180
Cancer Chemotherapy, Theoretical Foundations of
Ac
Ac
Ac
Ac
HAT
Active
Ac
Ac
HDAC
TF
(E2F,
p53)
Inactive
Ac
Ac
TF
(E2F,
p53)
Fig. 4
Acetylation control in the cell cycle. Acetylation (Ac) mediated by
acetyltransferases (HATS) can target histone tails in the form of
nucleosomes (yellow) or transcription factors (TF) involved in cell cycle
control, like E2F and p53. In most cases so far studied, acetylation appears
to activate transcription. In contrast, deacetylation mediated by histone
deacetylases (HDAC) causes transcriptional inactivity by targeting histones
in nucleosomes, leading to a more transcriptionally inert state, together with
dampening the activity of transcription factors. (See color plate p. xxv.)
a promising new approach to cancer
treatment.
8
Regulating Hsp90
Heat
shock
protein
90
(Hsp90)
is
a
molecular chaperone that regulates the
activity of a variety of cellular proteins,
enabling protein folding and preventing
denaturation, and perhaps aggregation,
of misfolded proteins. Hsp90 is gaining
recognition as a cancer target in part
because it is overexpressed in a variety
of tumor cells and associates with on-
coproteins including the tyrosine kinase
v-Src, the serine/threonine kinase Raf1,
HIF1 (discussed later), and mutated p53.
A small molecule inhibitor of Hsp90,
geldanamycin, blocks the interaction of
Hsp90 with client proteins, including v-
Src and Raf1, by interacting with the
hydrophobic ATP-binding pocket in the N-
terminal region and inhibiting the Hsp90
ATPase activity.
Geldanamycin
has
been
used
as
a
molecular probe to explore the regulation
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