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J. Biol. Chem., Vol. 282, Issue 27, 19410-19417, July 6, 2007

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Two Isoforms of the T-cell Intracellular Antigen 1 (TIA-1) Splicing Factor Display Distinct Splicing Regulation Activities

CONTROL OF TIA-1 ISOFORM RATIO BY TIA-1-RELATED PROTEIN^*

José M. Izquierdo¹ and Juan Valcárcel^¶||

From the Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain and Centre de Regulació Genòmica, ^¶Institució Catalana de Recerca i Estudis Avançats, ^||Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain

TIA-1 (T-cell Intracellular Antigen 1) and TIAR (TIA-1-related protein) are RNA-binding proteins involved in the regulation of alternative pre-mRNA splicing and other aspects of RNA metabolism. Various isoforms of these proteins exist in mammals. For example, TIA-1 presents two major isoforms (TIA-1a and TIA-1b) generated by alternative splicing of exon 5 that differ by eleven amino acids exclusive of the TIA-1a isoform. Here we show that the relative expression of TIA-1 and TIAR isoforms varies in different human tissues and cell lines, suggesting distinct functional properties and regulated isoform expression. We report that whereas TIA-1 isoforms show similar subcellular distribution and RNA binding, TIA-1b displays enhanced splicing stimulatory activity compared with TIA-1a, both in vitro and in vivo. Interestingly, TIAR depletion from HeLa and mouse embryonic fibroblasts results in an increased ratio of TIA-1b/a expression, suggesting that TIAR regulates the relative expression of TIA-1 isoforms. Taken together, the results reveal distinct functional properties of TIA-1 isoforms and the existence of a regulatory network that controls isoform expression.

Received for publication, January 24, 2007 , and in revised form, May 7, 2007.

^* This work was supported by Fondo de Investigaciones Sanitarias Grant PI051605 (to J. M. I.). The Centro de Biología Molecular "Severo Ochoa" (CBMSO) receives an institutional grant from Fundación Ramón Areces, Spain. 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: Departamento de Biología Molecular, CBMSO, Universidad Autónoma de Madrid, Facultad de Ciencias, Módulo C-V, Lab. 230, Cantoblanco, 28049 Madrid, Spain. Tel.: 34-914978461; Fax: 34-914974799; E-mail: jmizquierdo{at}cbm.uam.es.

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