Transient overexpression of murine dishevelled genes results in apoptotic cell death.
The Dishevelled (Dvl) gene family encodes cytoplasmic proteins that are implicated in Wnt signal transduction. In mammals, the manner in which Wnt signals are transduced remains unclear. The biochemical and molecular mechanisms defining the Wnt-1 pathway are of great interest because of its important role in development and its activation in murine breast tumors. In order to elucidate Dvl's role in Wnt signaling, we attempted to overexpress Dvl in cells, but were unable to obtain stable cell lines. We show here that the overexpression of Dvl genes alters nuclear and cellular morphology of COS-1 and C57MG cells and causes cell death due to the induction of apoptosis. Deletion studies demonstrate that all three conserved domains of Dvl (DIX, PDZ, and DEP) are required for Dvl-mediated cell death. Coexpression of protein phosphatase 2Calpha, a Dvl-interacting protein identified in yeast two-hybrid studies, protects cells from the cell death observed in cells overexpressing Dvl alone. Furthermore, the adenomatous polyposis coli (APC) gene product appears to be required for Dvl-mediated cell death. The relevance of these findings to Wnt signal transduction, as well as to developmental processes and disease, are discussed.
Strovel
E T
ET
Division of Human Genetics, University of Maryland at Baltimore, 655 West Baltimore Street, Room 11-049, Baltimore, Maryland 21201, USA.
Sussman
D J
DJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D019556:COS Cells; D000072261:Dishevelled Proteins; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D019073:HT29 Cells; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D011518:Proto-Oncogene Proteins / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection / Q000379:methods; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins; C087358:PTC1 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C