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J. Biol. Chem., Vol. 280, Issue 30, 28061-28071, July 29, 2005

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Transcriptional Activity of Sp1 Is Regulated by Molecular Interactions between the Zinc Finger DNA Binding Domain and the Inhibitory Domain with Corepressors, and This Interaction Is Modulated by MEK^*

Jung-Ahn Lee, Dong-Chul Suh, Jae-Eun Kang, Myung-Hwa Kim, Hyejin Park, Min-Nyung Lee, Jung-Min Kim, Bu-Nam Jeon, Hee-Eun Roh, Mi-Young Yu, Kang-Yell Choi¶, Kyu Yeun Kim||, and Man-Wook Hur**

From the Department of Biochemistry and Molecular Biology, BK21 Project for Medical Science, Institute of Genetic Science, Yonsei University School of Medicine, 134, ShinChon-Dong, SeoDaeMoon-Ku, Seoul, 120-752, the Department of Biochemistry, PoChon CHA University College of Medicine, 222 Yatop-Dong, Boondang-Ku, SeongNam-Si, Kyungki-Do, 463-836, the ^¶Department of Biotechnology, Yonsei University, 134, ShinChon-Dong, SeoDaeMoon-Ku, Seoul, 120-752, and the ^||Department of Biological Sciences, Ewha Womans University, 134, ShinChon-Dong, SeoDaeMoon-Ku, Seoul, 120-752, Korea

Sp1 activates the transcription of many cellular and viral genes with the GC-box in either the proximal promoter or the enhancer. Sp1 is composed of several functional domains, such as the inhibitory domain (ID), two serine/threonine-rich domains, two glutamine-rich domains, three C₂H₂-type zinc finger DNA binding domains (ZFDBD), and a C-terminal D domain. The ZDDBD is the most highly conserved domain among the Sp-family transcription factors and plays a critical role in GC-box recognition. In this study, we investigated the protein-protein interactions occurring at the Sp1ZFDBD and the Sp1ID, and the molecular mechanisms controlling the interaction. Our results found that Sp1ZFDBD and Sp1ID repressed transcription once they were targeted to the proximal promoter of the pGal4 UAS reporter fusion gene system, suggesting molecular interaction with the repressor molecules. Indeed, mammalian two-hybrid assays, GST fusion protein pull-down assays, and co-immunoprecipitation assays showed that Sp1ZFDBD and Sp1ID are able to interact with corepressor proteins such as SMRT, NcoR, and BCoR. The molecular interactions appear to be regulated by MAP kinase/Erk kinase kinase (MEK). The molecular interactions between Sp1ID and the corepressor might explain the role of Sp1 as a repressor under certain circumstances. The siRNA-induced degradation of the corepressors resulted in an up-regulation of Sp1-dependent transcription. The cellular context of the corepressors and the regulation of molecular interaction between corepressors and Sp1ZFDBD or Sp1ID might be important in controlling Sp1 activity.

Received for publication, December 16, 2004 , and in revised form, March 30, 2005.

^* This work was supported by a National Research Laboratory grant from the Korea Institute of Science and Technology Evaluation and Planning (to M.-W. H.). 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: Dept. of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 134 ShinChon-Dong, SeoDaeMoon-Ku, Seoul, 120-752, Korea. Tel.: 82-2-361-5185 or 5188; Fax: 82-2-312-5041; E-mail: mwhur2{at}yumc.yonsei.ac.kr.

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