Centre de Regulació Genómica
Gene Regulation Programme
Passeig Marítim 37-49
08003-Barcelona
Teléfono: 93-2240920 Fax: 93-2240899
Componentes del
Grupo
Fátima Gebauer, Jefa de Grupo, fatima.gebauer@crg.es
Rafael Cuesta, Postdoctoral, rafael.cuesta@crg.es
Irina Abaza, Becaria Predoctoral, irina.abaza@crg.es
Solenn Patalano, Becaria Predoctoral, solenn.patalano@crg.es
Olga Coll, Técnico de laboratorio, olga.coll@crg.es
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.
Publications
(1999-2003):
-
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.