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

Exp Cell Res. 2001 Apr 15;265(1):46-53. doi: 10.1006/excr.2001.5174.

Abstract

Frizzled (fz) functions as a 7-transmembrane receptor in the Frizzled-Dishevelled signal transduction cascade. It is involved in architectural control of development in species as divergent as Drosophila and vertebrates. Regulation of multicellular architecture requires control of cell alignment, but also involves an equilibrium among cell proliferation, differentiation, and apoptosis. Recently, modulation of the Frizzled-Dishevelled (Dvl) cascade has been related to apoptosis. However, the role of beta-catenin, a second 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 fz1, fz2, dvl1, and beta-catenin. The signal transduction pathway and the involvement of beta-catenin were further investigated by using different inhibitors. These experiments were performed in different cell types: COS7, 293, and PC12. Overexpression of fz1, fz2, and dvl1 induced apoptosis in COS7 and 293 cells. beta-Catenin appears to be the mediator for this process since beta-catenin overexpression as well as lithium and valproate induced apoptosis. In contrast, lithium treatment did not result in apoptosis in PC12 cells. We conclude that different components of the Frizzled-Dishevelled cascade can induce apoptosis, but that this effect is dependent on the cell type.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis*
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Chromones / pharmacology
  • Cytoskeletal Proteins / metabolism*
  • Dishevelled Proteins
  • Drosophila Proteins
  • Gene Expression
  • Humans
  • Lithium / pharmacology
  • Membrane Proteins*
  • Morpholines / pharmacology
  • PC12 Cells
  • Phosphoproteins / biosynthesis*
  • Phosphoproteins / genetics
  • Protein Biosynthesis*
  • Proteins / genetics
  • Rats
  • Signal Transduction* / drug effects
  • Trans-Activators*
  • Valproic Acid / pharmacology
  • Virulence Factors, Bordetella / pharmacology
  • beta Catenin

Substances

  • Adaptor Proteins, Signal Transducing
  • CTNNB1 protein, human
  • Chromones
  • Ctnnb1 protein, rat
  • Cytoskeletal Proteins
  • DVL1 protein, human
  • Dishevelled Proteins
  • Drosophila Proteins
  • Dvl1 protein, rat
  • Membrane Proteins
  • Morpholines
  • Phosphoproteins
  • Proteins
  • SFRP2 protein, human
  • Trans-Activators
  • Virulence Factors, Bordetella
  • WD repeat containing planar cell polarity effector
  • beta Catenin
  • dsh protein, Drosophila
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Valproic Acid
  • Lithium