Plakoglobin regulates the expression of the anti-apoptotic protein BCL-2.
Plakoglobin is a cytoplasmic protein and a homologue of beta-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 beta-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. The BCL-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.
Hakimelahi
S
S
Department of Cell Biology, University of Alberta, Edmonton T6G 2H7, Alberta, Canada.
Parker
H R
HR
Gilchrist
A J
AJ
Barry
M
M
Li
Z
Z
Bleackley
R C
RC
Pasdar
M
M
D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D002448:Cell Adhesion; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000502:physiology*; D051180:Desmoplakins; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D015534:Trans-Activators; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051176:beta Catenin; D051185:gamma Catenin
C495270:CTNNB1 protein, human; D061945:Caspase Inhibitors; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D051176:beta Catenin; D051185:gamma Catenin; C505407:CASP3 protein, human; D053148:Caspase 3