Overexpression of components of the Frizzled-Dishevelled cascade results in apoptotic cell death, mediated by beta-catenin.
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.
Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht, 6200 MD, The Netherlands.
M E
ME
van Gijn
F
F
Snel
J P
JP
Cleutjens
J F
JF
Smits
W M
WM
Blankesteijn
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008094:Lithium / Q000494:pharmacology; D008565:Membrane Proteins; D009025:Morpholines / Q000494:pharmacology; D016716:PC12 Cells; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014635:Valproic Acid / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D002867:Chromones; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008094:Lithium; D008565:Membrane Proteins; D009025:Morpholines; D010750:Phosphoproteins; D011506:Proteins; D015534:Trans-Activators; D014635:Valproic Acid; D010566:Virulence Factors, Bordetella; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; C000606578:DVL1 protein, human; C000606580:Dvl1 protein, rat; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C000606588:dsh protein, Drosophila; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one