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J Biol Chem. 2006 Apr 20; [Epub ahead of print] J Biol Chem. 2005 Oct 21;280(42):35684-95.
Epub 2005 Aug 22.
Inhibition of the
mitotic kinesin Eg5 upregulates
Hsp70 through the PI3K/Akt pathway in multiple myeloma
cells.
Liu
M, Aneja R, Liu
C, Sun
L, Gao J, Wang
H, Dong
JT, Sarli V, Giannis A, Joshi
HC, Zhou
J.
Department of Genetics and Cell Biology,
The microtubule-dependent motor protein Eg5 plays a critical role in
spindle assembly and maintenance in mitosis. Herein we show that
suppression of Eg5 by a specific inhibitor arrests
mitosis, induces apoptosis, and upregulates Hsp70
in human multiple myeloma cells. Mechanistically,
Hsp70 induction occurs at the transcriptional level via a cis-regulatory DNA element in Hsp70 promoter and is
mediated by the PI3K/Akt pathway. Eg5 inhibitor-mediated Hsp70 upregulation is cytoprotective,
because blocking Hsp70 induction directly by antisense
or small interfering RNA or indirectly by inhibiting the PI3K/Akt pathway
significantly increases Eg5 inhibitor-induced apoptosis. Furthermore, a farnesyltransferase inhibitor interacts synergistically
with the Eg5 inhibitor in inducing apoptosis through disrupting the
Akt/Hsp70 signaling axis. These findings provide the first evidence for Eg5
inhibitor activity in hematologic malignancy and
identify Hsp70 upregulation as a critical
mechanism responsible for modulating myeloma cell
sensitivity to Eg5 inhibitors. In addition, these findings suggest that
combination of Eg5 inhibitors with agents abrogating Hsp70 induction is
more useful for myeloma therapy in the clinic.
PMID: 16627469 [PubMed - as supplied by publisher]
Docking and rolling, a
model of how the mitotic motor Eg5 works.
Rosenfeld SS, Xing
J, Jefferson
GM, King
PH.
Department of Neurology,
Whereas kinesin I is designed to transport
cargoes long distances in isolation, a closely related kinesin
motor, Eg5, is designed to generate a sustained opposing force necessary
for proper mitotic spindle formation. Do the very different roles for these
evolutionarily related motors translate into differences in how they
generate movement? We have addressed this question by examining when in the
ATPase cycle the Eg5 motor domain and neck linker
move through the use of a series of novel spectroscopic probes utilizing
fluorescence resonance energy transfer, and we have compared our results to
kinesin I. Our results are consistent with a model
in which movement in Eg5 occurs in two sequential steps, an ATP-dependent
docking of the neck linker, followed by a rotation or "rolling"
of the entire motor domain on the microtubule surface that occurs with ATP
hydrolysis. These two forms of movement are consistent with the functions
of a motor designed to generate sustained opposing force, and hence, our
findings support the argument that the mechanochemical
features of a molecular motor are shaped more by the demands placed on it
than by its particular family of origin.