Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors.
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.
Lustig
Barbara
B
Max Delbrueck Center for Molecular Medicine, D-13092 Berlin, Germany.
Jerchow
Boris
B
Sachs
Martin
M
Weiler
Sigrid
S
Pietsch
Torsten
T
Karsten
Uwe
U
van de Wetering
Marc
M
Clevers
Hans
H
Schlag
Peter M
PM
Birchmeier
Walter
W
Behrens
Jürgen
J
D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D060466:Axin Protein; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014018:Tissue Distribution; D015534:Trans-Activators; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
C491761:AXIN2 protein, human; D060466:Axin Protein; C111729:Axin2 protein, mouse; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014404:Tubulin; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D051176:beta Catenin