UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Live Cell Imaging Unveils Multiple Domain Requirements for in vivo Dimerization of the Glucocorticoid Receptor
Autor/es:
DIEGO M. PRESMAN; M. FLORENCIA OGARA; MARTÍN STORTZ; LAUTARO D. ÁLVAREZ; JOHN R. POOLEY; R. LOUIS SCHILTZ; LARS GRØNTVED; THOMAS A. JOHNSON; PAUL R. MITTELSTADT; JONATHAN D. ASHWELL; SUNDAR GANESAN; GERARDO BURTON; VALERIA LEVI; GORDON L. HAGER; ADALÍ PECCI
Lugar:
Taos
Reunión:
Simposio; Nuclear Receptors: Biological Networks, Genome Dynamics and Disease; 2014
Resumen:
Glucocorticoids are essential for life but they are also implicated in the pathogenesis of disease, and produce many unwanted effects when given in chronic therapies. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here, we analyzed the GR oligomerization state in vivo using the Number and Brightness assay. Our results suggest a complete, reversible and DNA-independent, ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo while an additional mutation in the ligand-binding domain severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and its transcriptional activity was observed. Finally, dimerization status affects DNA binding only to a subset of GR binding sites. These results will have major implications on the future search for therapeutic glucocorticoids with reduced side effects.