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Molecular and Cellular Biology, December 2006, p. 8791-8802, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01677-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Activation of {alpha}-Tropomyosin Exon 2 Is Regulated by the SR Protein 9G8 and Heterogeneous Nuclear Ribonucleoproteins H and F{triangledown} ,{dagger}

J. Barrett Crawford and James G. Patton*

Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235

Received 7 September 2006/ Accepted 11 September 2006

The inclusion of exons 2 and 3 of {alpha}-tropomyosin is governed through tissue-specific alternative splicing. These exons are mutually exclusive, with exon 2 included in smooth muscle cells and exon 3 included in nearly all other cell types. Several cis-acting sequences contribute to this splicing decision: the branchpoints and pyrimidine tracts upstream of both exons, UGC-repeat elements flanking exon 3, and a series of purine-rich enhancers in exon 2. Previous work showed that proteins rich in serine-arginine (SR) dipeptides act through the exon 2 enhancers, but the specific proteins responsible for such activation remained unknown. Here we show that a 35-kDa member of the SR protein family, 9G8, can activate the splicing of {alpha}-tropomyosin exon 2. Using RNA affinity chromatography and cross-linking competition assays, we also demonstrate that the heterogeneous nuclear ribonucleoproteins (hnRNPs) H and F bind to and compete for the same elements. Overexpression of hnRNPs H and F blocked 9G8-mediated splicing both in vivo and in vitro, and small interfering RNA-directed depletion of H and F led to an increase in exon 2 splicing. These data suggest that the activation of exon 2 is dependent on the antagonistic activities of 9G8 and hnRNPs H and F.

* Corresponding author. Mailing address: Department of Biological Sciences, Box 1820 Station B, Vanderbilt University, Nashville, TN 37235. Phone: (615) 322-4738. Fax: (615) 343-6707. E-mail: James.G.Patton{at}vanderbilt.edu.

{triangledown} Published ahead of print on 25 September 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2006, p. 8791-8802, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01677-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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