Overexpression of components of the frizzled-dishevelled cascade results in apoptotic cell death, mediated by beta-catenin

Frizzled (fi) functions as a 7-transmembrane receptor in the Frizzled-Dishe velled signal transduction cascade. It is involved in architectural control of development in species as divergent as Drosophila and vertebrates. Regu lation of multicellular architecture requires control of cell alignment, bu t also involves an equilibrium among cell proliferation, differentiation, a nd apoptosis, Recently, modulation of the Frizzled-Dishevelled (Dvl) cascad e has been related to apoptosis. However, the role of beta -catenin, a seco nd messenger in the Frizzled-Dishevelled cascade, in programmed cell death is a matter of debate. To elucidate the role of this cascade in apoptosis, we studied the effect of overexpression of fil, fz2, dvl1, and beta -cateni n, The signal transduction pathway and the involvement of beta -catenin wer e further investigated by using different inhibitors. These experiments wer e performed in different cell types: COS7, 293, and PC12, Overexpression of fil, fz2, and dvl1 induced apoptosis in COS7 and 293 cells. beta -Catenin appears to be the mediator for this process since beta -catenin overexpress ion as well as lithium and valproate induced apoptosis, In contrast, lithiu m treatment did not result in apoptosis in PC12 cells. We conclude that dif ferent components of the Frizzled-Dishevelled cascade can induce apoptosis, but that this effect is dependent on the cell type. (C) 2001 Academic Pres s.