congresos y reuniones científicas
Glucocorticoid Receptor: role of multiple domains on in vivo dimerization and its transcriptional activity
PRESMAN DM; OGARA, MF; STORTZ, M; ALVAREZ, LD; BURTON, G.; LEVI, V; PECCI, A
Workshop; SISTAM 2012; 2012
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.