INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
Role of TPR-domain proteins on the subcellular localization of nuclear factors. A novel model for steroid receptor action
Autor/es:
GALIGNIANA, MD
Lugar:
Edinburgh
Reunión:
Congreso; 14th International Congress on Steroid Receptors, Steroid Hormones & Cancer; 2010
Institución organizadora:
EMBO
Resumen:
In the absence of hormone, corticosteroid receptors such as MR and GR are primarily located in the cytoplasm. Upon steroid-binding, they rapidly accumulate in the nucleus. Regardless of their primary location, these receptors and also those that are constitutively nuclear undergo a constant and dynamic nucleocytoplasmic shuttling, the final balance being regulated by a poorly understood mechanism. All members of the steroid receptor family are known to form large oligomeric structures with the heat-shock proteins of 90-kDa (hsp90) and 70-kDa (hsp70), the small acidic protein p23, and a tetratricopeptide repeat (TPR)-domain protein such as high molecular weight immunophilins FKBP51, FKBP52 or the immunophilins-like serine/threonine-protein phosphatase 5. It has always been believed that the hsp90-based complex ‘anchors’ corticosteroid receptors to the cytoplasm and masks their nuclear localization signal disfavoring nuclear translocation, whereas the dissociation of the chaperone heterocomplex (a process referred to as “transformation”) must be the first step that permits nuclear accumulation of steroid receptors. However the experimental evidence shows that the chaperone complex is required for the efficient retrotransport of both MR and GR, and also facilitates their passage through the nuclear pore. Recent evidence indicates that the hsp90-TPR domain factor heterocomplex interacts with structures related to the nuclear pore such as importin-â and the integral nuclear pore glycoprotein Nup62 facilitating the passage of the untransformed receptor through the nuclear pore. In turn, the balance of expression between the TPR-domain immunophilins FKBP51 and FKBP52 is related to the proportion of receptors present in each subcellular compartment, FKBP52 being an anchoring factor of receptors to nuclear structures. In summary, a novel mechanism of action for corticosteroid receptors is emerging where hsp90-binding TPR domain proteins are essential for the rapid steroid-dependent retrotransport of steroid receptors, their efficient passage through the nuclear pore, and also for stabilizing interactions in the nuclear compartment.