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Molecular and Cellular Biology, October 2001, p. 6768-6781, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6768-6781.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Down-Regulation of beta -Catenin by Activated p53

Einat Sadot, Benjamin Geiger, Moshe Oren, and Avri Ben-Ze'ev*

Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel

Received 6 February 2001/Returned for modification 5 April 2001/Accepted 9 July 2001

beta -Catenin is a cytoplasmic protein that participates in the assembly of cell-cell adherens junctions by binding cadherins to the actin cytoskeleton. In addition, it is a key component of the Wnt signaling pathway. Activation of this pathway triggers the accumulation of beta -catenin in the nucleus, where it activates the transcription of target genes. Abnormal accumulation of beta -catenin is characteristic of various types of cancer and is caused by mutations either in the adenomatous polyposis coli protein, which regulates beta -catenin degradation, or in the beta -catenin molecule itself. Aberrant accumulation of beta -catenin in tumors is often associated with mutational inactivation of the p53 tumor suppressor. Here we show that overexpression of wild-type p53, by either transfection or DNA damage, down-regulates beta -catenin in human and mouse cells. This effect was not obtained with transcriptionally inactive p53, including a common tumor-associated p53 mutant. The reduction in beta -catenin level was accompanied by inhibition of its transactivation potential. The inhibitory effect of p53 on beta -catenin is apparently mediated by the ubiquitin-proteasome system and requires an active glycogen synthase kinase 3beta (GSK3beta ). Mutations in the N terminus of beta -catenin which compromise its degradation by the proteasomes, overexpression of dominant-negative Delta F-beta -TrCP, or inhibition of GSKbeta activity all rendered beta -catenin resistant to down-regulation by p53. These findings support the notion that there will be a selective pressure for the loss of wild-type p53 expression in cancers that are driven by excessive accumulation of beta -catenin.

* Corresponding author. Mailing address: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. Phone: (972) 8-934 2422. Fax: (972) 8-946 5261. E-mail: avri.ben-zeev{at}weizmann.ac.il.

Molecular and Cellular Biology, October 2001, p. 6768-6781, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6768-6781.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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