UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Glucocorticoid Receptor: role of multiple domains on in vivo dimerization and its transcriptional activity
Autor/es:
DIEGO M. PRESMAN; MARIA F. OGARA; MARTÍN STORTZ; LAUTARO D. ÁLVAREZ; GERARDO BURTON; VALERIA LEVI; ADALÍ PECCI
Lugar:
Bariloche
Reunión:
Simposio; Second South American Spring Symposium in Signal Transduction and Molecular Medicine; 2012
Institución organizadora:
SISTAM 2012
Resumen:
The glucocorticoid receptor (GR) is a member of
the steroid receptor superfamily essential for survival. Previously, it was
assumed that after ligand binding GR dissociates from HSP90, forms homodimers
and translocates into the nucleus where it acts as a ligand-regulated transcription
factor. Although GR homodimerization is considered essential for the
GR-transactivation pathway, there are still discrepancies in the identification
of both, the regions involved in homodimerization and the mechanisms underlying
this process. According to crystal structure analysis, three putative
dimerization regions have been reported; one located in the DNA binding domain
(DBD) and the other two in the Ligand-binding domain (LBD) of the receptor. A
point mutation within the mouse GR DBD (A465T) named GRdim, has been suggested
to be crucial for dimerization. However, recent immunoprecipitation studies
showed GR-GR interaction between GRdim molecules. Here, we analyzed GR
oligomerization state in vivo by using the Number and Brightness assay. Our
results confirm that the GRdim is still able to form dimers in the nucleus and that
a mutation within the LBD (I634A) severely compromises homodimer formation. Moreover,
GR dimerization also seems to be dependent on the ligand structure, indicating
that the dimerization process is more complex than previously described. These
results throw light around GR behavior and may have implications on the search
on new glucocorticoids with dissociated activities.