Juan Valcárcel

Clincians

Research Focus

We are interested in understanding molecular mechanisms of alternative splicing regulation, for which we use biochemical assays in vitro, transient transfection of cells in culture and splicing-sensitive microarrays.

We have studied how the Drosophila protein Sex-lethal, which is expressed only in female flies, enforces female-specific patterns of splicing on target genes. We have also identified and characterised factors that influence splice site recognition. One example is the apoptotic-promoting protein TIA-1, which promotes U1 snRNP recruitment to weak splice sites followed by uridine-rich sequences. TIA-1 regulates alternative splicing of the apoptotic receptor Fas, while the Polypyrimidine-Tract-Binding protein (PTB) causes the opposite effect by interfering with molecular interactions leading to exon definition. The splicing factor U2AF is involved in these interactions and plays an important role in 3´ splice site recognition.

We study the function of U2AF and associated factors in constitutive and regulated splicing. Finally, we are using splicing-sensitive microarrays to study correlations between changes in alternative splicing occurring during cell differentiation and cancer progression and the expression of all known components and regulators of the spliceosome.

Publications

Hartmann, B., Castelo, R., Blanchette, M., Boue, S., Rio, D.C., Valcárcel, J. (2009). Global analysis of alternative splicing regulation by insulin and wingless signalling in Drosophila cells. Genome Biology 10(1), R11. [epub ahead of print]
Hartmann, B., Valcárcel, J. Decrypting the genome's alternative messages. (2009). Current Opinion in Cell Biology 2009 Mar 21. [epub ahead of print]
Ben-Dov, C., Hartmann, B., Lundgren, J., Valcárcel, J. (2008). Genome-wide analysis of alternative pre-mRNA splicing. Journal of Biological Chemistry 283(3), 1229-33.
Bonnal, S., Martínez, C., Förch, P., Bachi, A., Wilm, M. and Valcárcel, J. (2008). LUCA-15/RBM5/H37 regulates splice site pairing after exon definition. Molecular Cell 32(1), 81-95.
Ben-Dov, C., Hartmann, B., Lundgren, J., Valcárcel, J. (2007). Genome-wide analysis of alternative pre-mRNA splicing. Journal of Biological Chemistry 283, 1229- 1233.
Izquierdo, J.M., Valcárcel, J. (2007). Two isoforms of the T-Cell intracellular antigen 1 (TIA-1) splicing factor display distinct splicingregulation activities. Control of TIA-1 isoform ratio by TIA-1 related protein. Journal of Biological Chemistry 282(27), 19410-7.
Corsini, L., Bonna, S., Basquin, J., Hothorn, M., Scheffzek, K., Valcárcel, J., Sattler, M. (2007). U2AF-homology motif interactions are required for alternative splicing regulation by SPF45. Nature Structural and Molecular Biology 14(7), 620-9.
Izquierdo, J.M., Valcárcel, J. (2007). Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing. Journal of Biological Chemistry, 282(3), 1539-43.
Izquierdo, J.M. and Valcárcel, J. (2006). A simple principle to explain the evolution of pre-mRNA splicing. Genes and Development 23(2), 150-1.
Soares, L.M., Zanier K., Sattler M. and Valcárcel, J. (2006) Intron removal requires proofreading of U2AF / 3’ splice site recognition by DEK. Science 312(5782), 1961-5.
Mendes Soares, L.M., Valcárcel, J. (2006). The expanding transcriptome: the genome as the - Book of Sand. EMBO Journal 25, 923-931.
Izquierdo, J.M., Majos, N., Bonnal, S., Martínez, C., Castelo, R., Guigó, R., Bilbao, D., and Valcárcel, J. (2005). Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. Molecular Cell 19, 475-484.
Singh, R. and Valcárcel, J (2005). Building specificity with non-specific RNA binding proteins. Nature Structural and Molecular Biology 12, 645-653.
Relogio, A., Ben-Dov, C., Baum, M., Ruggiu, M., Benes, V., Darnell R.L. and Valcárcel, J. (2005). Splicing microarrays reveal functional expression of neuron-specific splicing regulators in Hodgkin lymphoma cells. Journal of Biological Chemistry 280, 4779-84.
Lallena, M.J., Chalmers, K., Llamazares, S., Lamond, A.I. and Valcárcel, J. (2002). Splicing regulation at the second catalytic step by Sex-lethal involves 3’ splice site recognition by SPF45. Cell 109, 285-296.
Förch, P., Puig, O., Kedersha, N., Martínez, C., Séraphin, B., Anderson, P. and Valcárcel, J. (2000). The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing. Molecular Cell 6, 1089-1098.