Plakoglobin Regulates the Expression of the Anti-apoptotic Protein BCL-2*
- Shahram Hakimelahi‡§,
- Henry R. Parker§¶,
- Anita J. Gilchrist‡‖,
- Michele Barry¶**,
- Zhi Li‡,
- R. Chris Bleackley¶‡ and
- Manijeh Pasdarत
- From the Departments of ‡Cell Biology and¶Biochemistry, University of Alberta, Edmonton T6G 2H7, Alberta, Canada
Abstract
Plakoglobin is a cytoplasmic protein and a homologue of β-catenin and Armadillo of Drosophila with similar adhesive and signaling functions. These proteins interact with cadherins to mediate cell-cell adhesion and associate with transcription factors to induce changes in the expression of genes involved in cell fate determination and proliferation. Unlike the relatively well characterized role of β-catenin in cell proliferation via activation of c-MYC and cyclin D1 gene expression, the signaling function of plakoglobin in regulation of cell growth is undefined. Here, we show that high levels of plakoglobin expression in plakoglobin-deficient human SCC9 cells leads to uncontrolled growth and foci formation. Concurrent with the change in growth characteristics we observe a pronounced inhibition of apoptosis. This correlates with an induction of expression of BCL-2, a prototypic member of apoptosis-regulating proteins. TheBCL-2 expression coincides with decreased proteolytic processing and activation of caspase-3, an executor of programmed cell death. Our data suggest that the growth regulatory function of plakoglobin is independent of its role in mediating cell-cell adhesion. These observations clearly implicate plakoglobin in pathways regulating cell growth and provide initial evidence of its role as a pivotal molecular link between pathways regulating cell adherence and cell death.
Footnotes
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↵* This work was supported in part by a grant from Medical Research Council of Canada (to M. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Contributed equally to this work.
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↵‖ Recipient of a studentship award from the Natural Science and Engineering Council of Canada.
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↵** Recipient of a postdoctoral fellowship award from the Alberta Heritage Foundation for Medical Research.
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↵‡ Medical Scientist of the Alberta Heritage Foundation for Medical Research, Medical Research Council of Canada Distinguished Scientist, and a Howard Hughes Scholar.
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↵§§ To whom correspondence should be addressed: 6–24 Medical Sciences Bldg., Dept. of Cell Biology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Tel.: 780-492-3356; Fax: 780-492-0450; E-mail: mpasdar@ualberta.ca.
- Abbreviations:
- LEF/TCF
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lymphoid enhancer factor/T-cell factor
- APC
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adenomatous polyposis coli
- TUNEL
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terminal transferase-catalyzed dUTP end labeling
- PIPES
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1,4-piperazinediethanesulfonic acid
- CMV
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cytomegalovirus
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- Received October 26, 1999.
- Revision received January 19, 2000.
- The American Society for Biochemistry and Molecular Biology, Inc.
