The PKCalpha-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals

Zhu, Y, Dong, Q, Tan, B, Lim, W, Zhou, S and Duan, W 2005, 'The PKCalpha-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals', Cancer Research, vol. 65, no. 11, pp. 4520-4524.


Document type: Journal Article
Collection: Journal Articles

Title The PKCalpha-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals
Author(s) Zhu, Y
Dong, Q
Tan, B
Lim, W
Zhou, S
Duan, W
Year 2005
Journal name Cancer Research
Volume number 65
Issue number 11
Start page 4520
End page 4524
Total pages 5
Publisher American Association for Cancer Research
Abstract 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 PKCa has been found in pituitary and thyroid tumors with more invasive phenotype. Although the PKCa-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 PKCa-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 PKCa 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 PKCa-D294G is a loss-of-function mutation. We propose that the wild-type PKCa may play important antitumorigenic roles in the progression of endocrine tumors. Therefore, developing selective activators instead of inhibitors of PKCa might provide effective pharmacological interventions for the treatment of certain endocrine tumors.
Subject Basic Pharmacology
DOI - identifier 10.1158/0008-5472.CAN-04-4506
ISSN 0008-5472
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