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Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors

Item Type:Article
Title:Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors
Creators Name:Lustig, B. and Jerchow, B. and Sachs, M. and Weiler, S. and Pietsch, T. and Karsten, U. and van de Wetering, M. and Clevers, H. and Schlag, P.M. and Birchmeier, W. and Behrens, J.
Abstract:Activation of Wnt signaling through beta-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 beta-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3beta. Here we show that conductin is upregulated in human tumors that are induced by beta-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 beta-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.
Keywords:Adenoma, Colorectal Neoplasms, Cytoskeletal Proteins, Physiological Feedback, Neoplastic Gene Expression Regulation, Intestinal Neoplasms, Liver Neoplasms, Proto-Oncogene Proteins, Signal Transduction, Tissue Distribution, Trans-Activators, Tubulin, Cultured Tumor Cells, Up-Regulation, Wnt Proteins, Wnt1 Protein, Zebrafish Proteins, beta Catenin, Animals, Mice
Source:Molecular and Cellular Biology
ISSN:0270-7306
Publisher:American Society for Microbiology (U.S.A.)
Volume:22
Number:4
Page Range:1184-1193
Date:1 February 2002
Official Publication:https://doi.org/10.1128/MCB.22.4.1184-1193.2002
PubMed:View item in PubMed

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