Live Cell Imaging Unveils Multiple domain Requeriments for in vivo Dimerization of the Glucocorticoid Receptor

PRESMAN DM; OGARA, MF; STORTZ, M; ALVAREZ LD; POOLEY, JR; SCHILTZ RL; GRONTVED L; JOHNSON, TA; MITTELSTADT PR; ASHWELL JD; GANESAN S; BURTON, G.; LEVI, V; HAGER, G; PECCI, A

Taos, New Mexico

Simposio; Nuclear Receptors: biological Neworks, Genome Dynamics and Disease; 2014

Keystone

Glucocorticoids (GCs) are among the most effective and widely used drugs for the treatment of inflammatory diseases. Extensive efforts have been made to detach ?side effects? from anti-inflammatory action in chronic GC regimens by the rational design of dissociated glucocorticoids. Unfortunately, this search has proven to be far more complex than anticipated. In the mid-nineties, a non-rigorous characterization of a mutated form of GR (A458T), named the GRdim because of its alleged inability to homodimerize, led to a model suggesting that side effects of chronic GC treatment are mainly due to the direct, DNA-dependent GR transactivation of gene expression, while the anti-inflammatory effects rely on GR transrepression. Under this reasoning, ligands able to dissociate these two GR mechanisms should disconnect desirable vs unwanted pharmacological effects. Although more recent work has failed to support this model, this general framework continues to guide the research of great part of the community interested in this subject. Under the GRdim model, transactivation is supposed to be mediated by the dimeric form of the receptor, while transrepression is induced by its monomeric form.