INVESTIGADORES
GALIGNIANA Mario Daniel
artículos
Título:
Geldanamycin, a heat shock protein 90-binding benzoquinone ansamycin, inhibits steroid-dependent translocation of the glucocorticoid receptor from the cytoplasm to the nucleus
Autor/es:
CZAR MJ, GALIGNIANA MD, SILVERSTEIN AM, PRATT WB
Revista:
BIOCHEMISTRY
Editorial:
AMER CHEMICAL SOC
Referencias:
Lugar: Washington; Año: 1997 vol. 35 p. 7776 - 7785
ISSN:
0006-2960
Resumen:
When they are translated, steroid receptors are assembled into a
multiprotein complex containing hsp90, p23, an immunophilin, and often
some hsp70. Some of the receptors, such as that for progesterone, have
nuclear localization signals that are functional in the absence of
hormone, and they move into the nucleus where they exist in the same
multiprotein heterocomplex with hsp90. Other receptors, such as the
glucocorticoid receptor, are localized predominantly in the cytoplasm in
the absence of hormone and move into the nucleus in a hormone-dependent
fashion. We have previously proposed that hsp90 and the immunophilin
play a role in receptor trafficking [Pratt, W. B. (1993) J. Biol. Chem.
268, 21455-21458]. In this work, we show that treatment of L cells with
geldanamycin, a benzoquinone ansamycin that binds to hsp90 and disrupts
its function, impedes dexamethasone-dependent trafficking of the
glucocorticoid receptor from the cytoplasm to the nucleus. Because
geldanamycin treatment of hormone-free cells causes a rapid loss of
steroid binding activity, receptors were prebound with dexamethasone by
incubating cells with hormone at 0 degrees C prior to shifting the
temperature to 37 degrees C for 20 min to permit receptor transformation
and translocation in the presence or absence of geldanamycin.
Geldanamycin does not cause steroid to dissociate from prebound
receptors, and it does not inhibit hormone-mediated receptor
transformation assayed by conversion to the DNA-binding state. However,
as reported previously for the progesterone receptor, geldanamycin
blocks assembly of the glucocorticoid receptor-hsp90 heterocomplex at an
intermediate state of assembly where the receptor is bound to hsp70 and
p60, both of which are required components in the assembly mechanism.
Our observations support the proposal that dynamic association of
receptors with hsp90 is required for receptor translocation from the
cytoplasm to the nucleus.