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

与高度非整倍体相关的染色体不稳定性（CIN）是人类癌症的一个主要特征，可以促进肿瘤发生和肿瘤进展。然而，引起CIN的分子机制和遗传病变在很大程度上是未知的。我们最近发现CHK2-BRCA1肿瘤抑制通路是维持人类体细胞染色体稳定性所必需的。此外，我们的初步结果表明，不适当的Wnt信号会导致非整倍体，这支持了Wnt通路作为有丝分裂、染色体分离和染色体稳定性的关键调节因子的新作用。我们的目的是详细研究Wnt信号在有丝分裂和染色体稳定性维持中的作用。通过活细胞显微镜结合功能缺失和功能获得研究，我们将研究沉默或激活Wnt信号通路是否与有丝分裂异常进展和染色体分离缺陷有关。特别是，我们将分析细胞周期调节的ß-catenin积聚在G2/M峰值的作用，我们将通过鉴定ß-catenin调节的新的G2/M基因来解决Wnt调节的基因表达是否参与有丝分裂的调节的问题。此外，我们将研究Axin-1在G2/M中的作用及其与包括Aurora-A和Plk1激酶在内的有丝分裂信号通路的串扰，并将表征涉及Wnt信号成分的有丝分裂蛋白复合物。

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.