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.
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