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J. Biol. Chem., Vol. 279, Issue 37, 38249-38259, September 10, 2004

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hnRNP A1 and the SR Proteins ASF/SF2 and SC35 Have Antagonistic Functions in Splicing of -Tropomyosin Exon 6B^*

Alain Expert-Bezançon, Alain Sureau, Patrice Durosay, Roland Salesse, Herman Groeneveld, Jean Pierre Lecaer¶, and Joëlle Marie||

From the Centre de Génétique Moléculaire, CNRS UPR 2167, Laboratoire Propre Associé à l'Université Pierre et Marie Curie, 91198 Gif-sur-Yvette, France, Unité Récepteur et Communication, INRA, 78352 Jouy-en-Josas, France, and ^¶Ecole Supérieure de Physique et de Chimie Industrielles (ESPCI), 10 Rue Vauquelin, 75005 Paris, France

Mutually exclusive splicing of exons 6A and 6B from the chicken -tropomyosin gene involves numerous regulatory sequences. Previously, we identified a G-rich intronic sequence (S3) downstream of exon 6B. This element consists of six G-rich motifs, mutations of which abolish splicing of exon 6B. In this paper, we investigated the cellular factors that bind to this G-rich element. By using RNA affinity chromatography, we identified heterogeneous nuclear ribonucleoprotein (hnRNP) A1, the SR proteins ASF/SF2 and SC35, and hnRNP F/H as specific components that are assembled onto the G-rich element. By using hnRNP A1-depleted HeLa nuclear extract and add-back experiments, we show that hnRNP A1 has a negative effect on splicing of exon 6B. In agreement with in vitro data, artificial recruitment of hnRNP A1, as a fusion with the MS2 coat protein, also represses splicing of exon 6B ex vivo. In contrast, ASF/SF2 and SC35 activate splicing of exon 6B. As observed with other systems, hnRNP A1 counteracts the stimulating effect of the SR proteins. Moreover, cross-linking experiments show that both ASF/SF2 and SC35 are able to displace binding of hnRNP A1 to the G-rich element, suggesting that the binding sites for these proteins are overlapping. These data indicate that the G-rich sequence is a composite element that acts as an enhancer or as a silencer, depending on which proteins bind to them.

Received for publication, May 14, 2004 , and in revised form, June 16, 2004.

^* This work was supported by CNRS, Association Française contre les Myopathies (AFM), Ligue Nationale Contre le Cancer (LNCC), and Association pour la Recherche sur le Cancer (ARC). 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. Tel.: 16-9823800; Fax: 16-9823877; E-mail: marie{at}cgm.cnrs-gif.fr.

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