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Kinetochore-microtubule Interaction and Chromosome Instability

Final Activity Report Summary - KINETOCHORE AND CANCER (Kinetochore-microtubule Interaction and Chromosome Instability)

The kinetochore and cancer project was initiated 2004 to seek answerers to several open questions regarding the biochemistry of cell division. The focus organelle of the project was kinetochore, a multi-molecule assemblage consisting over 60 proteins. Each human chromosome contains a pair of sister kinetochores that function during cell division. The kinetochore serves as the binding platform for the microtubules that are filamentous protein structures moving the chromosomes and other cargos in the dividing cells.

The objective of the project was to define molecular details regarding the cellular processes involving kinetochore biochemistry and potential links to tumour-igenesis. In cancer, cell division is abnormal and it is believed that errors in mitotic reactions are one contributing factor in cell transformation and cancer initiation. In our research, we focused on a handful of proteins that work at the kinetochore-centromere complex during cell division. We also carried out cell-based high-throughput screens to identify novel small molecule inhibitors with anti-cell division potency. The academic goal of the project was to promote student training and international networking.

Upon establishment of the research group, three persons were hired initially and more joined the group for later on. During its life span the project involved 10 scientists who worked a total of 208 person months within the 4-year long project. The work conducted has been published in respective scientific journals of the field and disseminated in several international meetings and workshops. The scientific results of the project have been widely communicated among the researchers working in the field of cell division and they have received special attention. Especially the findings on Polo-like kinase 1 and Aurora B kinase have promoted the understanding how mitotic kinases regulate cell division and how mistakes in the function of these proteins may contribute to cancer formation.

We have also identified several novel synthetic small molecules that inhibit cell division and decrease the survival rate of cancer cell lines. The best inhibitors have been directed to lead optimisation and further testing for their suitability to become anti-cancer drugs.

Also, in regards of the academic goals the project has been a success, two master theses have been completed within the project and the two hired PhD students are in the final phases of graduation. In summary, the project has given new insights into biochemical regulation of cell division and revealed new molecular roles for several mitotic proteins including Polo-like kinase 1, Shugoshin, Incenp, and Aurora B proteins. All people who worked in the project are continuing their scientific career in the field of cancer research. Also, the project continues with other funding until the on-going research and PhD theses work has been completed by the end of 2009.