KINETOCHORE AND CANCER · Kinetochore-microtubule Interaction and Chromosome Instability
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-08-01 → 2008-07-31
- EU contribution
- €1,267,133
- Participants
- 1
- Scheme
- EXT
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Imbalances in mitotic processes may lead to gain or loss of chromosomes, a hallmark of many human cancers. The spindle checkpoint ensures fidelity of cell division by monitoring connections between the kinetochores and spindle microtubules.Kinetochores that lack physical tension and/or stable microtubule attachments emit a signal to prevent the onset of anaphase by restraining a mitotic ubiquitin ligase, the anaphase-promoting complex (APC). The main principles of APC regulation by the spindle checkpoint a re well known but molecular details of how the inhibitory signals are created at the kinetochores and then broadcasted throughout the cell are unclear.Recently, molecules belonging to Aurora B protein complex (Aurora B/Survivin/Incenp), Ndc80 protein comp lex (Ndc80/Nuf2/Spc24/Spc25), and microtubule plus-end proteins (Mast/Adenomatous polyposis coli/EB1) have been implicated in regulation of kinetochore-microtubule connections and spindle checkpoint signalling.The objectives of this proposal are at two levels. First, we aim to elucidate how these kinetochore subcomplexes and microtubule plus-end proteins orchestrate the dynamic interaction between the chromosomes and microtubules, how they participate in generation and transmission of the checkpoint signals, and how malfunction or absence of these proteins may induce malignant cell growth.To achieve these goals the team will use modern live cell imaging techniques and molecular biology methods. Secondly, the proposal is intended to enable my return from my present junior faculty position in USA to Europe and set up a research group in Finland where this field of biology is underrepresented.My other academic objective is to create profound interrelations with the European and national bioscience communities. This would yield mutual benefits in terms of exchanging valuable research experience and methodological knowledge that together with the host expertise will lead the team to a high level of excellence.
Original text from CORDIS.
Participants
- VTT TECHNICAL RESEARCH CENTRE OF FINLAND · ESPOOCoordinatorFinland
Links
Data: CORDIS, © European Union