The role of the Wnt signalling pathway for the maintenance of chromosomal stability

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Chromosomal instability (CIN) associated with high-grade aneuploidy is a major characterisfic of human cancer and can contribute to tumorigenesis and tumor progression. However, the molecular mechanisms and genetic lesions causing CIN are largely unknown. We have recently uncovered that the CHK2-BRCA1 tumor suppressor pathway is required for the maintenance of chromosomal stability in human somatic cells. In addition to that our preliminary results showed that inappropriate Wnt signaling causes aneuploidy, which supports the emerging role of the Wnt pathway as a key regulator of mitosis, chromosome segregation and chromosomal stability. We are aiming to investigate the role of Wnt signaling in mitosis and for the maintenance of chromosomal stability in detail. By using live-cell microscopy combined with loss- and gain-of-function studies we will investigate whether silencing or activating the Wnt signaling pathway is associated with abnormal mitotic progression and defects in chromosome segregation. In particular, we will analyze the role of the cell cycle regulated accumulation of ß-catenin peaking at G2/M and we will address the question whether Wnt regulated gene expression is involved in the regulation of mitosis by identifying novel G2/M genes regulated by ß-catenin. Further, we will investigate the role of Axin-1 at G2/M and its cross-talk with mitotic signaling pathways including Aurora-A and Plk1 kinases and we will characterize mitotic protein complexes involving Wnt signaling components.