“Regulation of protein synthesis in eukaryotes”
Centre de Regulació Genómica
Gene Regulation Programme
Passeig Marítim 37-49
Teléfono: 93-2240920 Fax: 93-2240899
Componentes del Grupo
Fátima Gebauer, Jefa de Grupo, firstname.lastname@example.org
Rafael Cuesta, Postdoctoral, email@example.com
Irina Abaza, Becaria Predoctoral, firstname.lastname@example.org
Solenn Patalano, Becaria Predoctoral, email@example.com
Olga Coll, Técnico de laboratorio, firstname.lastname@example.org
We are interested in the regulation of mRNA translation by RNA-binding proteins and by elongation of the mRNA poly(A) tail (i.e. cytoplasmic polyadenylation). In the lab, these mechanisms of translational control are studied under three different biological contexts: X-chromosome dosage compensation, early embryonic patterning and cell cycle progression.
Dosage compensation in Drosophila is achieved by hypertranscription of the male X chromosome via the action of a ribonucleoprotein complex known as the MSL (for male specific lethal). This process is inhibited in female flies primarily because the expression of one of the MSL components, the protein MSL-2, is repressed. Sex-lethal (SXL), a female-specific RNA-binding protein, binds to stretches of uridines present in the 5’ and 3’ UTRs of msl-2 pre-mRNA, which ultimately results in inhibition of msl-2 mRNA translation. Translational repression requires additional factors that are nucleated by SXL in the 3´UTR of msl-2. Current research focuses on isolating and identifying the putative co-repressors as well as assessing their role in SXL-mediated translational regulation and development.
The establishment of the early antero-posterior and dorso-ventral axes in Drosophila is achieved by a series of translational control events affecting key patterning regulators. Two of these are the homeodomain protein Bicoid and the transmembrane receptor Toll. Expression of both Bicoid and Toll is activated at specific times in development by cytoplasmic polyadenylation of their respective maternal mRNAs. In order to study the translational regulation of Bicoid and Toll mRNAs, we have set up a cell-free system that recapitulates both cytoplasmic polyadenylation and translation of these transcripts. We are currently using this system to identify the cis-acting regulatory sequences responsible for translational control.
Regulation of p27kip mRNA translation
p27kip is a cyclin-dependent kinase (cdk) inhibitor that blocks the mammalian cell cycle in G1 by binding to cyclin E/cdk2. Proper modulation of p27kip levels is essential for cell proliferation. One of the mechanisms that modulate the level of p27kip is the translational regulation of its mRNA. Translation of p27kip mRNA is driven by an internal ribosome entry site (IRES) whose activity changes during the cell cycle. Our aim is to identify factors that specifically regulate p27kip mRNA translation and that could be used as therapeutic targets in oncology.
- Grskovic, M., Hentze, M. W. and Gebauer, F. 2003. A co-repressor assembly nucleated by Sex-lethal in the 3´UTR mediates translational control of Drosophila msl-2 mRNA. EMBO J. 22: 5571-5581.
- Gebauer, F., Grskovic, M. and Hentze.M. W. 2003. Drosophila sex-lethal inhibits the stable association of the 40S ribosomal subunit with msl-2 mRNA. Mol. Cell, 11: 1397- 1404.
- Bergamini, G. and Gebauer, F. 2002. Poly(A)-dependent cell-free translation
systems from animal cells. In: Cell-free translation systems. Alexander S. Spirin (Ed.) Springer-Verlag Berlin Heidelberg, pp.79-88.
- Gebauer, F., Ostareck, D., Ostareck-Lederer, A., Grskovic, M. and Hentze, M. W. 2001. Translational control via the 3’ UTR: single regulators and/or co-repressor assemblies?. In: Cold Spring Harbor Symposia on Quantitative Biology: The Ribosome. vol. 66, pp.329-336.
- Gebauer, F. and Hentze, M. W. 2001. Fertility facts: male and female germ cell development requires translational control by CPEB. Mol. Cell 8: 247-249.
- Castagnetti, S., Hentze, M. W., Ephrussi, A. and Gebauer, F. 2000. Control of oskar mRNA translation by Bruno in a novel cell-free system from Drosophila ovaries. Development. 127: 1063-1068.
- Gebauer, F., Corona, D. F. V., Preiss, T., Becker, P. B. and Hentze, M. W. 1999. Translational control of dosage compensation in Drosophila by Sex-lethal: cooperative silencing via the 5’ and 3’ UTRs of msl-2 mRNA is independent of the poly(A) tail. EMBO J. 18: 6146-6154.