Elsevier

Experimental Cell Research

Volume 253, Issue 2, 15 December 1999, Pages 637-648
Experimental Cell Research

Regular Article
Transient Overexpression of Murine Dishevelled Genes Results in Apoptotic Cell Death

https://doi.org/10.1006/excr.1999.4700Get rights and content

Abstract

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 2Cα, 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.

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      Similarly, elicited levels of DVL3 have been demonstrated in malignant mesotheliomas and lung cancer (32, 33). DVL is composed of several structural domains: a DIX binding domain located at the N terminus, a PDZ domain in the midregion, and a DEP domain located about midway between the PDZ domain and the C terminus of DVL (34, 35). Although the DIX domain enables the dimerization of DVL with other members of the family as well as with axin (36), the PDZ domain provides a docking site for the C terminus of Fz receptors (37).

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