INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
Regulation of Steroid Receptor Function by Hsp90-Binding Immunophilins.
Autor/es:
GALIGNIANA MD
Lugar:
Porto Alegre
Reunión:
Congreso; IX Cell Stress Society International Meeting on the Molecular Biology of Stress Responses; 2012
Institución organizadora:
CSSI
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 their
biological 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.