Cancer Chemotherapy, Theoretical Foundations of
181
and composition of Hsp90. Two distinct
sets of Hsp90 chaperone are endowed
with opposing functions, reflecting the
nucleotide occupying the binding pocket.
When ATP is present, Hsp90 assembles
with the cochaperone proteins p23 and
p50
Cdc37
, resulting in the stabilization
of client proteins. In contrast, in the
presence of ADP, Hsp90 assembles with
a
different
set
of
proteins,
including
Hsp70 and p60
Hop
,t
op
r
om
o
t
ec
l
i
e
n
t
protein ubiquitination and degradation
via the proteasome (Fig. 5). Binding of
geldanamycin to the nucleotide pocket
of Hsp90 locks Hsp90 in the form that
favors client protein degradation. The
mechanism through which Hsp90 causes
the degradation of client proteins remains
unclear, although E3 ligases that associate
with Hsp90 and ubiquitinate some client
proteins have been identi±ed. Thus, Hsp90
complexes have opposing functions, and
geldanamycin promotes formation of the
degrading Hsp90 chaperone complex.
An interesting property of Hsp90 in-
hibitors observed in preclinical studies is
the induction of cytostasis or apoptosis,
depending on the cell-type. This may re-
flec
tthena
tu
reo
ftheHsp90chape
rone
complex and the variation in target client
proteins present in cells. Some evidence
suggests that the integrity of pRb may dic-
tate sensitivity to Hsp90 inhibition, as cells
lacking pRb appear to be quite sensitive to
inhibitor-induced apoptosis.
In preclinical studies, Hsp90 inhibitors
have shown promising activity. While gel-
danamycin exhibits levels of hepato-toxicity
Hop
Hsp90
Hsp90
Hsp70
p50
p23
ATP
ADP
GA,
17 AAG
Protein
targeted to
proteasome
Protects and
renatures
proteins
Fig. 5
Regulation of Hsp90 activity. Hsp90 can form different protein chaperone
complexes with opposing activities. When ATP is bound to the nucleotide-binding
pocket, assembly with p23 and p50
Cdc37
occurs resulting in a chaperone complex that
stabilizes and protects client proteins, whereas ADP in the pocket causes Hsp90 to
assemble with Hsp70 and p60
Hop
, resulting in client protein degradation via the
proteasome. With geldanamycin (GA) or its derivative 17-allylaminogeldanamycin
(17AAG), the chaperone assembles with Hsp70 and p60
Hop
to favor client protein
degradation.
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