INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
REGULATION OF STEROID RECEPTOR FUNCTION BY HSP90-BINDING IMMUNOPHILINS. A POTENTIAL NEW PLATFORM FOR MORE EFFECTIVE THERAPEUTICS
Autor/es:
GALIGNIANA MD
Reunión:
Conferencia; Workshop on Steroid Hormones in Physiology and Disease: From Bench to Bedside; 2012
Institución organizadora:
IBYME-SAIC
Resumen:
Immunophilin (IMM) is the collective name given to proteins that bind immunosuppressive drugs. IMMs are ubiquitous chaperones able to form complexes with other proteins, although theirbiological functions are poorly understood. Almost a decade ago, we described one of the first functions reported for Hsp90-binding IMMs, i.e., the efficient steroid-dependent retrotransport of the GR, which depends on the association of peptidylprolyl-isomerase domain of FKBP52 with the dynein/dynactin motor complex. While both FKBP52 and dynein are recruited by the GR·Hsp90 complex upon steroid binding, the highly homologous FKBP51 is released. The ability of this IMM to bind dynein is poor and impairs both steroid binding capacity and GR-dependent transcriptional activity. After these findings, we and others have described the association of IMMs and motor proteins with other soluble proteins (MR, AR, p53, AIF, Rac3, MAGE proteins, AAV2, etc.), suggesting that factors able to interact with the Hsp90?IMM complex could share similar molecular machinery of movement. More recently, we demonstrated that when cargoes reach the nuclear envelope, the Hsp90 heterocomplex interacts with the nuclear translocation machinery of nucleoporins and importins. This facilitates the passage of cargoes through the nuclear pore. Other chaperones also form complexes with the nuclear pore providing a potential mechanism of selectivity for the transport of a number of cargoes that must be discriminated despite using the same translocators. IMMs are also related to the nuclear anchoring of proteins to particular nuclear speckles where they could undergo a maturation process previous to be launched to the promoter sites. Importantly, recent evidence demonstrates that the IMM·Hsp90 complex may also regulate the expression of key genes related to cell differentiation. Targeting Hsp90·IMM interactions is being currently assayed to regulate the subcellular localization of various nuclear factors. Many drugs disrupt receptor·Hsp90 complexes, geldanamycin and its derivatives being the most assayed. But these compounds lack client protein specificity and are ineffective in prostate cancers. On the other hand, conventional IMM ligands lack protein specificity and are immunosuppressive. Since the proline-rich loop of the IMM serves as an interaction surface for the Hsp90·IMM interaction, targeting this domain could be a viable option to disrupt signalling molecules regulated by IMMs.