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Anabella Srebrow

Research Focus

The way alternative splicing is controlled within cells, tissues and ultimately, multicellular organisms is still poorly understood. Our research goal is to understand the molecular mechanisms by which different extracellular stimuli activate signal transduction pathways that modulate the activity of the splicing machinery and consequently the splicing pattern of a variety of pre-mRNAs.

Considering that cells interact with their microenvironment in a dynamic way and that this interaction has profound effects on their pattern of gene expression leading to the proper balance between proliferation, differentiation and apoptotic programs, we emphasise the role of the cellular microenvironment as a regulator of alternative splicing. Different cell lines that recapitulate certain aspects of mammary gland normal development and tumorigenesis are used in our laboratory as a model system.

We identified signaling pathways and splicing factors (SR proteins) involved in the regulation of fibronectin alternative splicing by cell-extracellular matrix and cell-cell interactions, and revealed Akt/PKB as novel SR protein kinase. Our work shows that complex cross-talk between signaling pathways determines the splicing pattern of a single gene, and furthermore that Akt/PKB activation controls the activity of the SR proteins SF2/ASF and 9G8 at two different steps along mRNA metabolism, splicing and translation.

Publications

  1. Pelisch, F., Gerez, J., Druker, J., Schor, I.E., Muñoz, M.J., Risso, G., Petrillo, E., Westman, B.J., Lamond, A.I., Arzt, E., and Srebrow, A. (2010). The serine/arginine-rich protein SF2/ASF regulates protein sumoylation. Proceedings of the National Academy of Science USA, [Epub ahead of print].
  2. Blaustein, M., Pelisch, F. and Srebrow, A. (2007). Signals, Pathways and Splcing Regulation. The International Journal of Biochemistry and Cell Biology 39(11), 2031-2048.
  3. Srebrow, A. and Kornblihtt, A.R. (2006). The connection between splicing and cancer. Journal of Cell Science 119, 2635-2641.
  4. Blaustein, P., Pelisch, F., Tanos, T., Muñoz, M., Wengier, D., Quadrana, L., Sanford, J., Muschietti, J.P., Kornblihtt, A.R., Cáceres, J., Coso, O.A. and Srebrow, A. (2005). Concerted Regulation of Nuclear and Cytoplasmic Activities of SR Protein by AKT. Nature Structural and Molecular Biology 12 (12), 1037-1044. (Commented in “News and Views”, Nature Structural and Molecular Biology 12 (12), 1022-1023. Selected in Faculty of 1000 Biology).
  5. Pelisch, F., Blaustein, M., Kornblihtt, A.R. and Srebrow, A. (2005). Cross talk between signaling pathways regulates alternative splicing. A novel role for JNK. Journal of Biological Chemistry 280, 25461-25469. (Commented in Science Signal Transduction Knowledge Environment, Vol. 2005, Issue 292, pp. 251, 12 July 2005).
  6. Blaustein, M., Pelisch, F., Coso, O.A., Bissell, M.J., Kornblihtt, A.R. and Srebrow, A. (2004). Mammary epithelial-mesenchymal interaction regulates fibronectin alternative splicing via phosphatidylinositol 3-kinase. Journal of Biological Chemistry 279, 21029-21037.
  7. Srebrow, A., Blaustein, M., and Kornblihtt, A.R. (2002). Regulation of fibronectin alternative splicing by a basement membrane-like extracellular matrix. FEBS Letters 514, 285-289.

Key lab techniques: mouse mammary cell model systems, in vivo minigene analysis, transient transfections of mammalian cells, immunofluorescence, RNA interference in cultured mammalian cells, analysis of signaling pathways activity, protein-RNA interactions

Key lab reagents: reporter minigenes for alternative splicing, expression vectors for signaling molecules

Lab contact: Annabella Srebrow: asrebrow@fbmc.fcen.uba.ar

Lab website: www.fbmc.fcen.uba.ar/lfbm