systematic binding assays showed that the C-terminal nuclear receptor box (LVMQLL) of ASXL1 and the activation function-2 activation domain (AF-2 AD) core of the RAR are critical for ligand-dependent interaction. The interaction was confirmed using in vitro glutathione S-transferase pulldown and in vivo immunoprecipitation (IP) assays. Confocal microscopy revealed that ASXL1 localizes in the nucleus. In addition to the intrinsic transactivation function of ASXL1, its cotransfection together with an RA-responsive luciferase reporter increased the RAR activity. This ASXL1 activity appears to be mediated through the functional cooperation with SRC-1, as shown by GST pulldown, IP, chromatin IP, and transcription assays. In the presence of ASXL1, more acetylated histone H3 was accumulated on the RA-responsive promoter in response to RA. Finally, stable expression of ASXL1 increased the expression of endogenous RA-regulated genes and enhanced the antiproliferative potential of RA. Overall, these results suggest that ASXL1 is a novel coactivator of RAR that cooperates with SRC-1 and implicates it as a potential antitumor target of RA in RA-resistant cancer cells.

Received for publication, November 28, 2005 , and in revised form, March 16, 2006.

^* This work was supported in part by Grant 02-PJ1-PG1-CH10-0001 from Korea Health 21 R & D Project, Ministry of Health and Welfare and in part by Grant 2004-01348 from the Ministry of Science and Technology, Republic of Korea. 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 Supported by the BK21 Project from the Ministry of Education and Human Resources Development.

² To whom correspondence should be addressed: Dept. of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, Korea. Tel.: 82-2-3408-3641; Fax: 82-2-3408-3334; E-mail: umsj{at}sejong.ac.kr.

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