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The PKCα-D294G Mutant Found in
Pituitary and Thyroid Tumors Fails to Transduce Extracellular Signals
Yimin Zhu, Qihan
Dong, Bee Jen Tan, Wee Guan Lim, Shufeng
Zhou and Wei Duan
Departments of Biochemistry [Y.Z.,
B.J.T., W.G.L, W.D] and Pharmacy [S.Z],
Faculty of Science, The National University of Singapore, Singapore,
Singapore; and Department of Medicine and Sydney Cancer Centre,
University of Sydney, Sydney, Australia [Q.D]. Requests
for reprints: Wei Duan, Department of Biochemistry, Faculty of
Medicine, The National University of Singapore, 8 Medical Drive,
Singapore, 117597. Phone: 65-6874-3688; Fax: 65-6779-1453; E-mail: bchduanw@nus.edu.sg
. Received 12/20/04; revised 3/10/05; accepted 4/ 5/05.
Protein kinase C (PKC) is a key
regulator of cell proliferation, differentiation, and
apoptosis and is one of the drug targets of anticancer
therapy.
Recently, a single point mutation (D294G)
in PKCα has been found in pituitary and thyroid tumors with
more invasive phenotype.
Although the PKCα-D294G mutant is
implicated in the progression of endocrine tumors, no
apparent biochemical/cell biological abnormalities
underlying tumorigenesis with this mutant have been
found.
We report here that the PKCα-D294G
mutant is unable to bind to cellular membranes tightly
despite the fact that it translocates to the membrane as
efficiently as the wild-type PKCα upon treatment of
phorbol ester.
The impaired membrane binding
is associated with this mutant's inability to transduce
several antitumorigenic signals as it fails to mediate
phorbol ester–stimulated translocation of myristoylated alanine–rich
protein kinase C substrate (MARCKS), to activate mitogen-activated
protein kinase and to augment melatonin-stimulated neurite
outgrowth.
Thus, the PKCα-D294G is a
loss-of-function mutation.
We propose that the wild-type PKCα
may play important antitumorigenic roles in the progression
of endocrine tumors.
Therefore, developing selective activators
instead of inhibitors of PKCα might provide effective
pharmacological interventions for the treatment of certain
endocrine tumors.
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