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Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer

Item Type:Article
Title:Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer
Creators Name:Hadjihannas, M.V. and Brueckner, M. and Jerchow, B. and Birchmeier, W. and Dietmaier, W. and Behrens, J.
Abstract:Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/beta-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here we demonstrate that Wnt/beta-catenin signaling causes CIN via up-regulation of conductin. Human colon tumor samples with CIN show significantly higher expression of conductin than those without. Conductin is up-regulated during mitosis, localizes along the mitotic spindles of colon cancer cells, and binds to polo-like kinase 1. Ectopic expression of conductin or its up-regulation through small interfering RNA-mediated knock-down of APC leads to CIN in chromosomally stable colon cancer cells. High conductin expression compromises the spindle checkpoint, and this requires localized polo-like kinase 1 activity. Knock-down of conductin by small interfering RNA in colon carcinoma cells or gene ablation in mouse embryo fibroblasts enforces the checkpoint.
Keywords:Axin2/conductin, Colorectal cancer, Wnt signaling, Spindle checkpoint, APC
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:103
Number:28
Page Range:10747-10752
Date:11 July 2006
Official Publication:https://doi.org/10.1073/pnas.0604206103
PubMed:View item in PubMed

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