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J. Biol. Chem., Vol. 283, Issue 22, 15134-15141, May 30, 2008

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Cooperative Regulation of Fc Receptor -Chain Gene Expression by Multiple Transcription Factors, Including Sp1, GABP, and Elf-1^*

Kyoko Takahashi, Natsuko Hayashi^¶, Toshibumi Shimokawa, Nagayoshi Umehara^||, Shuichi Kaminogawa, and Chisei Ra¹

From the Department of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Sciences, Tokyo 173-8610, Nihon University College of Bioresource Sciences, Kanagawa 252-8510, Japan, the ^¶Department of Applied Biological Chemistry, Tamagawa University, Tokyo 194-8610, and the ^||Department of Obstetrics and Gynecology, Jikei Medical School, Tokyo 105-8461, Japan

The Fc receptor -chain (FcR), which was first identified as a constituent of the high affinity IgE receptor, associates with various cell surface receptors to mediate intracellular signals. We identified three transcriptional enhancer elements in the 5' region of the human FcR gene; one of the cis-elements was recognized by the transcription factor Sp-1 and another was recognized by GABP or Elf-1. The sequence of the other element was similar to a binding motif of the C/EBP family. Overexpression experiments showed that these transcription factors cooperatively activated the FcR promoter. Furthermore, inactivation of the GABP-binding site by nucleotide substitutions as well as repression of GABP expression by RNA interference reduced Sp1-mediated transactivation of the FcR promoter, demonstrating that Sp1 and GABP synergistically activated the FcR promoter. This synergistic activation was suggested to require physical interaction between the two transcription factors, because the Ets domain of GABP was demonstrated to directly bind Sp1. On the other hand, GABP and Elf-1, whose recognition sequences overlapped, were shown to bind the FcR gene with similar affinity in the context of chromatin, although Elf-1 exerted weaker enhancer activity for FcR gene expression than did GABP. Both were thought to compete for binding to the element, because additional expression of Elf-1 in combination with Sp1 and GABP reduced FcR promoter activity. Such functional and physical interactions among transcription factors involved in the cooperative regulation of FcR gene expression as revealed in this study will become promising targets for medical applications against various immune diseases involving FcR.

Received for publication, January 18, 2008 , and in revised form, March 5, 2008.

^* This work was supported in part by a grant-in aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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 To whom correspondence should be addressed: Dept. of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan. Fax: 81-3-3972-8227; E-mail: fcericra{at}med.nihon-u.ac.jp.

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