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

journal contribution
posted on 2005-06-01, 00:00 authored by Y Zhu, Q Dong, B Tan, W Lim, S Zhou, Wei DuanWei Duan
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.

History

Journal

Cancer research

Volume

65

Issue

11

Pagination

4520 - 4524

Publisher

American Association for Cancer Research

Location

Philadelphia, Pa.

ISSN

0008-5472

eISSN

1538-7445

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2005, American Association for Cancer Research

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