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J. Biol. Chem., Vol. 281, Issue 1, 401-409, January 6, 2006

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Cooperative Actions of Tra2 with 9G8 and SRp30c in the RNA Splicing of the Gonadotropin-releasing Hormone Gene Transcript^*

Eonyoung Park12, Jin Han12, Gi Hoon Son2, Mi Sun Lee2, Sooyoung Chung2, Sung Ho Park2, Kyungsook Park2, Kun Ho Lee, Sukwoo Choi, Jae Young Seong, and Kyungjin Kim3

From the School of Biological Sciences, Seoul National University, Seoul 151-742, Korea and the Graduate School of Medicine, Korea University College of Medicine, Seoul 136-705, Korea

In earlier studies, we demonstrated that excision of the first intron (intron A) from the gonadotropin-releasing hormone (GnRH) transcript is highly cell type- and developmental stage-specific. The removal of GnRH intron A requires exonic splicing enhancers on exons 3 and 4 (ESE3 and ESE4, respectively). Tra2,a serine/arginine-rich (SR)-like protein, specifically binds to ESE4, although it requires additional nuclear co-factors for efficient removal of this intron. In the present study, we demonstrate the cooperative action of multiple SR proteins in the regulation of GnRH pre-mRNA splicing. SRp30c specifically binds to both ESE3 and ESE4, whereas 9G8 binds to an element in exon 3 and strongly enhances the excision of GnRH intron A in the presence of minimal amount of other nuclear components. Interestingly, Tra2 can interact with either 9G8 or SRp30c, whereas no interaction between 9G8 and SRp30c is observed. Tra2 has an additive effect on the RNA binding of these proteins. Overexpression or knock-down of these three proteins in cultured cells further suggests their essential role in intron A excision activities, and their presence in GnRH neurons of the mouse preoptic area further strengthens this possibility. Together, these results indicate that interaction of Tra2 with 9G8 and SRp30c appears to be crucial for ESE-dependent GnRH pre-mRNA splicing, allowing efficient generation of mature mRNA in GnRH-producing cells.

Received for publication, May 27, 2005 , and in revised form, October 14, 2005.

^* This work was supported by a grant from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ These authors contributed equally to this work.

² Supported by a Brain Korea 21 Research Fellowship from the Korea Ministry of Education and Human Resources.

³ To whom correspondence should be addressed. Tel.: 82-2-880-6694; Fax: 82-2-884-6560; E-mail: kyungjin{at}snu.ac.kr.

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