Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.
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.
Hadjihannas
Michel V
MV
Nikolaus Fiebiger Center for Molecular Medicine, University Erlangen-Nuernberg, Glueckstrasse 6, 91054 Erlangen, Germany.
Brückner
Martina
M
Jerchow
Boris
B
Birchmeier
Walter
W
Dietmaier
Wolfgang
W
Behrens
Jürgen
J
D060466:Axin Protein; D002460:Cell Line; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
C491761:AXIN2 protein, human; D060466:Axin Protein; C111729:Axin2 protein, mouse; D003598:Cytoskeletal Proteins; D051153:Wnt Proteins; D051176:beta Catenin