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Departments of Pharmacology (M.D.G., W.B.P.), Physiology
(J.H., C.C.-S.), and Anatomy and Cell Biology (M.J.W.) The
University of Michigan Medical School Ann Arbor, Michigan 48109
Department of Pharmacology (J.L.S., P.R.H.) University of
South Carolina School of Medicine Columbia, South Carolina
29208
We use here a chimera of the green fluorescent
protein (GFP) and the glucocorticoid receptor (GR) to test the notion
that the protein chaperone heat shock protein-90 (hsp90) is required
for steroid-dependent translocation of the receptor through the
cytoplasm along cytoskeletal tracks. The GFP-GR fusion protein
undergoes steroid-mediated translocation from the cytoplasm to the
nucleus, where it is transcriptionally active. Treatment of 3T3 cells
containing steroid-bound GFP-GR with geldanamycin, a benzoquinone
ansamycin that binds to hsp90 and disrupts its function, inhibits
dexamethasone-dependent translocation from the cytoplasm to the
nucleus. The t1/2 for translocation in the
absence of geldanamycin is 
5 min, and the
t1/2 in the presence of geldanamycin is 45
min. In cells treated for 1 h with the cytoskeletal disrupting
agents colcemid, cytochalasin D, and ß,ß'-iminodipropionitrile to
completely disrupt the microtubule, microfilament, and intermediate
filament networks, respectively, the GFP-GR still translocates rapidly
to the nucleus in a strictly dexamethasone-dependent manner but
translocation is no longer affected by geldanamycin. After withdrawal
of the cytoskeletal disrupting agents for 3 h, normal cytoskeletal
architecture is restored, and geldanamycin inhibition of
dexamethasone-dependent GFP-GR translocation is restored. We suggest
that in cells without an intact cytoskeletal system, the GFP-GR moves
through the cytoplasm by diffusion. However, under physiological
conditions in which the cytoskeleton is intact, diffusion is limited,
and the GFP-GR utilizes a movement machinery that is dependent upon
hsp90 chaperone activity. In contrast to the GR, GFP-STAT5B, a
signaling protein that is not complexed with hsp90, undergoes
GH-dependent translocation to the nucleus in a manner that is not
dependent upon hsp90 chaperone activity.
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