Plakoglobin Regulates the Expression of the Anti-apoptotic Protein BCL-2

Abstract

Plakoglobin is a cytoplasmic protein and a homologue of ␤-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 ␤-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.

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

“…This would be consistent with data implicating plakoglobin in the development of squamous cell carcinoma through induction of Bcl-2 (Hakimelahi et al, 2000). Nuclear accumulation of plakoglobin and an increase in Bcl-2 expression has also been observed in advanced prostate cancer (Shiina et al, 2005).…”

Desmosomes: a role in cancer?

“…Unlike b-catenin, plakoglobin is a strong activator of c-myc, which is thought to be essential for plakoglobin's transforming ability. Another suggestion is that plakoglobin causes unregulated growth and foci formation (in human squamous carcinoma cells), as a result of induction of the pro-survival gene Bcl-2 and inhibition of apoptosis (Hakimelahi et al, 2000). In support of the latter idea, mutations within or near to a glycogen synthase kinase-3b consensus phosphorylation site have been discovered in advanced hormone refractory prostate cancer, and these coincide with strong nuclear accumulation of plakoglobin and a concomitant increase in Bcl-2 (Shiina et al, 2005).…”

Trolox and 17β-Estradiol Protect against Amyloid β-Peptide Neurotoxicity by a Mechanism That Involves Modulation of the Wnt Signaling Pathway

“…Previous findings in our laboratory indicate that the anti-apoptotic gene bcl-2 is regulated by Wnt signaling (60); in fact, lithium, a compound that mimics Wnt signaling activation (94), and Wnt-3a ligand cause a timedependent increase in bcl-2 mRNA levels in primary rat hippocampal neurons (60). Also, the ␤-catenin analogue plakoglobin induces bcl-2 expression (95). Previous findings have demonstrated that A␤ decreases neuronal bcl-2 protein levels in vitro (96) and that bcl-2 immunoreactivity is reduced in tangle-bearing neurons of AD patients (97).…”