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Molecular and Cellular Biology, February 2002, p. 1184-1193, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1184-1193.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Negative Feedback Loop of Wnt Signaling through Upregulation of Conductin/Axin2 in Colorectal and Liver Tumors

Barbara Lustig,1,2 Boris Jerchow,1 Martin Sachs,3 Sigrid Weiler,3 Torsten Pietsch,4 Uwe Karsten,1 Marc van de Wetering,5 Hans Clevers,5 Peter M. Schlag,2 Walter Birchmeier,1 and Jürgen Behrens3*

Max Delbrueck Center for Molecular Medicine, D-13092 Berlin,1 Department of Surgery and Surgical Oncology, Robert-Roessle-Klinik, D-13122 Berlin,2 Nikolaus-Fiebiger-Zentrum, University of Erlangen, D-91054 Erlangen,3 Department of Neuropathology, University of Bonn Medical Center, D-53105 Bonn, Germany,4 Department of Immunology, University Hospital Utrecht, NL-3584 CX Utrecht, The Netherlands5

Received 7 August 2001/ Returned for modification 12 September 2001/ Accepted 16 November 2001

Activation of Wnt signaling through ß-catenin/TCF complexes is a key event in the development of various tumors, in particular colorectal and liver tumors. Wnt signaling is controlled by the negative regulator conductin/axin2/axil, which induces degradation of ß-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3ß. Here we show that conductin is upregulated in human tumors that are induced by ß-catenin/Wnt signaling, i.e., high levels of conductin protein and mRNA were found in colorectal and liver tumors but not in the corresponding normal tissues. In various other tumor types, conductin levels did not differ between tumor and normal tissue. Upregulation of conductin was also observed in the APC-deficient intestinal tumors of Min mice. Inhibition of Wnt signaling by a dominant-negative mutant of TCF downregulated conductin but not the related protein, axin, in DLD1 colorectal tumor cells. Conversely, activation of Wnt signaling by Wnt-1 or dishevelled increased conductin levels in MDA MB 231 and Neuro2A cells, respectively. In time course experiments, stabilization of ß-catenin preceded the upregulation of conductin by Wnt-1. These results demonstrate that conductin is a target of the Wnt signaling pathway. Upregulation of conductin may constitute a negative feedback loop that controls Wnt signaling activity.

* Corresponding author. Mailing address: Nikolaus-Fiebiger-Zentrum, University of Erlangen, Glueckstr. 6, D-91054 Erlangen, Germany. Phone: 49-9131-8529109. Fax: 49-9131-8529111. E-mail: jbehrens{at}molmed.uni-erlangen.de.

Molecular and Cellular Biology, February 2002, p. 1184-1193, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.1184-1193.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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