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Molecular and Cellular Biology, April 2003, p. 2927-2941, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2927-2941.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Roles of hnRNP A1, SR Proteins, and p68 Helicase in c-H-ras Alternative Splicing Regulation

Sònia Guil,1 Renata Gattoni,2 Montserrat Carrascal,3 Joaquín Abián,3 James Stévenin,2 and Montse Bach-Elias1*

Institut d'Investigació Cardiovascular de Barcelona-Consejo Superior de Investigaciones Científicas,1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch Cedex, France,2 and Unidad de Espectrometría de Masas Estructural y Biológica, Departamento de Bioanalítica Médica, IIBB-CSIC, IDIBAPS, Barcelona, Spain3

Received 11 September 2002/ Returned for modification 25 October 2002/ Accepted 21 January 2003

Human ras genes play central roles in coupling extracellular signals with complex intracellular networks controlling proliferation, differentiation, and apoptosis, among others processes. c-H-ras pre-mRNA can be alternatively processed into two mRNAs due to the inclusion or exclusion of the alternative exon IDX; this renders two proteins, p21H-Ras and p19H-RasIDX, which differ only at the carboxy terminus. Here, we have characterized some of the cis-acting sequences and trans-acting factors regulating IDX splicing. A downstream intronic silencer sequence (rasISS1), acting in concert with IDX, negatively regulates upstream intron splicing. This effect is mediated, at least in part, by the binding of hnRNP A1. Depletion and add-back experiments in nuclear extracts have confirmed hnRNP A1's inhibitory role in IDX splicing. Moreover, the addition of two SR proteins, SC35 and SRp40, can counteract this inhibition by strongly promoting the splicing of the upstream intron both in vivo and in vitro. Further, the RNA-dependent helicase p68 is also associated with both IDX and rasISS1 RNA, and suppression of p68 expression in HeLa cells by RNAi experiments results in a marked increase of IDX inclusion in the endogenous mRNA, suggesting a role for this protein in alternative splicing regulation.

* Corresponding author. Mailing address: IICB-CSIC, c/Jordi Girona Salgado 18-26, 08034 Barcelona, Spain. Phone: 3493-4006134. Fax: 3493-2045904. E-mail: mbebmc{at}cid.csic.es.

Molecular and Cellular Biology, April 2003, p. 2927-2941, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2927-2941.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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